Polymorphic Variants of Adrenoceptors

Transcription

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PHARMACOLOGICAL REVIEWS
Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
http://dx.doi.org/10.1124/pr.113.008219
Pharmacol Rev 66:598–637, July 2014
ASSOCIATE EDITOR: PAUL A. INSEL
Polymorphic Variants of Adrenoceptors: Pharmacology,
Physiology, and Role in Disease s
Andrea Ahles and Stefan Engelhardt
Institut für Pharmakologie und Toxikologie, Technische Universität München, Munich, Germany (A.A., S.E.); and DZHK
(German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany (S.E.)
Address correspondence to: Stefan Engelhardt, Institut für Pharmakologie und Toxikologie, Technische Universität München,
Biedersteiner Straße 29, 80802 Munich, Germany. E-mail: [email protected]
This research was supported in part by grants from the Bundesministerium für Bildung und Forschung.
dx.doi.org/10.1124/pr.113.008219.
s This article has supplemental material available at pharmrev.aspetjournals.org.
598
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Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 599
I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 599
A. Adrenoceptor Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 599
B. Signaling through Adrenoceptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 601
C. Physiology of Adrenoceptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 601
D. Adrenoceptors as Drug Targets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 601
II. Adrenoceptor Variation: Definitions and Nomenclature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 602
III. Variants of a1A-, a1B-, and a1D-Adrenoceptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 602
A. Receptor Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 603
B. Role in Human Physiology and Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 604
C. Response to Therapeutic Drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 605
IV. Variants of a2A-, a2B-, and a2C-Adrenoceptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 606
A. Variants of the a2A-Adrenoceptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 607
1. Receptor Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 607
2. Role in Human Physiology and Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 607
B. Variants of the a2B-Adrenoceptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 609
3. Response to Therapeutic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 609
C. Variants of the a2C-Adrenoceptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 610
3. Response to Therapeutic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 611
V. Variants of the b1-Adrenoceptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 611
A. Receptor Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 612
B. Receptor Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 613
C. Role in Human Physiology and Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 614
D. Response to Therapeutic Drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 616
VI. Variants of the b2-Adrenoceptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 617
A. Receptor Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 617
B. Receptor Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 618
1. Functional Effects of Variation in the N Terminus of the b2-Adrenoceptor. . . . . . . . . . . . 619
2. Functional Effects of the b2-Adrenoceptor Variant p.Thr164Ile in Helix 4 . . . . . . . . . . . . 620
C. Role in Human Physiology and Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 621
1. Vasodilation and Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 621
2. Cardiac Function and Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 621
3. Asthma and Chronic Obstructive Pulmonary Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 621
4. Preterm Labor and Preterm Birth. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 621
Adrenoceptor Polymorphic Variants
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D. Response to Therapeutic Drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 621
1. Response to Agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 621
2. Response to Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 623
VII. Variants of the b3-Adrenoceptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 624
A. Receptor Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 625
B. Role in Human Physiology and Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 626
VIII. Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 627
Acknowledgments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 630
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 630
Abstract——The human genome encodes nine different adrenoceptor genes. These are grouped into three
families, namely, the a1-, a2-, and b-adrenoceptors,
with three family members each. Adrenoceptors are
expressed by most cell types of the human body and
are primary targets of the catecholamines epinephrine
and norepinephrine that are released from the sympathetic nervous system during its activation. Upon
catecholamine binding, adrenoceptors change conformation, couple to and activate G proteins, and thereby
initiate various intracellular signaling cascades. As
the primary receivers and transducers of sympathetic
activation, adrenoceptors have a central role in human
physiology and disease and are important targets for
widely used drugs. All nine adrenoceptor subtypes
display substantial genetic variation, both in their
coding sequence as well as in adjacent regions. Despite
the fact that some of the adrenoceptor variants range
among the most frequently studied genetic variants
assessed in pharmacogenetics to date, their functional
relevance remains ill defined in many cases. A substantial fraction of the associations reported from early
candidate gene approaches have not subsequently been
confirmed in different cohorts or in genome-wide association studies, which have increasingly been conducted in recent years. This review aims to provide
a comprehensive overview of all adrenoceptor variants that have reproducibly been detected in the
larger genome sequencing efforts. We evaluate these
variants with respect to the modulation of receptor
function and expression and discuss their role in
physiology and disease.
I. Introduction
thereby result in altered structure or function of these
receptors. Variations in the N terminus, the extracellular loops, or the ligand binding pocket itself may
possibly alter the accessibility of the ligand binding
pocket and thereby change the affinity of ligands as
well as their potency to induce intracellular signaling.
Some ligands at adrenoceptors are able to activate
multiple cellular signaling pathways (e.g., via different
G proteins or arrestin) (Reiter et al., 2012), allowing for
further impact of variation in adrenoceptors. Certain
adrenoceptor ligands were shown to preferentially activate a specific signaling pathway compared to other
ligands at the same receptor, a concept that has been
termed functional selectivity or biased signaling (Kenakin,
2013). Variations in the intracellular parts of adrenoceptor proteins in turn may be expected to preferentially alter the interaction with G proteins or other
interacting proteins. Genetic variation outside the coding
sequence in the 59- and 39-flanking regions may act in a
cis-regulatory manner and determine adrenoceptor gene
expression.
Adrenoceptors are central mediators in the sympathetic nervous system, adjusting organ functions to
maintain whole-body homeostasis under resting conditions and triggering the body’s fight-or-flight response, i.e., the ability to react to acute stress. Stress
conditions induce the release of epinephrine from the
adrenal medulla into the blood stream and of norepinephrine from sympathetic nerve endings. Both catecholamines bind to and activate the three subfamilies
of adrenoceptors: a1-adrenoceptors (ADRA1, subdivided
into ADRA1A, ADRA1B, and ADRA1D), a2-adrenoceptors
(ADRA2, subdivided into ADRA2A, ADRA2B, and
ADRA2C), and b-adrenoceptors (ADRB, subdivided into
ADRB1, ADRB2, and ADRB3) (Bylund et al., 1994;
Hieble et al., 1995). In addition, adrenoceptors serve to
recognize catecholamines that are released as neurotransmitters within the central nervous system. Sequencing of the respective genomic loci in human
populations from diverse ethnical backgrounds revealed that the genes encoding adrenoceptor subtypes
are polymorphic, meaning that the genomic sequence
in coding and regulatory regions differs among individuals at certain residues (Kirstein and Insel, 2004).
In general, any change in the amino acid sequence
may confer local steric or charge incompatibilities and
A. Adrenoceptor Structure
Adrenoceptors are class A G protein–coupled receptors (GPCRs). They consist of seven transmembrane
(TM)-spanning a-helical domains, an extracellular region
ABBREVIATIONS: ADRA, a-adrenoceptor; ADRB, b-adrenoceptor; CHO, Chinese hamster ovary; COPD, chronic obstructive pulmonary
disease; del, deletion; GPCR, G protein–coupled receptor; GRK, G protein–coupled receptor kinase; GWAS, genome-wide association study;
HEK-293, human embryonic kidney 293; IP3, inositol triphosphate; MAPK, mitogen-activated protein kinase; SNP, single-nucleotide
polymorphism; TM, transmembrane; UTR, untranslated region.
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Ahles and Engelhardt
(N terminus, three extracellular loops), and an intracellular region (three intracellular loops, C terminus)
(Fig. 1). Their low abundance, structural flexibility,
and instability in detergent solution have long hindered resolution of the structure of GPCRs, apart from
that of rhodopsin. However, recent advances in protein
engineering and crystallography techniques (Rasmussen
et al., 2007; Warne et al., 2008; Steyaert and Kobilka,
2011) resulted in the elucidation of the structure of
several GPCRs, including the turkey b1-adrenoceptor
(Warne et al., 2008, 2011, 2012) and the human
b2-adrenoceptor (Rasmussen et al., 2007, 2011a;
Rosenbaum et al., 2007, 2011). More recently, these
studies also partially revealed the structural changes
that occur upon activation and resolved the interaction
interface with G proteins (Rasmussen et al., 2011b)
and arrestins (Shukla et al., 2013). Ligand docking
initiates conformational rearrangements within the
helices, constricting the binding pocket and thereby the
release of the ligand (Ring et al., 2013). The largest
conformational changes in the prototypical b2-adrenoceptor
are an a-helical extension of TM5 and an outward
movement at the cytoplasmic end of TM6 (Rasmussen
et al., 2011b). The intracellular region of adrenoceptors
interacts with G proteins and additional proteins that
serve scaffolding and signaling functions. Adrenoceptors
are highly dynamic proteins that may adopt multiple
distinct conformations depending on the type of ligand
bound, the associated signaling proteins, and the membrane environment (Deupi and Kobilka, 2010). These
different conformations and their dynamic alteration
were assessed using techniques such as nuclear magnetic resonance spectroscopy (Nygaard et al., 2013),
fluorescence resonance energy transfer (Lohse et al.,
2012), or molecular dynamics simulations (Dror et al.,
2011). Some of these techniques were also applied
to the analysis of adrenoceptor variation (Ahles and
Engelhardt, 2009).
Fig. 1. Signal transduction of adrenoceptors. (A) Ga-dependent signaling pathways activated by three families of adrenoceptor subtypes.
Catecholamine-bound a1-adrenoceptors activate Gq proteins, which in turn activate PLC and thereby increase IP3 and intracellular Ca2+
concentrations. a2-Adrenoceptors are Gi coupled and inhibit AC. b1-, b2-, and b3-adrenoceptors couple to Gs, activate AC, and promote the generation of
cAMP. cAMP activates PKA regulating the activity of multiple cellular proteins. b2-Adrenoceptors are reported to undergo a PKA-dependent switch
from Gs to Gi coupling (Daaka et al., 1997). b3-Adrenoceptors also activate nitric oxide synthase via Gi coupling. Please note that the individual
adrenoceptors differ considerably with regard to the length of their non-TM regions. These differences are not represented within the schematic
receptor drawings. (B) Gbg-dependent and G protein–independent signaling of adrenoceptors. Once activated, adrenoceptors are phosphorylated by
PKA and PKC and by GRKs leading to b-arrestin recruitment. Arrestin prevents activation of G proteins and promotes receptor desensitization and
internalization. Both arrestin and Gbg mediate the activation of MAPKs. AC, adenylyl cyclase; b-Arr, b-arrestin; DAG, diacylglycerol; EPI,
epinephrine; NE, norepinephrine; PIP2, phosphoinositol-bis-phosphate; PKA, protein kinase A; PKC, protein kinase C; PLC, phospholipase C.
B. Signaling through Adrenoceptors
Each subfamily of adrenoceptors preferentially couples to a different type of G protein. Catecholamine
binding to a1 -adrenoceptors activates G q , whose
a-subunit then activates phospholipase C, which converts phosphatidylinositol-4,5-bisphosphate to the second
messengers inositol triphosphate (IP3) and diacylglycerol.
a2-Adrenoceptors couple to Gi with Gia inhibiting
adenylyl cyclase activity and thus intracellular cAMP
formation. Activated b-adrenoceptors primarily couple to the stimulatory G protein Gs and promote cAMP
formation. Figure 1A illustrates the canonical G protein
coupling of the three adrenoceptor families, albeit
coupling to alternative G proteins was reported for
several of their members. For example, Gi coupling
has been shown for both the ADRB2 and the ADRB3
(Soeder et al., 1999; Xiao, 2001).
G protein activation results in its dissociation and
thus the release of the bg-subunit that may promote
so-called alternative signaling by itself, such as the activation of mitogen-activated protein kinases (MAPKs)
and ion channel regulation. ADRA1A-mediated activation of MAPK and phosphoinositide 3 kinase were both
shown to depend on Gi (Snabaitis et al., 2005; Vettel
et al., 2012).
Furthermore, GPCRs, including adrenoceptors, have
been demonstrated to signal in a G protein–independent
manner through their interaction with several regulatory proteins (such as G protein–coupled receptor kinases [GRKs] and b-arrestins) and scaffolding proteins
(such as PDZ domain–containing proteins; Lefkowitz,
2007). Most of this G protein–independent signaling is
shown to involve MAPKs (Fig. 1B).
C. Physiology of Adrenoceptors
The majority of cells in the human body express one
or several of the nine adrenoceptor subtypes at their
surface (see Brunton et al., 2011). One particular receptor often dominates in certain cells in effector organs
of the sympathetic nervous system or in the central
nervous system. Likewise, the equipment of different
cell types with G proteins and downstream signaling
molecules is different. This heterogeneity allows for
diverse responses of tissues and organs to catecholamines released from the sympathetic nervous system
or within the central nervous system. These nonsympathetic sources of catecholamines are not specifically mentioned in the following but meant to be
included.
For example, sympathetic activation and the resulting release of epinephrine and norepinephrine may
induce both contraction and relaxation of vascular
smooth muscle cells depending on their preferentially expressed adrenoceptor subtype. Vascular smooth
muscle cells in the skin contract upon exposure to epinephrine, an effect that is dominated by a1-adrenoceptor
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signaling. By contrast, the predominance of b2-adrenoceptors
in vascular smooth muscle cells within skeletal muscle
arteries mediates their relaxation in response to epinephrine (Brunton et al., 2011). Together, the concerted
sympathetic activation of adrenoceptors elicits the fightor-flight-response, which has evolved during evolution
as a critical regulatory mechanism to adapt multiple
physiologic functions in a coordinated way. Among other
effects, the fight-or-flight response increases cardiac
output, elevates blood pressure, and thereby allows for
adequate organ perfusion and oxygen supply during
times of increased demand. At the same time, smooth
muscular organs such as the bladder or the uterus relax
(Kirstein and Insel, 2004). Inadequate activation of the
fight-or-flight-response was elucidated to serve a critical
role as a disease-aggravating factor in several civilizationrelated disorders such as high blood pressure and
coronary and myocardial disease (Lymperopoulos et al.,
2013). If genetic variation of adrenoceptors indeed affects
their expression or function, then one may reasonably
presume consequences not only for organ physiology
but also for disease development. However, even if
a given variant is relevant for the expression level or
function of an adrenoceptor, its association with a
phenotype may only become apparent under conditions of continuous receptor activation. For most cases,
such a scenario would typically necessitate long-term
activation of the sympathetic nervous system, a condition that is likely not met in many of the diseases
studied in this regard.
D. Adrenoceptors as Drug Targets
Adrenoceptors are important targets for widely used
classes of therapeutic drugs. Competitive antagonists
at b-adrenoceptors (also termed b-blockers) belong to
the most frequently used GPCR-targeting drugs and
are particularly important in cardiovascular medicine,
where they are applied in the treatment of hypertension, coronary artery disease, tachyarrhythmia, and
chronic heart failure (Lymperopoulos et al., 2013). Agonists at b1-adrenoceptors are used to provide inotropic
support in acute cardiac failure, and b2-agonists such as
salbutamol are a standard regimen in asthma. Antagonists at a1-adrenoceptors are used as antihypertensive
agents and for symptomatic treatment of benign
prostate hyperplasia, whereas agonists at a1- and/or
a2-adrenoceptors are widely used for nasal decongestion.
For several of these adrenoceptor-targeting drugs,
pronounced interindividual variation with regard to
treatment responses has been reported. In addition to
other factors, genetic heterogeneity of adrenoceptor
genes among patients is suggested as a possible underlying cause for the variation of therapeutic efficacy
when using these agents (Rosskopf and Michel, 2008).
Here, we review the current evidence regarding the
effect of adrenoceptor variation on receptor function and
expression and on its role in physiology and disease.
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II. Adrenoceptor Variation: Definitions
and Nomenclature
Approximately 4000 different variations in the genes
encoding adrenoceptors (excluding the promoter regions)
are reported to date, including single nucleotide variations as well as insertion/deletion mutants. Single
nucleotide variations have traditionally been classified with regard to their relative frequency in the
general population (i.e., their allelic frequency) into
mutations (allelic frequency ,1%) and single-nucleotide
polymorphisms (SNPs) (allelic frequency $1%). If the
exchange of one respective nucleotide in the coding
region does not change the amino acid sequence, the
variation is called synonymous. Despite resulting in an
unchanged protein sequence, such variations have the
potential to affect expression levels of the host gene in a
cis-regulatory manner (Cartegni et al., 2002). By contrast, nonsynonymous variations result in an amino acid
change and thus may alter protein function by changing
its primary structure.
The first nonsynonymous variant in a GPCR was
described in 1993 for the b2-adrenoceptor (Reihsaus
et al., 1993), followed by reports of amino acid variation
for all a1-, a2-, and b-adrenoceptor subtypes. This review
largely focuses on variation in coding regions, yet a
linkage to noncoding variants may become relevant
for certain phenotypes (see Sections IV and VII on
ADRA2A and ADRB3). Methods for identifying variants
have changed over time and include single-strand
conformational techniques, allele-specific polymerase
chain reaction, allele-specific oligonucleotide hybridization, single base extension and polymerase chain reaction
product restriction digestion, and increasingly direct
sequencing (Reihsaus et al., 1993; Hall et al., 1995; Turki
et al., 1995; Mason et al., 1999).
The variations were commonly indicated as follows
(exemplified in brackets for amino acids of a ADRB1
variant, Gly389Arg): wild type (i.e., Gly), position of
variant amino acid (i.e., 389), mutant (i.e., Arg). While
traditionally the first cloned sequence was termed the
wild-type sequence, this variant was not necessarily
the more common variant. A good example is position
389 in human b1-adrenoceptor, in which the Arg variant is indeed far more frequent than the Gly variant
that was cloned first (Frielle et al., 1987). Throughout
this article, we adopt the following nomenclature:
nucleotide position, major allele, and minor allele for
description at the genomic level (i.e., c.1165C.G); and,
accordingly, “major” amino acid, position, and “minor”
amino acid for description at the protein level (i.e.,
p.Arg389Gly). In-frame deletions are described using
“del” after indication of the first and last deleted
nucleotide/amino acid. Regarding variants in the 39and 59-untranslated regions (UTRs), the nucleotide 59
of the ATG-translation initiation codon is denoted as
21, and the nucleotide 39 of the translation stop codon
is denoted as *1. This nomenclature is consistent with
the guidelines proposed by the Human Genome Variation Society (www.hgvs.org/mutnomen/).
Because of the rapid progress in sequencing technologies, whole exomes and genomes of larger cohorts
can be read faster than ever. It thus became possible
to reassess the frequency of variants, which had often been reported from genotyping of only few individuals, in cohorts of .6000 individuals (both
European Americans and African Americans). Some
of these data are currently publicly available through
the Exome Variant Server (National Institutes of Health
National Heart, Lung, and Blood Institute Exome Sequencing Project, evs.gs.washington.edu/EVS) or the
1000 Genomes Project browser (browser.1000genomes.
org). The latter two sources provided the basis for the
selection of the adrenoceptor variations covered in this
review. The availability of whole genome sequences of
larger cohorts (as opposed to preselected SNP data
sets) also led to a revision of the above-mentioned
classification of genetic variation into SNPs and mutations. Variations occurring at a minor allelic frequency
of .5% are now classified as common. Those variations
occurring in 0.5–5% of individuals are classified as low
frequency, and those with frequencies of ,0.5% and
,0.05% as rare and very rare, respectively (Abecasis
et al., 2012). Singletons, by definition, are only found
on one allele of one individual in a particular study.
Naturally, singletons have a higher likelihood of representing sequencing artifacts, and are not covered in
this review. The terms genetic variation and variant
used throughout this review comprise both single nucleotide variations and deletion mutants.
This review puts special emphasis on genetic variants for which either structural, functional, or clinical
data have been reported (see Table 1 for an overview of
all functionally characterized adrenoceptor variants;
see Supplemental Table 1 for the reference SNP identification numbers of all other variants mentioned).
To address the exceedingly large numbers of clinical
studies, we set a threshold of $100 individuals analyzed for candidate gene approaches and $1000 individuals for genome-wide association studies (GWAS).
This threshold, however, was not applied for drug
response studies performed ex vivo or in healthy volunteers, because these are likely subjected to less confounding parameters than association studies performed in
patients. Wherever possible, we rank the studies according to the number of individuals studied within the
respective tables.
III. Variants of a1A-, a1B-, and a1D-Adrenoceptors
a1-Adrenoceptors are present in multiple tissues, including cardiac and smooth muscle, liver, various glands,
and the central nervous system (Brunton et al., 2011).
In the myocardium, activation of a1-adrenoceptors was
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TABLE 1
Summary of human adrenoceptor variants whose impact on receptor function has been assessed
Data are derived from the Exome Variant Server of the National Institutes of Health National Heart, Lung, and Blood Institute Exome Sequencing Project (2013).
Position
Gene
CDS
a1-Adrenoceptor
ADRA1A
a2-Adrenoceptor
ADRA2A
ADRA2B
ADRA2C
b-Adrenoceptor
ADRB1
ADRB2
ADRB3
Major/Minor Allele
MAF
dbSNP
rs61757009
rs56233953
rs2229125
rs3730287
rs1048101
rs2229126
460
497
599
739
1039
1395
Protein
154
166
200
247
347
465
rs1800544
rs1800035
rs553668
rs869244
rs10885122
rs28365031
rs61767072
21252
798
*427
+70 kb
+203 kb
901–909
964–975
301–303
322–325
rs2782980
rs1801252
rs1801253
rs1042711
rs1042713
rs1042714
rs1800888
rs4994
rs72655364
rs72655365
rs4995
222 kb
145
1165
247
46
79
491
190
493
769
794
49
389
“219”
16
27
164
64
165
257
265
266a
Codon
TCC/GCC
AGG/AAG
ATC/AGC
GGG/AGG
CGC/TGC
GAA/GAT
C/G
AAC/AAG
G/A
G/A
G/T
GAAGAGGAG/GGGGCGGGGCCG/C/T
AGC/GGC
CGA/GGA
TGT/CGT
GGA/AGA
GAA/CAA
ACC/ATC
TGG/CGG
TCG/CCG
TCT/CCT
ACG/ATG
Amino Acid
European Americans
African Americans
Ser/Ala
Arg/Lys
Ile/Ser
Gly/Arg
Arg/Cys
Glu/Asp
0.02
0.004
0.02
0.00
0.55
0.02
0.001
0.001
0.004
0.00
0.26
0.02
GluGluGlu/GlyAlaGlyPro/-
0.48
NDb
0.29
0.37
0.27
ND
0.14
0.48
NDb
0.29
0.37
0.27
ND
0.47
Ser/Gly
Arg/Gly
Cys/Arg
Gly/Arg
Gln/Glu
Thr/Ile
Trp/Arg
Ser/Pro
Ser/Pro
Thr/Met
0.29
0.11
0.26
0.42
0.38
0.42
0.02
0.08
NDc
NDc
0.00
0.29
0.19
0.37
0.19
0.49
0.18
0.003
0.11
NDc
NDc
0.01
Asn/Lys
CDS, coding region sequence; dbSNP, single nucleotide polymorphism database; kb, kilobase; MAF, minor allelic frequency; ND, not determined (i.e., not listed in the
Exome Variant Server).
a
Commonly described as variation at amino acid position 251.
b
MAF according to 1000 Genomes Browser: 0.02.
c
Allelic frequency in European Americans and African Americans was not determined. Variation was reported in Chinese individuals (Huang et al., 2013a).
reported to increase inotropy and to promote hypertrophy, albeit these effects may be more prominent in
rodents compared with humans (Brodde and Michel,
1999; O’Connell et al., 2014). a1-Adrenoceptor signaling induces the contraction of smooth muscle cells,
thereby controlling blood pressure, bladder, and prostate tone and pupil width. Furthermore, a1-adrenoceptors
are abundant postsynaptic receptors in the brain,
where they stimulate neurotransmitter release (Piascik
and Perez, 2001). The three subtypes of a1-adrenoceptors
(ADRA1A, ADRA1B, and ADRA1D) predominantly
couple to the heterotrimeric Gq/G11 protein. Receptor
activation increases intracellular calcium concentration through IP3-mediated release from internal stores
and by capacitive influx via membrane calcium channels. In addition, activation of MAP kinase signaling
has been reported, at least in part mediated by Gibg
(Snabaitis et al., 2005).
Crystal structures of a1-adrenoceptor subtypes are
lacking to date; thus, any structure-based assumptions are currently restricted to homology modeling
with known GPCR structures such as those of the
b2-adrenoceptor.To date, 15 variants are identified in
the coding region of the a1A-adrenoceptor (Fig. 2), along
with 6 in the a1B-adrenoceptor (Fig. 3) and 14 in the
a1D-adrenoceptor (Fig. 4). Several nonsynonymous variants
in the a1A-adrenoceptor have been functionally investigated, with c.1039C.T (p.Arg347Cys) receiving
the highest attention. By contrast, regarding the coding
region of the ADRA1B, only synonymous variants have
been studied (Büscher et al., 1999; McCaffery et al.,
2002) and none of the variants in the ADRA1D
displayed in Fig. 4 has been functionally investigated to
date.
A. Receptor Pharmacology
The ADRA1A gene has 14 transcripts (splice variants), 10 of which are predicted to allow for the
synthesis of functional proteins. The other four transcripts are presumed to undergo nonsense-mediated
decay or to result in aberrant protein. Six of the
ADRA1A splice variants have a C-terminal tail that
includes the variation c.1039C.T. At the respective
position in the translated protein, Arg is frequently
replaced by Cys (allelic frequencies of 45% Arg and
55% Cys in European Americans and 74% Arg and 26%
Cys in African Americans; note that this site was also
previously named Arg492Cys). Cys347 is predicted
to generate a potential additional palmitoylation site;
however, because of its close proximity to the primary
palmitoylation site at Cys345, it remains to be tested whether Cys347 indeed provides for additional
604
Fig. 2. Nonsynonymous variations in the human a1A-adrenoceptor. (A) Scheme of the ADRA1A gene locus (chromosome 8: 26,605,667–26,724,790,
reverse strand) and localization of the variations in the coding region (exons 1 and 2), the intron, the 39- and 59-UTRs, and the region 5 kb upstream or
downstream in transcript ENST00000276393, which is translated into a receptor protein of 466 amino acids. Exomic variation data were extracted
from the Exome Variant Server (evs.gs.washington.edu/EVS/) and the 1000 Genomes Project database (browser.1000genomes.org/index.html).
Singleton SNPs (i.e., variations observed only in one allele of all genotyped individuals) were excluded. Information on variations in the noncoding
regions was obtained from the 1000 Genomes Project database. (B) Localization of the functionally studied coding-region variations in the ADRA1A
protein. bp, base pair; EL, extracellular loop; IL, intracellular loop; kb, kilobase; MAF, minor allelic frequency.
palmitoylation of the a1A-adrenoceptor. If it exists,
such additional palmitoylation may affect the conformation of the receptor C terminus and its interaction
with other proteins. Upon expression in recombinant
cell systems, ligand binding, receptor-mediated calcium and IP3 signaling, and desensitization did not
differ between the two variants (Shibata et al., 1996;
Lei et al., 2005). Essentially, the current evidence indicates that this frequent variation does not affect
signaling through the a1A-adrenoceptor (Table 2).
Five additional repeatedly reported variants of the
a1A-adrenoceptor were subjected to pharmacological
analysis in vitro with regard to ligand binding affinity,
agonist-induced IP3 production, and desensitization
(Lei et al., 2005): c.460T.G (p.Ser154Ala) and c.497G.
A (p.Arg166Lys) in TM4, c.599T.G (p.Ile200Ser) in
TM5, as well as c.739G.A (p.Gly247Arg) in intracellular loop 3 and c.1395A.T (p.Glu465Asp) in the
C-terminal tail present in the two full-length splice
variants of the a1A -adrenoceptor (see Fig. 2 for
their location within the a1A -adrenoceptor). Table 2
summarizes the results of the functional analyses.
Interestingly, the very rare Arg247 variant of the
a1A-adrenoceptor (prevalence ,0.05%) increased proliferation of rat-1 fibroblasts by 2-fold compared with
the Gly247 variant. Enhanced cell proliferation in the
Arg247 variant was subsequently shown to result from
a1A-adrenoceptor–mediated transactivation of the endothelial growth factor receptor, which boosted MAPK
signaling. This effect was dependent on b-arrestin 1, but
did not necessitate agonist or G protein activation. The
authors suggested that p.Gly247Arg may alter the
conformation of the third intracellular loop and thus
facilitate its interaction with b-arrestin 1 (Oganesian
et al., 2011).
B. Role in Human Physiology and Disease
Several candidate gene approaches have been undertaken to study the association of the frequent variation
p.Arg347Cys with phenotypes in humans in those organs in which signaling through the a1A-adrenoceptor
is functionally important. The results of association
studies on p.Arg347Cys with regard to blood pressure regulation and heart rate were variable and not
605
Fig. 3. Nonsynonymous variations in the human a1B-adrenoceptor. ADRA1B gene locus (chromosome 5: 159,343,790–159,399,551, forward strand)
and localization of the variations in the coding region (exons 1 and 2) and adjacent regions. Variation data were extracted as described in Fig. 2. bp,
base pair; EL, extracellular loop; IL, intracellular loop; kb, kilobase; MAF, minor allelic frequency.
consistent (Table 3). However, two studies on a Chinese
population reported a significant association of Arg347
with lower antihypertensive effects of the calcium channel
blocker nifedipine and the angiotensin receptor antagonist irbesartan (Jiang et al., 2005; Zhang et al., 2009).
Regarding the role of a1A-adrenoceptors in the brain,
association studies on schizophrenia and schizophreniaassociated metabolic abnormalities were both negative
(Bolonna et al., 2000; Cheng et al., 2012). Finally, no
association could be determined with regard to the
onset of benign prostatic hyperplasia (Shibata et al.,
1996). In line with the negative overall outcome of
candidate gene approaches, the ADRA1A, ADRA1B,
and ADRA1D genomic regions did not show a significant association with any trait in the large GWAS
reported to date (also see Table 4 for an overview of
large GWAS).
C. Response to Therapeutic Drugs
Studies investigating the short-term response to specific
receptor agonists and antagonists should be subject to
fewer confounding factors than those of complex disease
phenotypes and can be expected to show less variation
if conducted in a well defined cohort. Antagonists at the
a1-adrenoceptors are applied as antihypertensives and are
first-line drugs for symptomatic treatment of benign
prostatic hyperplasia. In addition, several antipsychotics
possess high affinity to a1-adrenoceptors, which is suggested to contribute to their antipsychotic efficacy (Leucht
et al., 2013). However, p.Arg347Cys in the a1A-adrenoceptor
was not related to alterations in response to antipsychotics
drugs (Bolonna et al., 2000) or to urinary incontinence as
a side effect of the antipsychotic clozapine (Hsu et al.,
2000). Likewise, treatment efficacy of a1-adrenoceptor
antagonists for benign prostatic hyperplasia did not
Fig. 4. Nonsynonymous variations in the human a1D-adrenoceptor. ADRA1D gene locus (chromosome 20: 4,201,329–4,229,721, reverse strand) and
localization of the variations in the coding region (exons 1 and 2) and adjacent regions. For extraction of variation data, see Fig. 2. bp, base pair; EL,
extracellular loop; IL, intracellular loop; kb, kilobase; MAF, minor allelic frequency.
606
TABLE 2
Effects of a1A-adrenoceptor variations in vitro (overexpression in cell systems)
Variation
Parameter
Cell Line
Effect
Reference
c.460T.G (p.Ser154Ala)
Ligand binding affinity (pKd)
NE-induced IP3 production (max, EC50)
Desensitization of NE-induced IP3 response
Cell proliferation
Rat-1
Ser
Ser
Ser
Ser
=
=
=
=
Ala
Ala
Ala
Ala
Lei et al. (2005)
c.497G.A (p.Arg166Lys)
Agonist binding affinity (pKd)
Antagonist binding affinity (pKd)
NE-induced IP3 production (max, response)
NE-induced IP3 production (EC50)
Cell proliferation
Rat-1
Arg
Arg
Arg
Arg
Arg
Arg
. Lys
= Lys
= Lys
. Lys
= Lys
= Lys
Lei et al. (2005)
c.599T.G (p.Ile200Ser)
Cell proliferation
Rat-1
Ile
Ile
Ile
Ile
Ser
Ser
Ser
Ser
c.739G.A (p.Gly247Arg)
Rat-1
Gly
Gly
Gly
Gly
Gly
= Arg
= Arga
, Argb
= Arg
, Arg
Lei et al. (2005)
Rat-1
CHO-K1c
Rat-1
CHO-K1c
Rat-1
CHO-K1c
Rat-1
Arg
Arg
Arg
Arg
Arg
Arg
Arg
=
=
=
=
=
=
=
Cys
Cys
Cys
Cys
Cys
Cys
Cys
Lei et al. (2005)
Shibata et al. (1996)
Lei et al. (2005)
Lei et al. (2005)
Lei et al. (2005)
Rat-1
Glu
Glu
Glu
Glu
=
=
=
=
Asp
Asp
Asp
Asp
Lei et al. (2005)
Cell proliferation
c.1039C.T (p.Arg347Cys)
NE-induced increase in Ca2+
Desensitization of NE-induced Ca2+ response
Cell proliferation
c.1395A.T (p.Glu465Asp)
Cell proliferation
=
=
=
=
Lei et al. (2005)
max, maximum; NE, norepinephrine.
a
Cell line with high receptor expression: 1.5–2.4 pmol/mg.
b
Cell line with low receptor expression: 0.2–0.4 pmol/mg.
c
Receptor expression: 1 pmol/mg membrane protein.
depend on p.Arg347Cys (Mochtar et al., 2006). Finally,
this variant did not alter phenylephrine-mediated vasoconstriction in healthy subjects (Sofowora et al., 2004).
Taken together, the current evidence does not clearly
suggest functional differences for the variants present
in the a1A-, a1B-, and a1D-adrenoceptor genes. Interesting observations made for the a1A-adrenoceptor, such as
the increased MAPK activation and cell proliferation by the
Arg247 variant and limited responses to blood pressure–
lowering agents reported for the Arg347 variant, await their
confirmation in ex vivo systems and in independent cohorts.
IV. Variants of a2A-, a2B-, and a2C-Adrenoceptors
All three a2-subtypes (ADRA2A, ADRA2B, and ADRA2C)
couple to inhibitory Gi proteins (Fig. 1). a2-Adrenoceptors
regulate multiple physiologic processes, including neurotransmitter release, platelet aggregation, blood pressure,
insulin secretion, and lipolysis (Knaus et al., 2007). No
crystal structure of a a2-adrenoceptor has been reported
thus far.
All common coding variants (i.e., variants with an
allele frequency of .5%, which are depicted in red in
the corresponding figures) are located within the third
TABLE 3
Association studies of the c.1039C.T (p.Arg347Cys) variant in the a1A-adrenoceptor with heart rate and hypertension.
Data are an overview of candidate gene studies investigating .100 individuals.
Cohort
Risk of hypertension
HT + NT
HT + NT
HT + NT
BP reduction in response to
antihypertensive treatment
HT
HT
Number of Subjects
Population Origin
Variant-Dependent Effect
Reference
282/231
480 + 480
1568
Caucasian/African American
Chinese
Brazilian
Arg = Cys
Arg . Cys
Arg , Cys
Xie et al. (1999)
Gu et al. (2006)
Freitas et al. (2008)
447
696
Chinese
Chinese
Arg , Cys (nifedipine)
Arg , Cys (irbesartan)
Zhang et al. (2009)
Jiang et al. (2005)
BP, blood pressure; HT, hypertensive; NT, normotensive.
607
TABLE 4
GWAS of diseases/traits related to adrenoceptor function
Only studies with a sample size .1000 included. Data were extracted from the National Human Genome Research Institute (www.genome.gov/gwastudies).
Hits in Adrenoceptor Genes
Disease/Trait
Asthma/COPD
Pulmonary function
Birth weight
Blood pressure/
hypertension
Cardiac function
CVD risk factors
Coronary (heart)
disease
Heart failure/
cardiomyopathy
Heart rate/
arrhythmia
Glucose-related
traits
Total
Number of
Studies
Sample Size
Gene Variant
Up to 26,836
(European
ancestry)
74,064 (European
ancestry)
Up to 42,519
(European
ancestry)
48,607 (European
ancestry)
4 1029
Horikoshi et al.
(2013)
2 1029 (MAP)
Wain et al.
(2011)
ADRA2A rs10885122-G
Up to 46,186
(European
descent)
Up to 76,558
(European
ancestry)
3 10216 (FPG)
2 1026 (HOMA-B)
Dupuis et al.
(2010)
ADRA2A rs10885122-?
(interaction with BMI)
Up to 58,074
(European
ancestry)
Up to 38,422
(European
ancestry)
9 1028
Manning et al.
(2012)
Up to 3991
(European
ancestry)
Up to 840 (African
American)
3 10212 (EPI)
Johnson et al.
(2010)
—
—
ADRB1 rs1801253-G
(= Gly389)
17
ADRB1 rs2782980-T
5
4
28
—
—
—
3/2
—
27
—
20
5
—
—
45
—
Lipid traits
Metabolic
traits/syndrome
Obesity and
related traits/BMI
Insulin-related traits
Diabetes
Platelet aggregation
5
53
1
ADHD
Schizophrenia
Uric acid levels/gout
Gallstones
7
21
4/1
1
Reference
Replicate
19/5
8
2
11
P Value
Initial
—
—
ADRA2A rs869244-A
—
—
—
—
ADHD, attention deficit hyperactivity disorder; BMI, body mass index; CVD, cardiovascular disease; EPI, epinephrine; FPG, fasting plasma glucose; HOMA, homeostatic
model assessment; MAP, mean arterial pressure.
intracellular loop of the respective ADRA2 genes,
a region that is critical for G protein coupling and
kinase-mediated regulation of GPCRs (Chen et al.,
1993). To date, one coding variant is functionally characterized for each of the three a2-adrenoceptor subtypes:
c.798C.G (p.Asn266Lys) in ADRA2A, c.901_909del
(p.Glu301_Glu303del) in ADRA2B, and c.964_975del
(p.Gly322_Pro325del) in ADRA2C (see Figs. 5–7 for
an overview on the location of these and other variants in the a2-adrenoceptors).
A. Variants of the a2A-Adrenoceptor
1. Receptor Pharmacology. The Asn to Lys substitution at position 266 in the a2A-adrenoceptor (numbered
251 in earlier publications) is rare in Caucasians and
has an allelic frequency of approximately 2–4% in
African Americans (Small et al., 2000a). Upon overexpression in Chinese hamster ovary (CHO) and COS-7
cells, the two ADRA2A variants showed similar ligand
binding properties (Table 5). Interestingly, the authors
report that agonist-induced G protein activation [measured
by 59-O-(3-thiotriphosphate) binding] was approximately
40% higher in cells transfected with the Lys266 receptor
variant compared with Asn266. Consistent with this,
activation of the Lys266 variant led to stronger activation
of MAPK and inositol phosphate signaling and inhibition
of adenylyl cyclase activity (Small et al., 2000a). Together,
these data suggest a gain of function for the minor Lys266
variant. In addition, a single study described and characterized variants in the noncoding regions of the ADRA2A
gene. These are clustered with p.Arg266Lys within complex haplotypes and are reported to affect receptor
expression (Small et al., 2006).
2. Role in Human Physiology and Disease.
p.Asn266Lys was investigated for an association with
essential hypertension, but this small study did not
provide support for a role in blood pressure regulation
(Small et al., 2000a).
However, an association with insulin secretion and
the risk of type 2 diabetes was reported for a variation
located in the 39 UTR, which is expected to alter the
expression of ADRA2A: c.*427G.A (rs553668; minor
608
Fig. 5. Nonsynonymous variations in the human a2A-adrenoceptor. (A) ADRA2A gene locus (chromosome 10: 112,836,790–112,840,658, forward
strand) and localization of the variations in the coding region and adjacent regions. Variation data were obtained as in Fig. 2. (B) Localization of the
functionally studied coding-region variation Asn266Lys in the ADRA2A protein. The asterisk indicates that the Ensembl and the 1000 Genomes
Project databases list rs1800035 as p.Asn266Lys in the ADRA2A protein of 465 amino acids. However, other databases and publications on rs1800035
refer to this variation as p.Asn251Lys (in a protein of 460 amino acids). bp, base pair; CDS, coding region sequence; EL, extracellular loop; IL,
intracellular loop; kb, kilobase; MAF, minor allelic frequency.
allelic frequency, 29%). The minor allele was associated
with impaired insulin secretion in two Scandinavian
cohorts of 935 and 4935 individuals, respectively
(Rosengren et al., 2010), as well as in 1345 Italians
(Bo et al., 2012). Rosengren et al. (2010) reported that
carriers of the risk allele (A) display higher a2A adrenoceptor expression. The molecular mechanism
resulting in altered receptor expression remains to be
elucidated. It might involve the disruption of a microRNA-binding site, yet the site is rather poorly conserved and has not been studied to date with regard to
microRNA-dependent regulation.
Insulin secretion from pancreatic islets is inhibited
by the activation of a2A-adrenoceptors in b cells. Increased expression of the a2A-adrenoceptor would thus
promote impaired insulin release, which is a pathogenic
mechanism of type 2 diabetes. Indeed, the minor allele
went along with a significantly increased risk of type 2
diabetes in a study of Scandinavian individuals (2830
and 3740 participants with and without diabetes, respectively; Rosengren et al., 2010), in a study of lean
Chinese Han individuals (1042 patients with type 2
diabetes and 1052 control subjects; Li et al., 2012),
as well as in a meta-analysis (Talmud et al., 2011).
An impairment of lipid and glucose metabolism in
hypertensive patients was previously observed in an
early study that determined a DraI restriction fragment
length polymorphism, which corresponds to rs553668
(Michel et al., 1999). Furthermore, rs553668 was associated with increased blood pressure (Sõber et al.,
2009), yet Michel et al. (1999) did not report such an
association.
Another variant in the noncoding region of the
ADRA2A gene, located 1252 nucleotides upstream of the
start codon ATG, was associated with psychiatric disorders in few candidate gene studies: 10:g.112836503C.G
(rs1800544; Fig. 5). Namely, this variant was reported
to determine the treatment efficacy of antipsychotics
(Park et al., 2006; Lee et al., 2009) and that of the
sympathomimetic methylphenidate in the treatment
of attention deficit hyperactivity disorder in children
(Polanczyk et al., 2007; Cheon et al., 2009) but not in
adults (Contini et al., 2011).
With the advent and availability of high-throughput
genomic technologies, unbiased studies and GWAS
have become the gold standard in assessing the impact
of genetic variation on human phenotypic variation
(Motsinger-Reif et al., 2013). However, neither this 59upstream variant nor p.Asn266Lys or the 39-UTR
variation c.*427G.A were associated with any trait
609
TABLE 5
Effects of a2-adrenoceptor variations in vitro (overexpression in cell systems)
Variant
Parameter
Cell Line
a
Effect
ADRA2A, c.798C.G
(p.Asn266Lys)
Ligand binding
GTPgS binding
Agonist-induced inhibition of AC activity
MAPK activation
IP accumulation (EC50)
IP accumulation (max)
CHO-K1
COS-7a
CHO-K1a
CHO-K1a
CHO-K1a
Asn
Asn
Asn
Asn
Asn
Asn
ADRA2B, c.901_909del
(p.Glu301_Glu303del)
Ligand binding
Agonist-induced ADRA2B phosphorylation
CHO-K1a
CHO-K1a
COS-7a
NG108b
PC12a
CHO-K1a
PC12a
NG108a,b
PC12a
ins
ins
ins
ins
ins
ins
ins
ins
ins
= del
= del
. del
. del
. del
. del
. del
. del
. del
Small et al. (2001)
Small et al. (2001)
Small et al. (2001)
Salim et al. (2009)
Nguyen et al. (2011)
Small et al. (2001)
Salim et al. (2009)
CHO-K1a
HEK-293a
CHO-K1a
HEK-293a
CHO-K1a
CHO-K1a
ins
ins
ins
ins
ins
ins
= del
= del
. del
= del
. del
. del
Small et al. (2000b)
Montgomery and Bylund (2010)
Montgomery and Bylund (2010)
Agonist-induced ADRA2B desensitization
Agonist-induced ADRA2B downregulation
Nicotine-induced catecholamine secretion
ADRA2C, c.964_975del
Ligand binding
cAMP accumulation
IP accumulation
MAPK activation
= Lys
, Lys
, Lys
, Lys
. Lys
= Lys
Reference
Small et al. (2000a)
AC, adenylyl cyclase; GTPgS, 59-O-(3-thiotriphosphate); ins, insertion (wild-type variant); max, maximum; NG108, neuroblastoma/glioma hybrid cell.
a
Receptor expression: $0.5 pmol/mg membrane protein.
b
Receptor expression: #0.2 pmol/mg.
in large GWAS. However, GWAS recently reported
associations of two variants downstream of the
ADRA2A with agonist-induced platelet aggregation
(g.112909105G.A, rs869244; Johnson et al., 2010)
and fasting glucose (g.113042093T.G, rs10885122;
Dupuis et al., 2010). Because these variants are located
approximately 70 or 203 kilobases downstream of the
ADRA2A gene locus, the underlying mechanism remains to be determined and might also be independent
of the a2A-adrenoceptor.
Studies on ADRA2A variants with regard to the
response to therapeutic drugs have not been reported
to date.
B. Variants of the a2B-Adrenoceptor
1. Receptor Pharmacology. Three deletion variants
have been identified in ADRA2B. All of them are
relatively common, occur in-frame, and map to a small
region within the third intracellular loop (Fig. 6).
This region is rich in acidic residues (aspartate and
glutamate) and is thought to establish the milieu for
agonist-promoted phosphorylation by GRKs and desensitization of the receptor (Chen et al., 1993). One of
the deletion variants (p.Glu301_Glu303del) was subjected to functional analysis in several cell lines in
vitro. The authors report that transfection with the
deletion variant reduced GRK-mediated phosphorylation and desensitization in COS-7 or CHO cells (Small
et al., 2001), in neuroblastoma/glioma hybrid NG108
cells (Salim et al., 2009), and in the chromaffin PC12
cell line (Nguyen et al., 2011) (Table 5).
2. Role in Human Physiology and Disease. On the basis
of the reports on hyperfunctionality of p.Glu301_Glu303del
(Small et al., 2001; Salim et al., 2009; Nguyen et al.,
2011), several candidate gene studies have tested for
the association of the p.Glu301_Glu303del variation
of the a2B-adrenoceptor with cardiovascular disorders.
The four largest studies on this variant all delineated
an increased risk for sudden cardiac death and coronary events (Table 6). In addition, an association of
p.Glu301_Glu303del with the risk or early onset of
diabetes was previously reported (Siitonen et al., 2004;
Heinonen et al., 2005; Papazoglou et al., 2006) (Table 6).
However, hopes that one cause of these diseases may be
found in genetic variation of the a2B-adrenoceptor were
diminished when subsequent large GWAS could not
provide confirmation (Samani et al., 2007; Erdmann
et al., 2009, 2011; Reilly et al., 2011; Schunkert et al.,
2011; Lu et al., 2012) (Table 4).
3. Response to Therapeutic Drugs. Similar to endogenous catecholamines, synthetic a2-agonists activate
presynaptic a2-adrenoceptors. Activation of presynaptic
a2-adrenoceptors inhibits neurotransmitter release (e.g.,
norepinephrine release from sympathetic nerve endings
and acetylcholine release from parasympathetic nerve
endings). The a2-agonists in clinical use do not possess
relevant subtype selectivity. They are useful as sedative, hypnotic, and anesthetic-sparing drugs to lower
sympathetic tone during cardiac surgery and prevent
postoperative cardiovascular complications. a-Agonists
are furthermore frequently used as over-the-counter
nasal decongestants. This effect is likely mediated via
postsynaptic receptors (ADRA1 and ADRA2) (Gilsbach
and Hein, 2012).
Effects of p.Glu301_Glu303del in the a2B-adrenoceptor
on the therapeutic efficacy of a2-agonists have been
610
Fig. 6. Nonsynonymous variations in the human a2B-adrenoceptor. (A) ADRA2B gene locus (chromosome 2: 96,778,707–96,781,984, reverse strand)
and localization of the variations in the coding region and adjacent regions. Variation data were obtained as in Fig. 2. (B) Localization of the
functionally studied coding-region variation p.Glu301_Glu303del in the ADRA2B protein. The asterisk indicates that a composition bias is described
for amino acids 294–311, because this region is rich in acidic residues (aspartate and glutamate). bp, base pair; CDS, coding region sequence; EL,
studied in small, standardized cohorts of healthy
volunteers but not in larger cohorts of patients. Here,
no association with agonist-induced vasoconstriction
and blood pressure elevation was observed in the
majority of studies (Table 7).
C. Variants of the a2C-Adrenoceptor
1. Receptor Pharmacology. Similar to the a2Badrenoceptor, the human a2C-adrenoceptor contains
a common in-frame deletion variant in its third intracellular loop (Fig. 7). Because of the deletion of four
amino acids (Gly-Ala-Gly-Pro, p.Gly322_Pro325del),
this variant lacks an acidic motif in a region that is
assumed to be important for G protein coupling. This
location is suggestive of altered functionality of the
deletion variant, yet studies in cell lines reported divergent findings. Whereas Small et al. (2000b) reported
significantly less epinephrine-stimulated adenylyl cyclase inhibition and MAPK and inositol signaling for
the deletion variant in CHO cells, Montgomery and
Bylund (2010) found that there were no effects of this
variation on agonist-stimulated adenylyl cyclase activity
in human embryonic kidney 293 (HEK-293) cells. Variations in receptor subcellular localization, dimerization,
and downstream signaling components as well as the
presence of additional variants in downstream factors
are proposed to account for these discrepancies, yet they
are awaiting further experimental investigation.
2. Role in Human Physiology and Disease. Studies on
the p.Gly322_Pro325del variation in the a2C-adrenoceptor
have mostly focused on heart failure (Gilsbach and
Hein, 2012) (Table 6). The first analysis reported a
marked increase in the risk for heart failure for homozygous carriers of the deletion variant (Small et al.,
2002). A further increase in risk was reported for individuals that were also homozygous for the (hyperfunctional) Arg389 variant of the b1-adrenoceptor (Small
et al., 2002).The authors suggested that this combination of receptor variants might lead to enhanced
presynaptic norepinephrine release (controlled through
a putatively less functional a2C-adrenoceptor variant) coupled with enhanced postsynaptic signaling
(through the hyperfunctional Arg389 variant of the
b1-adrenoceptor; see Section V). It should be noted,
however, that the number of homozygotes for both
p.Gly322_Pro325del in the a2C -adrenoceptor and
Arg389 in the b1-adrenoceptor in this original report
was low (2 of 84 control subjects and 15 of 78 patients
611
TABLE 6
Clinical impact of variations in a2-adrenoceptors
Data are an overview of candidate gene studies investigating .100 individuals.
a2-Subtype, Variation
Risk of (early onset) hypertension,
blood pressure
Risk of cardiovascular event (stroke,
myocardial infarction, cardiac death)
Risk/onset of diabetes
Obesity
Number of Subjects
Population Origin
Variation Effect
109
155 HT sibling pairs
173
943 HT (817 controls)
Italian
American
American
Swedish
ins = del
ins = del
ins = del
ins , del
912
224 healthy individuals
3398
Finnish
American
American
ins = del
ins = del
ins = del
Korean
Finnish
Finnish
Finnish
German
601 with ACS
616 IS (512 controls)
2072 with ACS
African American
Korean
Caucasian
ins = del
ins = del
ins . del
Greek
ins , del
(diabetic neuropathy)
ins , del (onset)
ins , del
ins , del (onset)
ins = del (progression)
T2D, 130 with diabetic
neuropathy (60 controls)
199 with T2D (204 controls)
506 with T2D
996 with T1D
909
Greek
Finnish
Finnish
Greek
ins
ins
ins
ins
ins
,
,
,
,
.
616 IS (512 controls)
683
912
1606
345 with DCM
del
del
del
del
del
ins = del
Reference
Iacoviello et al. (2006)
Baldwin et al. (1999)
Etzel et al. (2005)
Von Wowern
et al. (2004)
Snapir et al. (2001)
Kurnik et al. (2007)
Li et al. (2006)
Oh et al. (2013)
Snapir et al. (2003b)
Snapir et al. (2001)
Laukkanen et al. (2009)
Regitz-Zagrosek
et al. (2006)
Cresci et al. (2012)
Oh et al. (2013)
Papanas et al. (2007)
Papazoglou et al. (2006)
Siitonen et al. (2004)
Heinonen et al. (2005)
Dionne et al. (2001)
ACS, acute coronary syndrome; DCM, dilated cardiomyopathy; HT, hypertensive; ins, insertion (indicates the wild-type variant); IS, ischemic stroke; onset ins , del, onset
earlier for deletion; T1D, type 1 diabetes; T2D, type 2 diabetes.
with heart failure) and that subsequent studies did
not corroborate this association. Three independent
studies on different ethnic cohorts including African
Americans (the population in which this association
was originally reported) reported no association of
the p.Gly322_Pro325del alone or in combination with
the Arg389 variant of the b1-adrenoceptor in heart
failure (Table 8) (Nonen et al., 2005; Metra et al.,
2006; Canham et al., 2007). Likewise, p.Gly322_Pro325del
was not associated with essential hypertension (Table 6)
(Li et al., 2006). Taken together, the current body of
evidence, including candidate gene studies and GWAS,
does not suggest an association of the ADRA2C variation p.Gly322_Pro325del with cardiovascular disease
(Table 4).
3. Response to Therapeutic Drugs. Similar to
ADRA2A and ADRA2B, the impact of genetic variation
in a2C-adrenoceptors has not been intensely studied with
regard to the efficacy of therapeutic drugs. A single study
in healthy volunteers reported increased norepinephrine
spillover and higher heart rates caused by the a2-antagonist
yohimbine in carriers of the Gly322_Pro325del variant of
the a2C-adrenoceptor compared with controls (Neumeister
et al., 2005).
In summary, the current body of evidence suggests
that at least two a2-adrenoceptor variants might be
functionally relevant. The risk allele of rs553668 in the
39-UTR of the a2A-adrenoceptor leads to enhanced
receptor expression and is reproducibly shown to be
associated with diabetes. Likewise, the deletion variant p.Glu301_Glu303del in the coding region of the
a2B-adrenoceptor alters receptor function and is associated with impaired glucose tolerance/diabetes and cardiovascular disease in multiple studies. Recent GWAS
on platelet aggregation and fasting glucose reported two
additional variants located in the 39-downstream region
of the a2A-adrenoceptor, with a possible (but not proven)
cis-regulatory effect on the receptor gene, which might
regulate expression of the ADRA2A.
V. Variants of the b1-Adrenoceptor
b1-adrenoceptors (ADRB1) are key mediators of
excitation-contraction coupling in the heart (Dorn, 2010).
The ADRB1 gene encodes a protein of 477 amino acids.
Nine nonsynonymous variants are reported in the coding
sequence (Fig. 8); yet with regard to receptor function,
only the two most common variants are functionally
characterized. First, at position 49 in the amino terminus
of the b1-adrenoceptor, serine is in approximately 15% of
the healthy population replaced by glycine [c.145A.G
(p.Ser49Gly)] (Maqbool et al., 1999; Börjesson et al.,
612
Fig. 7. Nonsynonymous variations in the human a2C-adrenoceptor. (A) ADRA2C gene locus (chromosome 4: 3,768,075–3,770,218, forward strand) and
localization of the variations in the coding region and adjacent regions. Variation data were obtained as in Fig. 2. (B) Localization of the functionally
studied coding-region in-frame deletion variation p.Gly322_Pro325del in the ADRA2C protein. bp, base pair; CDS, coding region sequence; EL,
2000). Second, at position 389 in the proximal C
terminus, arginine is substituted by glycine [c.1165C.G
(p.Arg389Gly)] (Maqbool et al., 1999; Mason et al., 1999;
Tesson et al., 1999) with frequencies of approximately
27% in Caucasians and Asians and 42% in African
Americans. Because of linkage disequilibrium between
codons 49 and 389, the haplotype Gly49–Gly389 is
extremely rare.
A. Receptor Structure
The first crystal structure of the turkey b1-adrenoceptor
with the antagonist cyanopindolol bound was reported
in 2008 (Warne et al., 2008). The receptor protein was
modified for expression and crystallization purposes
without disturbing its functionality (Baker et al.,
2011). Six thermostabilizing mutations were introduced (Arg68Ser, Met90Val, Tyr227Ala, Ala282Leu,
Phe327Ala, Phe338Met) that shifted the receptor equilibrium toward the inactive state. N and C termini
were truncated, the major part of intracellular loop 3 was
deleted, and the C-terminal palmitoylation site Cys358
was removed by mutation to Ala358. A structure of
the fully active state has not been obtained, because
the thermostabilized receptor protein tends toward an
inactive state and the structure was obtained in the
absence of a G protein, the latter being most likely
indispensable to stabilize the active conformation
(Rasmussen et al., 2011b). In addition, the adrenoceptor
structures resolved to date could not resolve the
N-terminal parts (including p.Ser49Gly within the
b1-adrenoceptor), which is suggested to be due to the lack
of clearly structured parts and the resulting spatial
flexibility of the N terminus (Venkatakrishnan et al.,
2013). An additional hurdle for future attempts to
resolve the structure of the N terminus of the
b1-adrenoceptor is its poor interspecies conservation,
which would necessitate studies with the human
protein.
Detailed structural data have been obtained from
a truncated version of the turkey b1-adrenoceptor that
retained the region surrounding position 355 (which
corresponds to position 389 in humans). Position 355 in
the turkey b1-adrenoceptor is located in helix 8, which
is formed by a stretch of amino acids starting from the
distal seventh TM-spanning domain to the membraneanchoring palmitoylated cysteine (Fig. 8B). The structure of the antagonist-bound turkey receptor suggests
that Arg355 forms a hydrogen bond with Thr69 in helix
1. Because the interspecies variation in this region
is low, these data also appear to be valid for the human b1-adrenoceptor. Given this finding, it is postulated that Arg389, but not Gly389, in the human
b1-adrenoceptor specifically interacts with this threonine residue in TM1. This interaction would stabilize
613
TABLE 7
Drug response in dependence of a2-adrenoceptor variation: studies with healthy volunteers
Drug
Number of
Subjects
Population Origin
Variation Effect
Agonist-mediated vasoconstriction
ADRA2B, c.901_909del (p.Glu301_Glu303del)
Epinephrine
Dexmedetomidine
Dexmedetomidine
Dexmedetomidine
Azepexole
16
16
38
49
50
Finnish
Finnish
African American
American
American
ins . del/ins
ins = del (finger blood volume)
ins = del (dorsal hand vein)
Antagonist-mediated inhibition
of catecholamine spillover
ADRA2C, c.964_975del (p.Glu322_Glu325del)
Yohimbine
29
African American
ins . del
Reference
Snapir et al. (2003a)
Talke et al. (2005)
Muszkat et al. (2005a)
Muszkat et al. (2005b)
King et al. (2005)
Neumeister et al. (2005)
ins, insertion (indicates the wild-type variant).
the receptor and lower the energy barrier toward an
active state (Warne et al., 2012), thereby suggesting
a structural basis for hyperfunctionality of the Arg389
variant. This hypothesis still awaits experimental testing.
B. Receptor Pharmacology
p.Ser49Gly and p.Arg389Gly were characterized
in vitro regarding their ligand binding properties,
agonist-induced conformational changes, and signaling
efficacy. Ligand binding and agonist-stimulated adenylyl
cyclase activity were found to be very similar for the two
variants at position 49 when moderately overexpressed
in Chinese hamster fibroblasts or HEK-293 cells (Rathz
et al., 2002). With higher (supraphysiological) expression
levels (.0.5 pmol/mg protein in HEK-293 cells), the
Gly49 variant displayed enhanced affinity for agonists
and antagonists, as well as constitutive activity with
increased basal and agonist-stimulated adenylyl cyclase
activity and agonist-induced receptor downregulation
(Levin et al., 2002; Rathz et al., 2002) (Table 9). This
finding, however, was recently not reproduced in HEK293 cells expressing the variant at different densities
(Baker et al., 2013) and also not in an ex vivo analysis of
agonist-induced contractility of cardiac tissue (Molenaar
et al., 2002; Sarsero et al., 2003). Of note, the in vitro
studies conducted in cell lines on p.Ser49Gly were carried
out on the Gly389 background, despite the fact that the
haplotype Gly49–Gly389 does not seem to exist (or, at
least, is extremely rare).
Likewise, the variation p.Arg389Gly has been intensely investigated in vitro (Table 9). Upon overexpression in cell lines, the Arg389 variant–expressing
cells displayed higher basal and agonist-induced adenylyl
cyclase–mediated cAMP formation (Mason et al., 1999;
Joseph et al., 2004). This was paralleled by enhanced
coupling to Gs and high-affinity ligand binding solely in
the absence of GTP (Mason et al., 1999). The latter was
regarded as indirect evidence that position 389 was
located in the putative G protein coupling region of the
receptor protein, albeit current evidence from the
b2-adrenoceptor–Gs structure locates G protein coupling to intracellular loop 3 (Rasmussen et al., 2011b;
Venkatakrishnan et al., 2013). In addition, alternative
methodology using fluorescence resonance energy
transfer to monitor G protein activation found no
difference for p.Arg389Gly regarding activation of Gs.
However, the latter study reported an increased basal
beating frequency of primary Arg389-overexpressing
cardiomyocytes compared with Gly389-overexpressing
cells (Rochais et al., 2007). The authors found differential conformational changes of the Arg389 variant
toward specific b-adrenoceptor antagonists and suggested that position 389 influences conformation of the
receptor protein itself (Rochais et al., 2007).
In agreement with a higher efficacy, the Arg389
variant exhibited greater agonist-promoted desensitization than the Gly389 variant (Liggett et al., 2006).
Studies analyzing in vitro the respective c.[145A.G;
1165C.G] (p.[Ser49Gly;Arg389Gly]) haplotypes supported
TABLE 8
Disease association studies of the a2C-adrenoceptor deletion variant c.964_975del (p.Glu322_Glu325del) in combination
with c.1165C.G (p.Arg389Gly) in the b1-adrenoceptor
Cohort
Number of Subjects
Population Origin
Risk of heart failure
ICM/DCM
ICM/DCM
ICM/DCM
Dallas Heart Study
78
91
260 (230 controls)
1121
Black American
Japanese
Italian
Black American
Arg
Arg
Arg
Arg
Risk of IDC
IDC
132 (429 controls)
South African
Arg = Gly
DCM, dilated cardiomyopathy; ICM, ischemic cardiomyopathy; IDC, idiopathic dilated cardiomyopathy.
Variation Effect
. Gly
= Gly
= Gly
= Gly
Reference
Small et al. (2002)
Nonen et al. (2005)
Metra et al. (2006)
Canham et al. (2007)
Woodiwiss et al. (2008)
614
Fig. 8. Nonsynonymous variations in the human b1-adrenoceptor. (A) ADRB1 gene locus (chromosome 10: 115,803,806–115,806,667, forward strand)
and localization of the variations in the coding region and adjacent regions. Variation data obtained as in Fig. 2. The asterisk indicates that although G
(Gly389 codon GGA) is the minor allele at position 389, it is referred to as the wild-type allele and C (Arg389 codon CGA) is referred to as the variant
allele in most databases, because the first cloned b1-adrenoceptor contained Gly389 (Dixon et al., 1986). The pound sign (#) indicates variation in the
second nucleotide of codon for 389: G.T. Starting from the wild-type GGA (Gly), this results in codon GTA (Val). However, starting from the more
common Arg389 variant (codon CGA), exchange of the second nucleotide leads to codon CTA (Leu). The latter is not taken into account in the majority
of SNP databases. (B) Localization of the functionally studied coding-region variations p.Ser49Gly and p.Gly389Arg in the ADRB1 protein. bp, base
pair; CDS, coding region sequence; EL, extracellular loop; IL, intracellular loop; kb, kilobase; MAF, minor allelic frequency.
this notion at least for Gly49/Arg389 with higher cAMP
formation, receptor downregulation, and relative desensitization of cAMP formation (Sandilands et al., 2004).
Upon cardiomyocyte-specific transgenic overexpression
of the human b1-adrenoceptor variants Arg389/Gly389
in mice, increased basal and dobutamine-induced contractility levels were reported for the Arg389 variant
compared with the Gly389 variant, with enhanced
desensitization of the Arg389 variant in older animals
(Mialet Perez et al., 2003). Finally, ex vivo studies in
heart tissue examining the native receptors did not
uniformly support the hyperfunctional role of Arg389
compared with Gly389 (Table 9). The different disease
conditions of the patients are a possible reason for
these discrepancies; thus, the hyperfunctionality of
Arg389 may only become apparent when contraction
force is severely impaired (Molenaar et al., 2002;
Sandilands et al., 2003).
C. Role in Human Physiology and Disease
Stimulation of cardiac b1-adrenoceptors is believed
to be the strongest endogenous mechanism to increase
cardiac output and it is this adrenoceptor subtype that
functionally dominates in the myocardium. Its cardiac
role and its tight control of renin release also explain
the central role of b1-adrenoceptors in the control of
blood pressure.
To test whether the variation p.Arg389Gly influences cardiac responsiveness in vivo, several groups
investigated dynamic exercise–evoked increases in
heart rate and contractility and plasma renin activity
in healthy subjects. These studies (analyzing up to 890
individuals) showed no genotype-dependent differences
(Büscher et al., 2001; Xie et al., 2001; Liu et al., 2003;
Sofowora et al., 2003; Leineweber et al., 2006a; Nieminen
et al., 2006).
The numerous clinical studies on the relevance of the
variants p.Ser49Gly and p.Arg389Gly in b1-adrenoceptors
have primarily focused on cardiovascular diseases,
namely hypertension and heart failure. Using a candidate gene approach, several studies have addressed
a potential association of these variants with hypertension. Although the results of the smaller studies are
highly divergent, three larger cohorts revealed that
615
TABLE 9
Impact of b1-adrenoceptor variation in vitro and ex vivo
Variation
c.145A.G
(p.Ser49Gly)
Parameter
Overexpression in cell lines
(studies in vitro)
Ligand binding affinity
Basal/maximal agonist-stimulated
AC activity
Agonist-induced downregulation
Endogenous receptor expression
(studies ex vivo)
NE-induced increase in contractility
CGP-12177–induced increase
in contractility
c.1165C.G
(p.Arg389Gly)
(studies in vitro)
Agonist binding affinity
Ligand-induced
conformational changes
G protein activation
Basal/maximal agonist-stimulated
AC activity cAMP formation
MAPK activation
Beating frequency
Endogenous receptor expression
(studies ex vivo)
High-affinity ligand binding
Agonist-induced increase
in contractility
CGP-12177–induced increase
in contractility
Cell/Tissue
Variant Effect
CHW-1102a
HEK-293b
HEK-293c
HEK-293c
CHW-1102a
HEK-293c
HEK-293c
HEK-293b
Ser = Gly
Ser = Gly
Ser , Gly
Ser = Gly
Ser = Gly
Ser , Gly
Ser , Gly
Ser , Gly
Isolated right atria (CABG)
87 b-blocker treated
20 without b-blocker
Isolated right atria
(60, nonfailing)
Ser = Gly
Ser = Gly
Ser = Gly
CHW-1102b
CHO-AA8a
HEK-293c
HEK-293c
HEK-293c
COS-7c
HEK-293c
CHW-1102b
CHO-AA8a
HEK-293c
HEK-293c
NRCM
Membranes from nonfailing
left ventricle (17)
Isolated right atria (CABG)
87 b-blocker treated
20 without b-blocker
(54, CABG,
AVR, or MVR)
Isolated right ventricular
trabeculae
22 nonfailing
31 failing (end-stage HF)
(61, nonfailing)
Reference
Rathz et al. (2002)
Rathz et al. (2002)
Levin et al. (2002)
Baker et al. (2013)
Rathz et al. (2002)
Levin et al. (2002)
Levin et al. (2002)
Rathz et al. (2002)
Molenaar et al. (2002)
2 GTP: Arg . Gly
+ GTP: Arg = Gly
Arg = Gly
Arg = Gly
Arg = Gly
Bisoprolol/metoprolol:
Arg = Gly
Carvedilol: Arg . Gly
Arg . Gly
Arg = Gly
Arg . Gly
Arg . Gly
Arg . Gly
Arg . Gly
Arg . Gly
Arg . Gly carriers
Sarsero et al. (2003)
Mason et al. (1999)
Joseph et al. (2004)
Rochais et al. (2007)
Baker et al. (2013)
Mason et al. (1999)
Mason et al. (1999)
Joseph et al. (2004)
Zhang and Steinberg, 2013)
Zhang and Steinberg, 2013)
O’Connor et al. (2012)
Arg = Gly
Arg = Gly
Arg . Gly
Sandilands et al. (2003)
Liggett et al. (2006)
Arg . Gly carriers
Arg . Gly carriers
Arg = Gly
Sarsero et al. (2003)
AC, adenylyl cyclase; AVR, aortic valve replacement; CABG, coronary artery bypass graft; HF, heart failure; MVR, mitral valve replacement; NE, norepinephrine; NRCM,
neonatal rat cardiac myocyte.
a
b
Receptor expression: .0.2 and ,0.5 pmol/mg.
c
Arg389 was consistently associated with the risk for
hypertension (Table 10).
The largest GWAS on blood pressure to date (including .120,000 European individuals) found a variation approximately 22 kilobases upstream of the
ADRB1 gene to be significantly associated with mean
arterial pressure (g.115781527C.T, rs2782980; Fig. 8)
(Wain et al., 2011). This suggests an implication of
the ADRB1 genomic region in blood pressure regulation, yet requires further analysis. The p.Arg389Gly
variation, however, did not emerge in any of the 17
GWAS, which assessed blood pressure or hypertension
in a cohort size larger than 1000 individuals (Table 4).
This negative outcome of the GWAS casts some doubt
on the interpretation of the respective candidate gene
studies. In contrast to studies on hypertension, the
number of candidate gene studies and GWAS addressing heart failure were significantly smaller. In summary,
they do not indicate the ADRB1 locus to be consistently
associated with heart failure (Tables 4 and 11).
616
TABLE 10
Association of the variations c.145A.G (p.Ser49Gly) and c.1165C.G (p.Arg389Gly) in the b1-adrenoceptor with risk for
hypertension, elevated heart rate, and systolic/diastolic blood pressure
Data are an overview of candidate gene studies investigating $100 individuals.
Variant (Cohort)
c.145A.G (p.Ser49Gly)
HT
Sibling pairs
HT
Twin pairs
HT
HT/NT
HT/NT
CAD
HT/NT
c.1165C.G (p.Arg389Gly)
HT
Sibling pairs
HT
Twin pairs
HT
HT
HT/NT
HT/NT
HT/NT
CAD
HT/NT
Number of
Subjects
Population Origin
Variation-Dependent Effect
Reference
101
102
117
145
223
292/265
526/192
890
935
989/389
Swedish
Finnish
American
European American
Chinese
Swedish
Italian
Finnish
Belgian
Japanese/Chinese
Ser = Gly
Ser = Gly
Ser = Gly
Ser . Gly carriers
Ser = Gly
Ser = Gly
Ser = Gly
Ser $ Gly carriers
Ser = Gly
Ser carriers . Gly
Karlsson et al. (2004)
Bengtsson et al. (2001a)
Humma et al. (2001)
McCaffery et al. (2002)
Liu et al. (2006)
Filigheddu et al. (2004)
Nieminen et al. (2006)
Defoor et al. (2006)
Ranade et al. (2002)
101
102
117
145
147
223
292/265
526/192
775/1105
890
935
989/389
1881
7677
86,588
Swedish
Finnish
American
European American
English
Chinese
Swedish
Italian
Japanese
Finnish
Belgian
Japanese/Chinese
White, Belgian
Danish Caucasian
European
Arg = Gly
Arg . Gly carriers
Arg . Gly carriers
Arg , Gly carriers
Arg = Gly
Arg = Gly
Arg . Gly carriers
Arg = Gly
Arg carriers . Gly
Arg = Gly
Arg carriers . Gly
Arg = Gly
Arg . Gly carriers
Arg . Gly carriers
Arg . Gly
Karlsson et al. (2004)
Humma et al. (2001)
McCaffery et al. (2002)
O’Shaughnessy et al. (2000)
Liu et al. (2006)
Shioji et al. (2004)
Nieminen et al. (2006)
Defoor et al. (2006)
Tikhonoff et al. (2008)
Gjesing et al. (2007)
Johnson et al. (2011)
CAD, coronary artery disease; HT, hypertensive; NT, normotensive.
A recent genome-wide analysis found that the
p.Arg389Gly variant of the b1-adrenoceptor was significantly associated with birth weight in 69,308 Europeans
(Horikoshi et al., 2013). Again, the mechanistic basis for
this association remains speculative at this point and
requires further analysis.
D. Response to Therapeutic Drugs
All data published to date on the effect of b1-adrenoceptor
variation with regard to the response to b-agonists and
b-antagonists refer to candidate gene studies with no
genome-wide data available. Infusion of the b-agonist
dobutamine into healthy individuals that were homozygous for Arg389 induced significantly larger increases
in contractility, heart rate, or plasma renin activity
than in Gly389 carriers (La Rosée et al., 2004; Bruck
et al., 2005b). Accumulating evidence shows that
p.Arg389Gly affects the response to b-adrenoceptor
antagonists (i.e., b-blockers) that are widely used
therapeutic agents in cardiovascular disease, including
hypertension and heart failure. In healthy individuals,
the effect of b-blockers has been studied under conditions of increased heart rate and blood pressure (by
exercise or dobutamine infusion). Whereas basal and
maximal hemodynamics did not differ between Arg389
and Gly389 homozygotes, the relative decrease of
these parameters evoked by b-blockers was greater
for Arg389 in four of five studies (Table 12). This
suggests a stronger response of the Arg389 variant to
b-blockers under normal conditions (i.e., in healthy
individuals).
Most studies in patients have focused on heart
failure and investigated the influence of b1-adrenoceptor
variation on the response to b-blockers. Several large
trials in heart failure had previously established a
strong, mortality-lowering effect of bisprolol, metoprolol, and carvedilol (Cardiac Insufficiency Bisoprolol
Study Investigators and Committees, 1994; MERIT-HF
Study Group, 1999; Poole-Wilson et al., 2003). Consequently, several smaller studies (i.e., patient cohort size
,1000) reported a higher efficacy of various b-blockers
for the Gly49 and Arg389 variants. Moreover, two metaanalyses of studies in patients with heart failure
comprising 504 and 1561 individuals, respectively,
indicated a significantly greater improvement of left
ventricular ejection fraction for individuals who received b-blockers and were homozygous for Arg389
compared with treated Gly389 carriers (Muthumala
et al., 2008; Liu et al., 2012). Additional support for
the clinical relevance of the variation at position
389 of the b1-adrenoceptor comes from the b-Blocker
Evaluation of Survival Trial and its substudies, which
reported a higher clinical efficacy for bucindolol in
Arg389 carriers with heart failure (Liggett et al.,
2006; O’Connor et al., 2012; Aleong et al., 2013)
(Table 13).
In summary, the available data strongly suggest
functional relevance of polymorphic variation in the
617
TABLE 11
Association of the variations c.145A.G (p.Ser49Gly) and c.1165C.G (p.Arg389Gly) in the b1-adrenoceptor with heart failure
Data are an overview of candidate gene studies investigating $ 100 individuals.
Variant (Cohort)
Number of Subjects
Population Origin
Variant-Dependent Effect
Reference
Risk of HF
DCM
CHF
DCM
177
201 (141 controls)
375 (492 controls)
Italian
Brazilian
Swedish
Ser . Gly
Ser = Gly
Ser = Gly
Forleo et al. (2004)
Biolo et al. (2008)
Magnusson et al. (2005)
Risk of MI
CAD
628 women
American
Ser = Gly
Pacanowski et al. (2008b)
HF-associated mortality
DCM
CHF
CHF
DCM
CHF
184 (77 controls)
201
227
375 (492 controls)
444
Swedish
Brazilian
American
Swedish
French
Ser . Gly carriers
Ser = Gly
Ser = Gly
Ser . Gly carriers
Ser = Gly
Börjesson et al. (2000)
Biolo et al. (2008)
Shin et al. (2007)
de Groote et al. (2005)
Frequency in LV tachycardia
DCM
163 (157 controls)
Japanese
Arg . Gly carriers
Iwai et al. (2002)
Exercise capacity
ICM/DCM
263
American
Arg . Gly
Wagoner et al. (2002)
Frequency in HF/risk of HF
DCM
DCM
CHF
CHF
CHF
DCM
DCM
163
177
201
256
260
375
426
controls)
controls)
controls)
controls)
controls)
Japanese
Italian
Brazilian
Italian
Italian
Swedish
French
Arg
Arg
Arg
Arg
Arg
Arg
Arg
Iwai et al. (2002)
Biolo et al. (2008)
Covolo et al. (2004)
Metra et al. (2006)
Tesson et al. (1999)
Frequency in AMI/risk of MI
AMI
CAD
354 (354 controls)
628 women
Japanese
American
Arg . Gly carriers
Arg , Gly
Iwai et al. (2002)
Pacanowski et al. (2008b)
CHF
CHF
CHF
ACS
ACS
CAD
201
227
444
601
2072
2922
Brazilian
American
French
African American
Caucasian
American
Arg . Gly
Arg = Gly
Arg = Gly
Arg = Gly
Arg = Gly
Ser49Arg389 .
Ser49Gly389/Gly49Arg389
Biolo et al. (2008)
Shin et al. (2007)
Pacanowski et al. (2008a)
(157 controls)
(141
(230
(230
(492
(395
=
=
=
=
=
=
=
Gly
Gly
Gly
Gly
Gly
Gly
Gly
ACS, acute coronary syndrome; AMI, acute myocardial infarction; CAD, coronary artery disease; CHF, chronic heart failure; DCM, dilated cardiomyopathy; HF, heart
failure; HT, hypertensive; ICM, idiopathic cardiomyopathy; LV, left ventricular; MI, myocardial infarction; NT, normotensive.
ADRB1 gene. With some confidence, the more common
Arg389 variant can be regarded as hyperfunctional
compared with the Gly389 variant. Arg389 has rather
consistently been associated with a stronger response
to b-agonists and b-blocking agents in healthy volunteers and in patients, respectively. By contrast, an
association of Arg389 with various diseases has yielded
mixed results. The mechanistic basis underlying the
variant in the 59 upstream region (g.115781527C.T)
determining blood pressure remains to be established,
including its relation to the b1-adrenoceptor.
VI. Variants of the b2-Adrenoceptor
Thirteen nonsynonymous variants have been identified in the coding region of human b2-adrenoceptor
(ADRB2; Fig. 9). The two N-terminally located variants
c.46G.A (p.Gly16Arg) and c.79G.C (p.Gln27Glu) as
well as c.491C.T (p.Thr164Ile) in TM4 are shown to
affect the functional properties of the receptor both in
vitro and in vivo. Additional variants are located within
the 59-UTR upstream of the start codon (McGraw et al.,
1998). Of these, c.-47T.C appears to be functionally
relevant. This variant is located within a short open
reading frame, called the b-upstream peptide or the
59-leader cistron of the b2-adrenoceptor, and was formerly termed Arg19Cys. Strong linkage disequilibrium
between codons 16 and 27 favors a combination of Arg16
with Gln27 (Dewar et al., 1998).
A. Receptor Structure
Despite remarkable success in the crystallization of
the human b2-adrenoceptor protein bound to agonists
(Rosenbaum et al., 2011; Rasmussen et al., 2011a,b;
Ring et al., 2013) or antagonists (Cherezov et al., 2007;
Rasmussen et al., 2007; Rosenbaum et al., 2007), the
618
TABLE 12
Response to b-blockers in dependence of the c.1165C.G (p.Arg389Gly) variation in the b1-adrenoceptor: studies with healthy volunteers
Parameter (b-Blocker)
Number of Subjects
Population Origin
Variant Effect
Reference
Attenuation of exercise-induced HR and SBP increases
(metoprolol)
Attenuation of dobutamine-induced HR, contractility
and PRA increases (bisoprolol)
Attenuation of exercise-induced tachycardia (esmolol)
Attenuation of exercise-induced HR and PRA increases
(metoprolol)
Attenuation of exercise-induced SBP and MAP response
(atenolol)
16
Chinese
Arg . Gly
Liu et al. (2003)
18
German
Arg . Gly
Bruck et al. (2005b)
27
29
Caucasian
Danish
Arg . Gly
Arg , Gly
Muszkat et al. (2013)
Petersen et al. (2012)
34
American
Arg . Gly
Sofowora et al. (2003)
HR, heart rate; MAP, mean arterial pressure; PRA, plasma renin activity; SBP, systolic blood pressure.
structural impact of the two most common variants of
the b2-adrenoceptor (both located in the N terminus)
remains obscure. The N-terminal part was not visible
in the structures or it was intentionally cleaved upfront
and the T4 lysozyme was fused to the truncated N
terminus (Rasmussen et al., 2011a). Agonist binding
affects the conformation of the receptor’s extracellular
regions, suggesting that amino acid variations in this
region might affect receptor activation despite not being
directly involved in ligand binding (Bokoch et al., 2010).
Position 164 is located within the upper part of TM4
(Fig. 9B). The substitution of threonine by isoleucine
converts a polar to a hydrophobic residue. Based on the
structure of the b1-adrenoceptor, Warne et al. (2011)
suggested that this could affect the interaction between
helices 4 and 5 and thereby affect the probability of
transition into the activated state.
B. Receptor Pharmacology
The b2-adrenoceptor variants p.Gly16Arg, p.Gln27Glu,
and p.Thr164Ile as well as c.-47T.C in the 59-UTR have
been evaluated in vitro upon overexpression in heterologous cell systems. c.-47T.C in the b-upstream peptide
affects b2-adrenoceptor expression at a translational
level in transfected COS-7 cells (Scott et al., 1999) and
in human airway smooth muscle cells (McGraw et al.,
TABLE 13
Patients’ response to b-blockers in dependence of variations in the b1-adrenoceptor
Parameter (b-Blocker)
Improvement in LVEF (carvedilol)
1-yr survival (not detailed)
Improvement of LVEF
(carvedilol or bisoprolol)
SBP/DBP response (atenolol)
2.8-yr survival (carvedilol or metoprolol)
Improvement in LVEF (carvedilol)
BP and HR response (bisoprolol/atenolol)
HR reduction (atenolol)
BP and HR response (metoprolol)
Improvement of LVEF (carvedilol)
Improvement of LVEF
(carvedilol or bisoprolol)
BP response (bisoprolol)
Improvement of LVEF (carvedilol)
SBP/DBP response (atenolol)
Heart rate response (bisoprolol/carvedilol)
HR reduction, survival and adverse effects
(metoprolol CR/XL) (MERIT-HF)
5-yr survival (bucindolol, BEST study)
Risk of cardiac event (bucindolol,
BEST substudy)
Prevention of new-onset AF
(bucindolol, BEST substudy)
Treatment response (atenolol)
Cohort
Number of Subjects
Population Origin
Variation Effect
Ser = Gly
Ser = Gly
Ser = Gly
Reference
CHF
CABG
CHF
135
185
199
Australian
German
French
HT
DCM
CHF
267
375 (492 controls)
637
Italian
Swedish
American
Ser = Gly
Ser , Gly carriers Magnusson et al. (2005)
Ser = Gly
Sehnert et al. (2008)
CHF
HT
135
147
164
165
183
185
199
Australian
British
American
Chinese
Italian
German
French
Arg . Gly carriers
Arg = Gly
Arg . Gly
Arg . Gly
Arg = Gly
Arg = Gly
Arg = Gly
CHF
CHF
CABG
CHF
HT
CHF
HT
DCM
CHF
CHF
Chen et al. (2007)
Frey et al. (2011)
Chen et al. (2007)
O’Shaughnessy et al. (2000)
Kurnik et al. (2008)
Luo et al. (2007)
Metra et al. (2010)
Frey et al. (2011)
233
Finnish
Arg = Gly
Suonsyrjä et al. (2010)
224
American
Arg carriers . Gly Mialet Perez et al. (2003)
255
Italian
Arg = Gly
375 (492 controls)
Swedish
Arg = Gly
421
Caucasian
Arg = Gly
Rau et al. (2012)
600
British and Dutch
Arg = Gly
White et al. (2003)
CHF
CHF
CHF
CHF
637
859
1040
1040
American
American
American
American
Arg = Gly
Arg = Gly
Arg . Gly carriers
Arg . Gly
O’Connor et al. (2012)
HFREF
1040
American
Arg . Gly
Aleong et al. (2013)
CAD
2973
American
Arg . Gly
Pacanowski et al. (2008a)
AF, atrial fibrillation; BEST, b-Blocker Evaluation of Survival Trial; BP, blood pressure; CABG, coronary artery bypass graft; CAD, coronary artery disease; CHF, chronic
heart failure; CR/XL, controlled release/extended release; DBP, diastolic blood pressure; DCM, dilated cardiomyopathy; HFREF, heart failure with reduced left ventricular
ejection fraction; HR, heart rate; HT, hypertensive; LVEF, left ventricular ejection fraction; MERIT-HF, Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart
Failure; SBP, systolic blood pressure.
619
Fig. 9. Nonsynonymous variations in the human b2-adrenoceptor. (A) ADRB2 gene locus (chromosome 5: 148,206,156–148,208,196, forward strand)
and localization of the variations in the coding region and adjacent regions. Variation data were extracted as described in Fig. 2. (B) Localization of the
functionally studied coding-region variations p.Gly16Arg, p.Glu27Gln, and p.Trp164Ile in the ADRB2 protein and c.-47T.C in the b-upstream peptide.
bp, base pair; BUP, b-upstream peptide; CDS, coding region sequence; EL, extracellular loop; IL, intracellular loop; kb, kilobase; MAF, minor allelic
frequency.
1998), but not in lymphocytes (Lipworth et al., 2002)
(Table 14).
1. Functional Effects of Variation in the N Terminus
of the b2-Adrenoceptor. The impact of the polymorphic
loci in the extracellular N terminus, p.Gly16Arg, and
p.Gln27Glu was first studied in membrane preparations from Chinese hamster fibroblasts that were
transfected with expression constructs for the ADRB2
variants. Neither ligand binding nor adenylyl cyclase
activity was altered between genotypes (Green et al.,
1994). By contrast, upon overexpression in HEK-293
cells and short-term stimulation with epinephrine, the
Gly16 variants (Gly16/Gln27 and Gly16/Glu27) of the
b2-adrenoceptor displayed hyperfunctionality compared with the Arg16 variant (Arg16/Gln27) with
regard to cAMP formation. This hyperfunctionality of
the Gly16 variants was attributed to the speed of
receptor activation since conformational changes occurred faster compared with the hypofunctional Arg16
variant. These differential changes in b2-adrenoceptor
activation depended on phosphorylation of the receptor
by GRKs (Ahles et al., 2011). Further in vitro analysis
showed a faster interaction with b-arrestin2 (Ahles
et al., 2011), suggesting a basis for the enhanced desensitization, and stronger downregulation for the Gly16
variant was reported (Green et al., 1994). In combination with Arg16, Glu27 appeared to be resistant against
agonist-promoted downregulation (Green et al., 1994).
This haplotype combination studied in vitro, however,
is extremely rare in humans.
It should be noted that several studies, which investigated cAMP formation in isolated, nontransfected
human cells (examining endogenous N-terminal b2adrenoceptor variants), had discrepant results. These
studies investigated cAMP solely after long-term receptor stimulation (i.e., .24 hours, a time frame involving substantial receptor desensitization) but did
not elucidate potential differences of the individual
receptor variants before desensitization had occurred
(Aziz et al., 1998; Lipworth et al., 1999; Bruck et al.,
2003a). Table 14 summarizes these ex vivo studies and
further analyses of agonist-promoted downregulation.
620
TABLE 14
In vitro and ex vivo effects of b2-adrenoceptor variations
Variation
c.-47T.C
Parameter
ADRB2 density
Endogenous receptor
ADRB2 density
Speed of ADRB2 activation
Basal/maximal isoproterenolstimulated AC activity (membranes)
EPI-stimulated cAMP formation
Endogenous receptor
ADRB2 density
Basal/maximal isoproterenolstimulated AC activity
Terbutaline-induced lipolysis
Basal/maximal lipolysis
EPI-induced inotropic and
lusitropic effect
c.79G.C (p.Gln27Glu)
Basal/maximal isoproterenolstimulated AC activity (membranes)
Endogenous receptor
ADRB2 density
Short- and long-term desensitization
EPI-induced inotropic and
lusitropic effect
c.[46G.A;79G.C]
(p.[Gly16Arg;Gln27Glu])
Isoproterenol -induced relaxation
of internal mammary arteries
c.491C.T (p.Thr164Ile)
(membrane preparations)
Endogenous receptor
Isoproterenol -stimulated
cAMP formation
Terbutaline-induced lipolysis
Isoproterenol-induced inhibition
of IgE-mediated histamine release
Salmeterol/terbutaline-induced
inhibition of IgE-mediated
histamine release
Basal/maximal histamine release
Cell/Tissue
Variant Effect
Reference
COS-7
T . C (“Cys . Arg”)
McGraw et al. (1998)
HASM
Lymphocytes
T . C (“Cys . Arg”)
T = C (“Cys = Arg”)
McGraw et al. (1998)
Lipworth et al. (2002)
CHW-1102
HEK-293
HEK-293
CHW-1102
Gly = Arg
Gly = Arg
Gly . Arg
Gly = Arg
Green et al. (1994)
Ahles et al. (2011)
Ahles et al. (2011)
Green et al. (1994)
HEK-293
Gly . Arg
Ahles et al. (2011)
Lymphocytes
Lymphocytes
Lymphocytes
HASM
Lymphocytes
HLM
Lymphocytes
Adipocytes
Adipocytes
Right atria
(48 failing + b-blocker)
Gly = Arg
Gly = Arg
Gly = Arg
Gly = Arg
Gly . Arg
Gly , Arg
Gly . Arg
Gly . Arg
Gly = Arg
Gly = Arg
Bruck et al. (2003a)
Moore et al. (2000)
Chong et al. (2000)
Aziz et al. (1998)
Large et al. (1997)
Large et al. (1997)
CHW-1102
CHW-1102
Gln = Glu
Gln = Glu
Green et al. (1994)
Green et al. (1994)
Lymphocytes
Lymphocytes
Lymphocytes
HLM
HASM
Right atria
(48 failing + b-blocker)
Gln = Glu
Gln = Glu
Gln = Glu
Gln . Glu
Gln . Glu
Gln = Glu
Chong et al. (2000)
Moore et al. (2000)
Arterial segments
ArgGln = GlyGlu .
GlyGln
Khalaila et al. (2007)
CHW-1102
CHW-1102
Thr . Ile
Thr . Ile
Green et al. (1993)
Green et al. (1993)
Lymphocytes
Thr . Ile
Büscher et al. (2002)
Lymphocytes
Adipocytes
HLM
Thr . Ile
Thr . Ile
Thr . Ile
Hoffstedt et al. (2001)
Kay et al. (2007)
HLM
Thr . Ile
Kay et al. (2003)
Thr = Ile
Receptor expression in overexpression systems: . 0.5 pmol/mg membrane protein. EPI, epinephrine; HASM, human airway smooth muscle; HLM, human lung mast cell.
2. Functional Effects of the b2-Adrenoceptor Variant
p.Thr164Ile in Helix 4. Interestingly, signaling defects were observed with the less common Ile164
b2-adrenoceptor in vitro. This variant exhibited a 3- to
4-fold lower affinity for isoproterenol and catecholamines than Thr164 b2-adrenoceptors and a markedly
decreased agonist-receptor-Gs interaction (Green et al.,
1993). Consequently, basal and agonist-stimulated
adenylyl cyclase activities were also decreased upon
overexpression both in cell systems and in transgenic
mice (Turki et al., 1996), suggesting a loss of function of
p.Thr164Ile.
In humans, Ile164 occurs with a low frequency
(approximately 2% in Caucasians) and nearly almost
in a heterozygous state, which makes it difficult to
analyze its impact in nontransfected cell systems ex
vivo. Here, the potency of b-agonists to induce either
lipolysis in adipocytes or inhibition of IgE-mediated
histamine release in human lung mast cells was lower
in Ile164 carriers (Hoffstedt et al., 2001; Kay et al.,
2003, 2007) (Table 14). This correlated with the in vitro
efficacy of this particular variant, yet basal and maximal
agonist responses were not affected.
C. Role in Human Physiology and Disease
1. Vasodilation and Hypertension. Activation of b2adrenoceptors is a potent vasodilatory mechanism.
Therefore, genetic variants that alter receptor function
and regulation can be assumed to affect b2-adrenoceptor–
mediated vasoregulation and possibly blood pressure.
Studies in healthy individuals that were exposed
to mental stress or handgrip exercise did not show
genotype-dependent differences with regard to the
extent of vasodilation (Eisenach et al., 2004, 2005;
Trombetta et al., 2005). When evaluating a possible
association of b2-adrenoceptor variants with the risk
for hypertension, the strong linkage disequilibrium
between codons 16 and 27 has to be considered: This
permits only three of four haplotypes (Arg16/Gln27,
Gly16/Gln27, and Gly16/Glu27).
The results of the studies that examined the impact of the b2-adrenoceptor variants p.Gly16Arg and
p.Gln27Glu on vasodilation, blood pressure regulation,
and risk for hypertension are very divergent, with
the majority of the largest trials (with approximately
1500–66,000 individuals involved; Kato et al., 2001;
Herrmann et al., 2002; Sethi et al., 2005; Thomsen
et al., 2012a) showing no association of both variants
with blood pressure or hypertension (Table 15).
Because of the low allelic frequency of the c.491C.T
(p.Thr164Ile) variant (and thus the rareness of homozygotes), a large number of participants in cohorts
would be needed to improve the statistical power.
Studies involving ,1000 individuals generally found
no association of this variant with blood pressure
or hypertension. By contrast, the two largest studies
reported to date detected an association with increased blood pressure in female Ile164 carriers
(Table 15) (Sethi et al., 2005; Thomsen et al., 2012a).
However, none of the variations of the ADRB2 locus
displayed significant association in the seven larger
GWAS reported to date regarding hypertension
(Table 4). Whether subgroup analysis in female participants would yield different results remains to be
analyzed.
2. Cardiac Function and Failure. The b2-subtype
accounts for approximately 30% of the total b-adrenoceptors
in the healthy myocardium, with a relative increase
in cardiac disease as b1-adrenoceptor levels decrease
621
(Lymperopoulos et al., 2013). Several candidate gene
studies have analyzed the three most frequent
b2-adrenoceptor variants with regard to the incidence
and progression of heart failure. As illustrated in
Table 16, the results do not favor a strong impact of
b2-adrenoceptor genetic variation. In addition, none
of the GWAS reported to date yielded a significant
association of the ADRB2 locus with cardiac disease
(Table 4) (Samani et al., 2007; Erdmann et al., 2009,
2011; Reilly et al., 2011; Schunkert et al., 2011; Lu
et al., 2012).
3. Asthma and Chronic Obstructive Pulmonary
Disease. Activation of pulmonary b2-adrenoceptors
induces strong relaxation of bronchial smooth muscle.
Consequently, b2-adrenoceptor agonists have become
an important part of asthma management, where they
are used as bronchodilatory agents (British Thoracic
Society, 2009).
A considerable number of candidate gene studies
have investigated the association of p.Gly16Arg,
p.Gln27Glu, and p.Thr164Ile variants with asthma
and chronic obstructive pulmonary disease (COPD)
(Table 17). The largest of these studies (.60,000
individuals) was recently published and yielded a (relatively weak) association of the Ile variant at position
164 with reduced lung function and increased risk of
COPD in the general population, albeit no association
of the variants at positions 16 and 27 with reduced
lung function, asthma, or COPD was reported (Thomsen
et al., 2012b). In contrast with the latter large candidate
gene study, none of the 18 large (n . 1000) GWAS in
this focus reported a significant association of any
variant in b2-adrenoceptors (Table 4). Together, this
suggests that there is no major impact of genetic
variation in the b2-adrenoceptor on asthma or COPD
progression and severity.
4. Preterm Labor and Preterm Birth. b2-Adrenoceptors are
likewise expressed in smooth muscle cells of the
myometrium and their activation inhibits uterine
contraction. A potential association of b2-adrenoceptor
variants with preterm birth has been addressed in few,
relatively small studies. As summarized in Table 18, the
results are inconsistent and do not favor a major impact
of b2-adrenoceptor genetic variation at positions 16 and
27 to the risk of preterm delivery. Data are also scarce
and not unequivocal for the progress of regular labor at
term (measured as a function of cervical dilatation; see
Table 18).
D. Response to Therapeutic Drugs
1. Response to Agonists. The impact of the variants
p.Gly16Arg and p.Gln27Glu on b-agonist–induced
vasodilation has been investigated in healthy volunteers (Table 19). Depending on the application mode
(local or systemic infusion), divergent effects have been
observed. Local infusion of either isoproterenol or
terbutaline elicited stronger vasodilatory effects in
622
TABLE 15
Association of b2-adrenoceptor variants with vasodilation and hypertension
Data are an overview of candidate gene studies investigating $ 100 individuals.
Parameter
Number of Subjects
Population Origin
Variation Effect
Reference
Japanese
Scandinavian
German
African American
Caucasian
Italian
European American
Caucasian
White American
(non-Hispanics)
Brazilian
Gly . Arg
Gly , Arg
Gly , Arg
Gly = Arg
Gly , Arg (,50 yr)
Gly = Arg
Gly . Arg
Gly = Arg
Gly . Arg
Gly . Arg
Pereira et al. (2003)
Italian
Caucasian
Gln = Glu
Gln = Glu
Iaccarino et al. (2004)
Galletti et al. (2004)
Italian
Danish
Thr = Ile
ThrIle . Thr Thr (women)
ThrIle = Thr Thr (men)
Sethi et al. (2005)
Czech
African Caribbean
African American
South African black
European American
European American/
African American
Chinese
Gly , Arg
Gly . Arg
Gly = Arg
Gly = Arg
Gly16Gln27 protected
Gly = Arg
Resting hemodynamic
function/blood pressure
NT
HT/HT + T2D/NT
HT
HT/overweight/obese
160
124/291/265
332 dizygotic twins
550 (275 twins)
571
775
790 (395 twins)
405/563/160
1418
1576
HT
HT/overweight/obese
HT
775
405/563/160
775
9185
Masuo et al. (2005)
Bengtsson et al. (2001b)
Busjahn et al. (2000)
Snieder et al. (2002)
Castellano et al. (2003)
Snieder et al. (2002)
Galletti et al. (2004)
Bray et al. (2000)
Risk of essential hypertension
(case control studies)
Child of HT/NT parents
HT/NT
HT/NT
HT/NT
HT/NT
101/105
136/81
180/240
192/123
200/410
137/106
HT/NT
271/267
HT/NT
HT/NT
298/298
201 + 155/179 + 128
HT/NT
HT/NT
HT/NT
HT/NT
HT/MI
638
503/504
595/264
747/390
1147/853
707/1178 (1187 controls)
66,750
HT/NT
HT/NT
HT/NT
HT/NT
HT/NT
HT/NT
HT/MI
180/240
192/123
200/410
298/298
201 + 155/179 + 128
595/264
638
880
707/1178 (1187 controls)
4441
66,750
Caucasian
European American
+ African American
Polish
Chinese
Chinese
Chinese
Japanese
Caucasian
Danish
Gly , Arg (Yi Chinese)
Gly = Arg (Han Chinese)
Gly = Arg
Gly = Arg
Gly = Arg
Gly . Arg
Gly . Arg
Gly . Arg
Gly = Arg
Gly = Arg
Gly = Arg
Jindra et al. (2002)
Kotanko et al. (1997)
Bao et al. (2005)
Candy et al. (2000)
Bao et al. (2005)
Herrmann et al. (2000)
Wu et al. (2006)
Jia et al. (2000)
Xie et al. (2000)
Tomaszewski et al. (2002)
Ge et al. (2005)
Lou et al. (2011)
Kato et al. (2001)
Thomsen et al. (2012a)
African American
South African black
European American
Caucasian
European American
+ African American
Chinese
Polish
European American
Caucasian
African American
Danish
Gln = Glu
Gln = Glu
Gly16Gln27 protected
Gln = Glu
Gln = Glu
Bao et al. (2005)
Candy et al. (2000)
Bao et al. (2005)
Jia et al. (2000)
Xie et al. (2000)
Gln = Glu
Gln = Glu
Gln = Glu
Gln = Glu
Gln . Glu
Gln = Glu
Hindorff et al. (2005)
Heckbert et al. (2003)
Polish
Danish
Thr = Ile
ThrIle . ThrThr (women)
ThrIle = ThrThr (men)
638
66,750
probands homozygous for Gly16 in three of four
studies, which is in good agreement with the hyperfunctionality of the Gly16 variant reported in vitro
(Ahles et al., 2011). By contrast, systemic infusion
resulted in larger vasodilation in individuals homozygous for the Arg16 variant than in Gly16 homozygotes
(Gratze et al., 1999; Hoit et al., 2000; Snapir et al.,
2003a). The reason for this discrepancy is currently not
understood but may involve effects on heart rate, blood
pressure, and the consecutive activation of various
compensatory mechanisms that typically occur after
systemic stimulation of b1- and b2-adrenoceptors.
623
TABLE 16
Impact of b2-adrenoceptor variants on heart function and failure
Variant
Number of Subjects
Population Origin
Variation Effect
Reference
171
227
256 (230 controls)
309/520 (328 controls)
4441 white + 808 black; 155
cardiac arrest (144 controls)
Caucasian
American
Caucasian
German
American
Gly(Glu27) . Arg(Gln27)
Gly(Glu27) , Arg(Gln27)
Gly = Arg
Gly = Arg
Gly = Arg
Shin et al. (2007)
Leineweber et al. (2006b)
Sotoodehnia et al. (2006)
(+ c.79G.C (p.Gln27Glu))
Risk of HF, HTx, or death
DCM
CHF
CHF
HTx/CHF
CHF
CHF
CABG
ACS
ACS
ACS
259 (212 controls)
444
185
597
601
2072
American
Caucasian
German
American
African American
Caucasian
Gly = Arg
Gly = Arg
Gly , Arg
Gly , Arg
Gly , Arg
Gly = Arg
Risk of MI
MI
523 (2092 controls)
American
Arg(Gln27) = Gly(Glu27) ,
Gly(Gln27)
256 (230 controls)
309/520 (328 controls)
Caucasian
German
Gln = Glu
Gln = Glu
259 (212 controls)
444
601
2072
4441 white + 808 black, 155
cardiac arrest (144 controls)
American
Caucasian
African American
Caucasian
American
Gln = Glu
Gln = Glu
Gln = Glu
Gln = Glu
Gln . Glu
Sotoodehnia et al. (2006)
171
309/520 (328 controls)
Caucasian
German
Thr = Ile
Thr = Ile
259 (212 controls)
444
American
Caucasian
Thr , Ile
Thr = Ile
Frey et al. (2011)
Lanfear et al. (2005)
Zee et al. (2005)
CHF
HTx/CHF
CHF
CHF
ACS
ACS
DCM
HTx/CHF
CHF
CHF
ACS, acute coronary syndrome; CABG, coronary artery bypass graft; CHF, coronary heart disease; DCM, dilated cardiomyopathy; HTx, heart transplantation; MI,
myocardial infarction.
The response of Ile164 carriers to b2-agonists was
investigated in healthy volunteers (Brodde et al., 2001;
Bruck et al., 2003b) and in patients with congestive
cardiomyopathy (Barbato et al., 2007). In both groups,
cardiac responses to infusion of the b2-agonist terbutaline were weaker in Ile164 carriers compared with noncarriers, supporting data obtained in vitro (Table 19).
Moreover, patients carrying the Arg16 b2-adrenoceptor
showed a better response to short-term administration
of short-acting antiasthmatic b2-agonists (albuterol,
terbutaline) than those carrying Gly16. Studies on
treatment efficacy with long-acting b2-agonists showed
inconsistent results (Table 20), suggesting that Arg16
may only provide benefit in short-term treatment.
Together, these interesting findings may explain
why patients suffering from asthma and other obstructive pulmonary diseases exhibit individually
diverse responses to b2-agonists. By contrast, no
impact of p.Gln27Glu was observed with regard to
b2-agonist treatment outcome in patients with asthma
(Table 20).
Agonists at b2-adrenceptors are also frequently used
as short-term uterine relaxing (i.e., tocolytic) agents to
treat preterm labor despite limited evidence as to their
overall clinical benefit (Simhan and Caritis, 2007). One
small candidate gene study investigated the influence
of b2-adrenoceptor variation on the clinical efficacy of
tocolytic therapy with the b2-agonist hexoprenaline
and reported a (nonsignificant) trend toward later delivery in Arg16 homozygotes (Landau et al., 2005).
2. Response to Antagonists. Current data concerning the responses to b-blockers do not support an
implication of b2-adrenoceptor variants p.Gly16Arg
and p.Gln27Glu, because the majority of studies
624
TABLE 17
Impact of b2-adrenoceptor variants on the phenotype of risk of asthma, COPD, and bronchial hyperresponsiveness
Variant
Number of Subjects
Population Origin
Variant Effect
Reference
120
95 with severe asthma, 59
with mild asthma (92 controls)
Japanese
New Zealander
Gly . Arg carriers
Gly = Arg
Fukui et al. (2006)
Holloway et al. (2000)
Chinese Han
African American
Australian
American
British
Mexican Mestizo
Caucasian
American
British
Gly . Arg (asthma severity)
Gly carriers , Arg
Gly = Arg
Gly = Arg
Gly = Arg
Gly = Arg
Gly . Arg (nocturnal asthma)
Gly , Arg
Gly = Arg
Gly , Arg (+ Gln27)
Qiu et al. (2010)
Tsai et al. (2006)
Ramsay et al. (1999)
Bleecker et al. (2007)
Dewar et al. (1998)
Santillan et al. (2003)
Matheson et al. (2006)
Hall et al. (2006)
201 with asthma (276 controls)
264 with asthma (176 controls)
332
405 with asthma
630
907
1090
2250 with asthma
8018
c.[46G.A;79G.C]
(p.[Gly16Arg;Gln27Glu])
95 with severe asthma, 59
with mild asthma (92 controls)
332
630
907
1090
New Zealander
Gln= Glu
Holloway et al. (2000)
Australian
British
Mexican Mestizo
Caucasian
Gln = Glu
Gln = Glu
Gln , Glu
Gln . Glu
Ramsay et al. (1999)
Dewar et al. (1998)
Santillan et al. (2003)
Matheson et al. (2006)
104 children with severe asthma
American
4-fold risk for Arg16Gly-Gln27Gln
Carroll et al. (2012)
Arg16Gln27 = Gly16Glu27 ,
Gly16Gln27
D’amato et al. (1998)
248
Italian
630
8018
53,777 + 8971
British
British
Danish
comprising .100 patients report no difference in treatment efficacy (Table 20).
In summary, the N-terminal genetic variants
p.Gly16Arg and p.Gln27Glu exert rather minor
functional effects, with the Gly16 variant reported as
hyperfunctional in some (but not all) studies performed
in vitro. In vivo, this variant has been linked to higher
blood pressure, yet the underlying mechanism is unclear. The relatively infrequent p.Thr164Ile variation
might determine b2-adrenoceptor function to a more
relevant degree. The Ile164 variant is hypofunctional
in various in vitro systems and ex vivo. It also appears
to predispose to hypertension and is apparently
less efficacious when studied in healthy volunteers
and thus might be classified as a loss-of-function
variant.
Thr = Ile
Thr = Ile
Thr , Ile
Dewar et al. (1998)
Hall et al. (2006)
Thomsen et al. (2012b)
VII. Variants of the b3-Adrenoceptor
The b3-adrenoceptor (ADRB3) is most prominently
expressed in adipose tissue, gall bladder, and parts of
the colon (Krief et al., 1993; Berkowitz et al., 1995).
The b3-adrenoceptor was originally assigned a role in
promoting lipolysis and thermogenesis (Emorine et al.,
1989; Arch, 2008), yet this function is most likely
restricted to rodents (Michel et al., 2010). Multiple
other roles for the b3-adrenoceptor were subsequently
elucidated, including activation of nitric oxide synthase
in cardiomyocytes, relaxation of the urinary bladder
(Michel et al., 2010), and most recently release of hematopoietic stem cells and progenitor cells from the bone
marrow in myocardial infarction (Dutta et al., 2012).
The b3-subtype was the last of the b-adrenoceptors to
TABLE 18
Association of b2-adrenoceptor variants with preterm labor and preterm birth
Variant
Risk for spontaneous preterm birth
Rate of cervical dilatation in term and late preterm active labor
Number of
Subjects
Population Origin
Variant Effect
Reference
156
176
279
156
176
279
549
Turkish
Hungarian
Hispanic
Turkish
Hungarian
Hispanic
Australian
Gly = Arg
Gly carriers , Arg
Gly carriers , Arg
Gln , Glu carriers
Gln = Glu
Gln = Glu
Gln , Glu
Ozkur et al. (2002)
Doh et al. (2004)
Landau et al. (2002)
Ozkur et al. (2002)
Doh et al. (2004)
Landau et al. (2002)
Gibson et al. (2007)
103
401
103
American
American
American
Gly = Arg
Gly . Arg
Gln , Glu
Reitman et al. (2011)
Miller et al. (2011)
Reitman et al. (2011)
625
TABLE 19
Association of b2-adrenoceptor variants with vasodilation and hypertension in healthy volunteers
Parameter
c.46G.A (p.Gly16Arg), c.79G.C (p.Gln27Glu) and
haplotype c.[46G.A;79G.C] (p.[Gly16Arg;
Gln27Glu])
Isoproterenol infusion–induced dilation of dorsal
hand vein
Terbutaline infusion–induced dilation of dorsal
hand vein
Isoproterenol infusion–induced increase in forearm
blood flow
hand vein
Intravenous epinephrine infusion–induced decrease
in DBP
Intravenous terbutaline infusion–induced increase in
lower limb blood flow
Intravenous salmeterol infusion–induced decrease in
peripheral resistance
hand vein
Terbutaline infusion–induced dilation of dorsal
hand vein
Number of
Subjects
Population Origin
Variant Effect
26
American
GlyGlu . GlyGln = ArgGln
Dishy et al. (2001)
35
Caucasian
GlyGlu = GlyGln # ArgGln
41
Caucasian
GlyGlu = GlyGln . ArgGln
Garovic et al. (2003)
127
Caucasian
Gly . Arg carriers; Gln , Glu
Gly , Arg carriers
Reference
Cockcroft et al. (2000)
16
Finnish
20
Caucasian
57
Austrian
Gly carriers , Arg
Gratze et al. (1999)
26
American
ThrThr . ThrIle
Dishy et al. (2004)
35
Caucasian
ThrThr . ThrIle
Gly , Arg
Snapir et al. (2003a)
Hoit et al. (2000)
DBP, diastolic blood pressure.
be cloned and has been studied considerably less
compared with the b1- and the b2-subtype. To date,
there is no crystal structure of a b3-adrenoceptor (although
a high similarity to the b1- and b2-adrenoceptors seems
likely) and therapeutic drugs specifically targeting the
b3-adrenoceptor were only recently approved.
The Exome Variant Server currently lists 10 variants that have reproducibly been reported within the
coding sequence of the ADRB3 gene (Fig. 10), with two
variants occurring at a frequency .0.5%: c.491C.T
(p.Trp64Arg) and c.1075C.G (p.Arg353Cys). Two further variations in the coding region were described
in Chinese individuals: c.493T.C (p.Ser165Pro) and
c.769C.T (p.Ser257Pro) (Huang et al., 2013a). Of
these, the variation at position 64, which resides at
the intracellular end of TM1, has attracted the most
scientific interest.
A. Receptor Pharmacology
The effect of the b3-adrenoceptor variants containing
either tryptophan or arginine at position 64 has been
investigated upon transfection in different cell lines,
yet with inconclusive results. Although agonist binding
properties were found to be unchanged for both variants, the impact on downstream signaling effects
(i.e., adenylyl cyclase activation and cAMP formation)
differed in the various cell lines studied (that also
exhibited greatly varying receptor densities) (Table
21). Studies investigating the function of endogenously
expressed b3-adrenoceptor variants in adipocytes must
be interpreted with some caution, because most of the
agonists used are not specific for the b3-subtype and
may act through ADRB1 and ADRB2. These studies
are likewise contradictory, with some, but not all,
suggesting hypofunctionality of the Arg64 variant with
regard to agonist-induced lipolysis (Table 21).
p.Trp46Arg is in linkage to several noncoding
variants in the ADRB3 intronic region or 39-UTRs
and 39-downstream regions (Hoffstedt et al., 1999;
Teitsma et al., 2013). These “haplotype blocks”
have not been studied in detail to date, but are
suggested to contribute to the phenotypic effects reported in vivo through a potential effect on receptor
expression.
A larger study in a Chinese cohort recently reported
that two frequent variants within the b3-adrenoceptor
(p.Ser165Pro and p.Ser257Pro) are both associated
with type 2 diabetes (see below) (Huang et al., 2013a).
Neither of these variants was previously found in
other ethnicities. Position 165 is located in helix 4,
where an amino acid change to proline may reasonably be expected to impair receptor structure and
function. Serine at position 257 lies within the third
intracellular loop and represents a putative phosphorylation site, which would be lost in the Pro257
variant. Both the Pro165 and Pro257 variants showed
less agonist-induced cAMP formation after overexpression in two different cell lines, whereas phosphorylation of MAPK was retained (Table 21).
Finally, the very rare variant c.794C.T (p.Thr265Met),
located in intracellular loop 3 in the ADRB3 protein
(Fig. 10B), was functionally studied in vitro. No differences were reported with regard to ligand binding
affinity and agonist-induced cAMP formation upon overexpression of the Thr265 and Met265 variants in HEK293 cells (Table 21).
626
TABLE 20
Patients’ response to b-agonists and blockers in dependence of variations in the b2-adrenoceptor
Data are an overview of candidate gene studies investigating $100 individuals
Drug
Number of Subjects
Population Origin
Variant Effect
Reference
195 children with asthma
1182 young individuals
with asthma
Korean
Scottish
Gly , Arg
Gly , Arg
Cho et al. (2005)
Basu et al. (2009)
108 with mild to moderate
asthma
183 with asthma
190 with asthma
269 with asthma
New Zealander
Gly . Arg
Taylor et al. (2000)
American
American
American (Caucasian
or Hispanic)
American
Gly = Arg
Gly . Arg
Gly , Arg
Israel et al. (2000)
Martinez et al. (1997)
Gly = Arg
British
Gly . Arg
Palmer et al. (2006)
New Zealander
Gln = Glu
Taylor et al. (2000)
British
Gln = Glu
Palmer et al. (2006)
Response to agonists—acute bronchodilator
response/risk for exacerbations
Inhaled short-term agonist
Albuterol
Response to agonists—chronic response/
adverse effects
Regular salbutamol, salmeterol
Salmeterol + fluticasone
Albuterol, long-term
Albuterol
Salmeterol
Salmeterol
Regular salbutamol, salmeterol
Salmeterol
544 with asthma
(albuterol as needed)
546 children and young
adults, 546
108 with mild to moderate
asthma
546 children and young
adults with asthma
Response to antagonists—improvement
in LVEF/SBP/survival
Carvedilol
Carvedilol
Not detailed
Carvedilol or bisoprolol
Bisoprolol
Atenolol
Not detailed
Carvedilol or metoprolol
135
183
185
199
233
264
298
637
CHF
CHF
CABG
CHF
HT
HT
HT, 298 NT
CHF
Australian
Italian
German
French
Finnish
Italian
Caucasian
American
Gly
Gly
Gly
Gly
Gly
Gly
Gly
Gly
= Arg
= Arg
. Arg
= Arg
= Arg
= Arg
= Arg
= Arg
Chen et al. (2007)
Metra et al. (2010)
Frey et al. (2011)
Jia et al. (2000)
Carvedilol
Carvedilol
Carvedilol or bisoprolol
Bisoprolol
Not detailed
Carvedilol or metoprolol
135
183
199
233
298
637
CHF
CHF
CHF
HT
HT, 298 NT
CHF
Australian
Italian
French
Finnish
Caucasian
American
Gln
Gln
Gln
Gln
Gln
Gln
= Glu
, Glu
= Glu
= Glu
= Glu
= Glu
Chen et al. (2007)
Metra et al. (2010)
Jia et al. (2000)
CHF, chronic heart failure; HT, hypertensive; LVEF, left ventricular ejection fraction; NT, normotensive; SBP, systolic blood pressure.
B. Role in Human Physiology and Disease
Because of its role in fat and muscle, the most
common b3-adrenoceptor variation, p.Trp64Arg, has
most intensely been investigated with regard to a
potential role in metabolic abnormalities. Arg64 carriers showed a lower resting metabolic rate, an increased risk for obesity and insulin resistance, and
a lower age of onset of noninsulin-dependent diabetes
mellitus compared with Trp64 carriers in early studies
(Clément et al., 1995; Kadowaki et al., 1995; Walston
et al., 1995; Widén et al., 1995). Although not all
studies confirmed an association of Arg64 with metabolic disorders (Table 22), a meta-analysis of .100
studies including .44,000 individuals showed an
ethnicity-dependent susceptibility of the Arg64 allele
for weight gain (determined as body mass index), as it
was significantly associated with obesity specifically in
Asians (Kurokawa et al., 2008). Furthermore, four
studies investigated an association of the p.Trp64Arg
variant with the risk of hyperuricemia or gout and
found this to be significant (Table 22). The smooth
muscle relaxing properties of b3-adrenoceptors stimulation led to a large study (.1000 individuals) that
tested for association of the p.Trp64Arg variation with
bladder function in the context of benign prostate
hyperplasia, but no significant differences among genotypes were reported (Teitsma et al., 2013).
Candidate gene studies investigating an association
of p.Trp64Arg with cardiac disease reported inconsistent results (Table 22). With regard to the risk of type 2
diabetes, the largest study (including 7606 Danish
individuals) reported an association of p.Trp64Arg
627
Fig. 10. Nonsynonymous variations in the human b3-adrenoceptor. (A) ADRB3 gene locus (chromosome 8: 37,820,516–37,824,483, reverse strand) and
localization of the variations in the coding region (exons 1 and 2) and adjacent regions. Variation data were extracted as described in Fig. 2. The
asterisk indicates variants found in Chinese individuals. (B) Localization of the functionally studied coding-region variation p.Trp64Arg in the ADRB3
protein.
(Gjesing et al., 2008). In addition, in a Chinese cohort
including 650 patients with type 2 diabetes and 1337
healthy controls, the variations p.Ser165Pro and
p.Ser257Pro were associated with susceptibility to
type 2 diabetes and disease development (Huang
et al., 2013a).
The latter findings of an association of b3-adrenoceptor
variation with type 2 diabetes require further analysis,
because the currently available GWAS results do not
support an association of the ADRB3 locus with obesityor metabolism-related phenotypes (including type 2
diabetes; Table 4). This might suggest that neither
p.Trp46Arg nor p.Ser165Pro and p.Ser257Pro are
associated with disease.
VIII. Summary and Conclusions
Adrenoceptors execute activation of the sympathetic
nervous system on the cellular level. As such, they are
key molecules to determine multiple organ functions in
health and disease and are targets of widely used
therapeutic drugs. All nine adrenoceptor genes display
genetic variation, including nonsynonymous variations
in their coding regions. This variation has fueled speculations about their possible functional relevance
and has consequently been the basis of a multitude of
studies on adrenoceptor variation. As a result, ADRB1
and ADRB2 range among the most frequently studied
genes with regard to a potential involvement of their
genetic variation in human physiology, disease, or
drug response. Despite the enormous effort invested in
these studies, hard evidence for a significant impact of
adrenoceptor variation on any parameter related to
adrenoceptor function remains disappointingly scarce
and refers to a very small number of variants (for
details, see the summaries at the end of Sections III–
VII). What are the likely reasons underlying this overt
discrepancy? A number of early and exciting candidate
gene studies (i.e., studies that specifically investigate
variations in a selected gene, as opposed to a genomewide approach) originally reported on associations of
adrenoceptor variation and human disease. Unfortunately, the restriction to a specific candidate gene
made these studies vulnerable to undetected bias
and false positive results. Although many studies had
been conducted, some reports typically confirmed such
628
TABLE 21
In vitro and ex vivo phenotype variants in the b3-adrenoceptors
Variation
c.190T.C (p.Trp64Arg)
Parameter
Basal AC activity
Maximal agoniststimulated AC activity
cAMP formation
(+ACIII)
Iso-induced desensitization
Insulin secretion
Endogenous receptor
Agonist-induced lipolysis
c.493T.C (p.Ser165Pro)
c.769T.C (p.Ser257Pro)
c.794C.T (p.Thr265Met)
cAMP formation
cAMP formation
Ligand binding affinity
cAMP formation
Cell/Tissue
Variant Effect
Reference
CHOa
CHO-K1b
HEK-293c
HEK-293a
COS-7
CHOa
CHOa
CHO-K1b
HEK-293c
HEK-293a
COS-7
COS-7
3T3-L1 preadipocytes
HEK-293a
Rat insulinoma
Trp = Arg
Trp = Arg
Trp = Arg
Trp = Arg
Trp = Arg
Trp = Arg
Trp = Arg
Trp . Arg
Trp . Arg
Trp = Arg
Trp = Arg
Trp , Arg
Trp . Arg
Trp = Arg
Trp . Arg
Candelore et al. (1996)
Piétri-Rouxel et al. (1997)
Subcutaneous/visceral
adipocytes
Visceral adipocytes
Trp = Arg (CGP, NE)
Vrydag et al. (2009)
Isogaya et al. (2002)
Piétri-Rouxel et al. (1997)
Isogaya et al. (2002)
Kimura et al. (2000)
Perfetti et al. (2001)
Li et al. (1996)
Hoffstedt et al. (1999)
Omental adipocytes
Trp = Arg (Iso, Dob, Ter)
Trp . Arg (CGP)
Trp = Arg (Iso, CGP)
Trp . Arg (L-755,507)
HEK-293
CHO-K1
Ser = Pro
Ser = Pro
Huang et al. (2013a)
HEK-293
CHO-K1
Ser = Pro
Ser = Pro
HEK-293a
HEK-293a
Thr = Met
Thr = Met
Umekawa et al. (1999)
AC, adenylyl cyclase; CGP, CGP-12177; Dob, dobutamine; Iso, isoproterenol; NE, norepinephrine; Ter, terbutaline.
a
b
Receptor expression: .0.2 and ,0.5 pmol/mg.
c
associations and others did not (see Tables 15–17 and
22). The larger the numbers of individuals included
in a study (listed toward the bottom of Tables 15–17
and 22), the less likely such an association was often
reported.
The recent broad application of genome-wide association undoubtedly led to a change of human genetics in
a paradigmatic way (Katsanis and Katsanis, 2013) and
also changed our appreciation of previously reported
candidate gene–centered association studies. We must
acknowledge that previously accepted standards for
the reporting of genetic associations have apparently
not been rigorous enough to prevent false interpretations. The problematic validity of candidate gene
studies raises the question of whether they can be
expected to contribute meaningful results to our understanding of adrenoceptor variation.
With the recent formation of very large consortia (i.e.
.10,000 subjects), we can expect an even higher
sensitivity to detect genetic determinants of specific
traits in the future. For candidate gene studies, we
envision a less prominent role in very defined and less
complex settings, such as the testing of acute drug
responses in primary human cells or humans (see
below).
GWAS have become the gold standard to associate
a variation with a certain trait, but the number of such
studies is currently too low to draw a comprehensive
picture on the role of adrenoceptor variation. Only two
of the nine adrenoceptor subtypes appear in GWAS. For
the ADRA2A gene, variations in the 39-downstream
region were found to be associated with fasting glucose–
related traits and epinephrine-induced platelet aggregation. Variations in the ADRB1 gene identified in the
59-upstream region and in the coding region were associated with blood pressure and birth weight, respectively. The latter represents the most common variation
in the b1-adrenoceptor, c.1165C.G (p.Arg389Gly), and
is the only variation within the coding region of an
adrenoceptor that yielded a GWAS “hit” (i.e., a significant association with a predefined trait).
Aside from weighing the pros and cons of genecentered studies versus GWAS, there is also a need to
discuss the apparent ambiguity of some of the studies
that analyzed adrenoceptor variation in vitro. Typically, the functional and biochemical consequences of
629
TABLE 22
Association of the c.190T.C (p.Trp64Arg) variation in the b3-adrenoceptor with disease
Association
With metabolic syndrome/risk
of obesity-related phenotype
(BMI gain, visceral
fat accumulation, insulin
resistance, serum LDL, BP)
Number of Subjects
102
122 (from 40 obese families)
97 NT, 126 HT,
137 CHD (188 controls)
145 obese
213
217 nondiabetic obese
74 + 161
265 obese
275 healthy
185 obese (94 controls)
188 with T2D
110 NIDDM, 183 insulin
resistant (82 controls)
149 HT obese, 139 HT
nonobese, 149 NT nonobese
335 (207 + 128 NIDDM)
335
350
379
417 T2D
382 (122 hyperglycemic,
among 77 T2D)
559
528
553 children
242
381 obese, 236 gastric
banding surgery
(198 controls)
642 (among 390 NIDDM)
658
711
802
1000 CAD
1063
1259
1355
1416
1886
2500 twin pairs
7605
Risk of T2D
200 T2D (300 controls)
382 (122 hyperglycemic,
among 77 T2D)
358, 200 overweight (111 T2D)
802
7606
Gestational diabetes
179
309 GDM, 277 normal
649 GDM (1232 controls)
Gallstone formation
143
Risk of hyperuricemia/overactive 100 OAB (101 controls)
203 hyperuricemia (203 controls)
bladder syndrome
410 hyperuricemia (420 controls)
421 gout (312 controls)
1015 OAB
1051 hyperuricemia
Population Origin
Variant Effect
Reference
South African
Polish
Japanese
Chinese
Japanese
Kyrgyz
Caucasian
African American +
Caucasian
Italian
Japanese
French
Japanese
Turkish
Finnish
Trp = Arg
Trp . Arg
Trp = Arg
Trp = Arg
Trp , Arg
Trp , Arg
Trp , Arg carriers
Trp = Arg
Rooyen et al. (2008)
Malczewska-Malec et al. (2003)
Ikegami et al. (1996)
Sheu et al. (1999)
Yamakita et al. (2010)
Mirrakhimov et al. (2011)
de Luis et al. (2008)
Lima et al. (2007)
Trp , Arg (males)
Trp carriers , Arg
Trp , Arg
Trp = Arg
Trp = Arg
Trp = Arg
Bracale et al. (2007)
Kotani et al. (2008)
Clément et al. (1995)
Nonen et al. (2008)
Mergen et al. (2007)
Rissanen et al. (1997)
Chinese
Trp , Arg
Mo et al. (2007)
Trp , Arg
Trp = Arg
Widén et al. (1995)
Mattevi et al. (2006)
Finnish
European-derived
Brazilians
Japanese
Danish
German
Chinese
Japanese
Trp , Arg
Trp = Arg
Trp , Arg (males)
Trp = Arg
Trp = Arg
Taiwan
Balinese
Trp = Arg
Trp , Arg
(rural females)
Japanese
Trp , Arg carriers
Québec family study
Trp = Arg
Swedish
German
Trp = Arg
Kadowaki et al. (1995)
Urhammer et al. (2000)
Ringel et al. (2000)
Zhu et al. (2010)
Ishii et al. (2001)
Chou et al. (2012)
Malik et al. (2011)
Endo et al. (2000)
Gagnon et al. (1996)
Evans et al. (2000)
German
Japanese
Japanese
Cebu Filipino
British
Danish
Trp , Arg
Trp = Arg
Trp = Arg
Trp , Arg (obesity)
Trp = Arg (HT,
dislipidemia)
Trp = Arg
Trp , Arg
carriers Male
Trp = Arg
Trp , Arg
Trp = Arg
Trp . Arg
Trp = Arg
Trp = Arg
Büettner et al. (1998)
Takeuchi et al. (2012)
Tamaki et al. (2006)
Marvelle et al. (2008)
Haworth et al. (2008)
Kashmiri
Japanese
Trp , Arg
Trp = Arg
Hameed et al. (2013)
Ishii et al. (2001)
Polish
Southern Chinese
Danish
Trp = Arg
Trp = Arg
Trp , Arg
Kasznicki et al. (2005)
Thomas et al. (2000)
American
Italian
Scandinavian
Trp , Arg
Trp = Arg
Trp = Arg
Festa et al. (1999)
Fallucca et al. (2006)
Shaat et al. (2007)
German
Trp , Arg
Klass et al. (2007)
Japanese
Korean
Chinese
Chinese
Dutch
Spanish
Trp , Arg
Trp , Arg
Trp , Arg
Trp , Arg
Trp = Arg
Trp , Arg
Honda et al. (2014)
Rho et al. (2007)
Huang et al. (2013b)
Wang et al. (2011)
Teitsma et al. (2013)
Morcillo et al. (2010)
Pima Indian
Japanese
Caucasian
Southern Chinese
German
Spanish
Walston et al. (1995)
Shiwaku et al. (1998)
Wang et al. (2006)
Thomas et al. (2000)
Stangl et al. (2001)
Corella et al. (2001)
(continued )
630
TABLE 22—Continued
Association
Cardiac disease (CHD,
CAD, arteriosclerosis)
Number of Subjects
171 IDC
198 IHD (230 controls)
185 nondiabetic with CHD,
119 NIDDM (82 controls)
357 HT
971
1000 CAD (1000 controls)
1297
3409
15,236
Population Origin
Variant Effect
Italian
Japanese
Finnish
Trp = Arg
Trp = Arg
Trp = Arg
Tamaki et al. (1999)
Pulkkinen et al. (1999)
Reference
Japanese
White American
German
Chinese
American
Dutch
Trp . Arg
Trp = Arg
Trp = Arg
Trp , Arg
Trp , Arg
Trp = Arg
Iwamoto et al. (2011)
Morrison et al. (1999)
Stangl et al. (2001)
Wang et al. (2010)
Fan et al. (2010)
Zafarmand et al. (2008)
BMI, body mass index; BP, blood pressure; CAD, coronary artery disease; CHD, coronary heart disease; GDM, gestational diabetes mellitus; HT, hypertensive; IHD,
ischemic heart disease; NIDDM, noninsulin-dependent diabetes mellitus; NT, normotensive; OAB, overactive bladder; T2D, type 2 diabetes.
adrenoceptor variation have been analyzed by expressing the wild-type receptors and their respective genetic
variants in heterologous cell systems. However, such
assays also display considerable variability, as can be
seen for the c.190T.C (p.Trp64Arg) variant of the
b3-adrenoceptor, when examined in different cell lines,
upon different degrees of overexpression, or upon
application of different ligands (also see Tables 2 and
21). Such discrepancies might be due to ligand-dependent
selectivity for certain signaling pathways (“biased
agonism”; Evans et al., 2010) and cell line-specific
equipment with G proteins, other receptor interacting
proteins and signal pathway components as well as
abnormal G protein coupling caused by high-level overexpression of receptors. All of these factors can potentially
determine certain downstream effects, agonist-promoted
receptor phosphorylation, and receptor desensitization.
Future studies in vitro on adrenoceptor variation will
benefit from more rigorously controlled cellular systems,
such as better defined “knock-in” cell lines (Pan et al.,
2011), which permit the head-to-head comparison of
receptor variants expressed from the same genetic locus
in a defined copy number.
Most available data on the drug response of
adrenoceptor variants suffer similar limitations as
candidate gene studies do for disease association
(i.e., heterogeneity and limited size of the study
population). In this regard, the appreciation of the
functional impact of the p.Arg389Gly variation in
the b1-adrenoceptor appears as most unequivocal. The
presence of a glycine at position 389 in the b1adrenoceptor [c.1165C.G (p.Arg389Gly)] has repeatedly been observed in large clinical trials to reduce the
efficacy of treatment with b-blockers. Cardiac and
blood pressure responses to b-blocker treatment were
significantly stronger in Arg389–b1 -adrenoceptor
homozygotes than in subjects carrying one or two
alleles of the Gly389–b1-adrenoceptor in patients with
essential hypertension and chronic heart failure. While
not supported by hard evidence from clinical studies to
date, the prospective determination of adrenoceptor
genotypes may aid to personalize patient treatment
with several drugs currently prescribed. For example,
by assessing the b1-adrenoceptor genotype of a patient,
the responsiveness to b1-agonists or b1-antagonists
could be predicted (Arg389, good responders; Gly389,
poor responders) and the dose of the drug might be
adopted depending on the genotype (Gly389, higher
dose). Other adrenoceptor variants did not show a
consistent correlation with drug response, yet they
have been comparably less intensely studied, with
room for improvement. Ultimately, we may expect that
GWAS on drug response will help to elucidate which
adrenoceptor variations determine drug response and
which do not.
Acknowledgments
The authors thank T. Meitinger (Institute of Human Genetics,
German Research Center for Environmental Health, Munich,
Germany) for his advice on Exome Variant Server and GWAS data
interpretation, and B. Laggerbauer (Institute of Pharmacology and
Toxicology, Technische Universität München, Munich, Germany) for
critically reading the manuscript. This review aims to cover the most
relevant findings in the field, yet the authors can only discuss
a fraction due to the enormous number of studies on this topic. They
apologize to all authors whose work could not be cited.
Authorship Contributions
Performed data analysis: Ahles.
Wrote or contributed to the writing of the manuscript: Ahles,
Engelhardt.
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Polymorphic Variants of Adrenoceptors

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