?2-Adrenergic Receptor Genetic Variants and Risk of
Sudden Cardiac Death
Nona Sotoodehnia, MD, MPH; David S. Siscovick, MD, MPH; Matteo Vatta, PhD;
Bruce M. Psaty, MD, PhD; Russell P. Tracy, PhD; Jeffrey A. Towbin, MD, MS;
Rozenn N. Lemaitre, PhD, MPH; Thomas D. Rea, MD, MPH; J. Peter Durda, BS;
Joel M. Chang, BS; Thomas S. Lumley, PhD; Lewis H. Kuller, MD, PhD;
Gregory L. Burke, MD, MSc; Susan R. Heckbert, MD, PhD
Background—Sympathetic activation influences the risk of ventricular arrhythmias and sudden cardiac death (SCD),
mediated in part by the ?2-adrenergic receptor (B2AR). We investigated whether variation in the B2AR gene is
associated with SCD risk.
Methods and Results—In this study, 4441 white and 808 black Cardiovascular Health Study (CHS) participants were
followed up prospectively for SCD and genotyped for B2AR Gly16Arg and Gln27Glu polymorphisms. The study was
replicated in 155 case and 144 control white subjects in a population-based case-control study of SCD, the Cardiac
Arrest Blood Study (CABS). In CHS, Gly16 and Gln27 allele frequencies were 62.4% and 57.1% among white and
50.1% and 81.4% among black participants. Over a median follow-up of 11.1 years, 156 and 39 SCD events occurred
in white and black participants, respectively. The Gln27Glu variant was associated with SCD risk (P?0.008 for general
model). SCD risk was higher in Gln27 homozygous participants than in Glu27 carriers (ethnicity-adjusted hazard ratio
[HR], 1.56; 95% confidence interval [CI], 1.17 to 2.09; P?0.003). The increased risk did not differ significantly
between white (HR, 1.62; 95% CI, 1.18 to 2.23) and black (HR, 1.23; 95% CI, 0.61 to 2.48) participants, although the
confidence interval was wide in blacks. In the CABS replication study, Gln27 homozygous participants similarly had
higher SCD risk than Glu27 carriers (odds ratio, 1.64; 95% CI, 1.02 to 2.63; P?0.040). Gly16Arg was not associated
with SCD risk in either study.
Conclusions—Gln27 homozygous individuals have an increased risk of SCD in 2 study populations. Our findings suggest
that B2AR plays a role in SCD in humans. Study of genetic variation within the B2AR gene may help identify those
at increased SCD risk. (Circulation. 2006;113:1842-1848.)
Key Words: death, sudden ? epidemiology ? genetics ? receptors, adrenergic, beta
arrhythmias have been associated with cardiac sympathetic
activation and higher cardiac and serum norepinephrine
levels.2–4Animal studies suggest that the ?2-adrenergic
receptor (B2AR) partly mediates this response to sympathetic
activation.5,6A family history of SCD is associated with a
doubled SCD risk, suggesting a genetic susceptibility.7
Whether genetic variation in the B2AR gene is associated
with SCD risk in humans has not previously been explored.
B2AR is a small intronless gene. Thirteen single nucleotide
polymorphisms (SNPs) have been described that are in
udden cardiac death (SCD) accounts for 450 000 deaths
in the United States each year.1SCD and ventricular
Editorial p 1818
Clinical Perspective p 1848
linkage disequilibrium.8Two common SNPs result in the
amino acid substitutions Gly16Arg and Gln27Glu. In trans-
fected cell lines, these amino-terminus SNPs alter cellular
trafficking of the receptor protein, resulting in variation in
agonist-promoted receptor downregulation.9These 2 variants
are in strong linkage disequilibrium; Glu27 almost always is
paired with Gly16 in humans. Therefore, 3 common haplo-
types exist: H1 (Gly16-Glu27), H2 (Arg16-Gln27), and H3
(Gly16-Gln27).8Because the disease association of a SNP
Received August 11, 2005; revision received January 12, 2006; accepted January 23, 2006.
From the Cardiovascular Health Research Unit, Department of Medicine (N.S., D.S.S., B.M.P., R.N.L., T.D.R., T.S.L., S.R.H.), Division of Cardiology,
Department of Medicine (N.S.), Department of Epidemiology (D.S.S., B.M.P., S.R.H.), and Department of Biostatistics (T.S.L.), University of
Washington, Seattle; Department of Pediatrics, Baylor College of Medicine, Houston, Tex (M.V., J.A.T., J.M.C.); Department of Pathology, University
of Vermont, Burlington (R.P.T., J.P.D.) Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pa (L.H.K.); and Department of Public Health
Sciences, Wake Forest University, Winston-Salem, NC (G.L.B.).
Correspondence to Nona Sotoodehnia, MD, MPH, Cardiovascular Health Research Unit, 1730 Minor Ave, Suite 1360, UW Box 358085, Seattle, WA
98101. E-mail email@example.com
© 2006 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.orgDOI: 10.1161/CIRCULATIONAHA.105.582833
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may depend on its cis interactions with other SNPs in a gene, we
examined haplotypes in addition to individual SNPs. To inves-
tigate whether functional variants of the B2AR gene influence
SCD risk, we genotyped 5249 elderly individuals who were
followed up prospectively to identify SCD events. We validated
the findings in a population-based case-control study of SCD.
Cardiovascular Health Study
The Cardiovascular Health Study (CHS) is a population-based
prospective cohort study of cardiovascular disease in the elderly. In
1989 to 1990 and 1992 to 1993, 4 field centers recruited 5888
participants ?65 years of age from Medicare eligibility lists.
Individuals were excluded if they were unable to participate in the
baseline examination or were not expected to return for the 3-year
follow-up. Details of the CHS study design and participant recruit-
ment are described elsewhere.10For this analysis, participants were
excluded if they did not have DNA available (n?213), did not
consent to use of their genetic information (n?273), were missing
genotype data (n?114), or did not self-identify as white or black
(n?39), leaving 4441 white and 808 black participants.
Participants underwent annual evaluations that included assessment
of cardiovascular risk factors, comorbidities, and clinical and laboratory
measurements. Comprehensive data were gathered on cardiovascular
events and deaths from hospital records, interviews with physicians,
next of kin and/or witnesses, death certificates, and autopsy reports.
Cause of death and nonfatal myocardial infarctions were adjudicated by
committee.11This analysis included events occurring by June 30, 2001,
from the updated CHS database. SCD was operationally defined as a
sudden pulseless condition from a cardiac origin in a previously stable
individual occurring out of hospital or in the emergency room. By
definition, SCD cases could not have a life-threatening noncardiac
comorbidity or be under hospice or nursing home care. SCD cases were
identified by a cardiologist’s record review of all cardiac deaths blinded
to genotype information. A blinded second physician review of a
random sample of 70 of these death records showed an 88% inter-
reviewer agreement and ??0.74 for SCD.
Cardiac Arrest Blood Study
The Cardiac Arrest Blood Study (CABS) is a population-based
case-control study of the determinants of cardiac arrest in the
community. SCD was defined as a sudden pulseless condition in the
absence of evidence of a noncardiac cause of cardiac arrest. Cases
were out-of-hospital cardiac arrests attended by paramedics in
Seattle and suburban King County, Wash, between October 1988 and
2002. Emergency medical services incident reports, death certifi-
cates, medical examiner reports, and autopsy reports were reviewed
to exclude patients with cardiac arrest attributable to a noncardiac
cause. The 155 CABS cases were out-of-hospital cardiac arrests that
had a blood sample collected by the paramedics at the time of the
arrest and met the eligibility criteria of the CABS study. Because a
primary aim of the CABS study focused on dietary polyunsaturated
fatty acids, cases were restricted to out-of-hospital cardiac arrests
without overt heart disease to minimize the possibility of bias from
changing diet as a result of the knowledge of presence of heart
disease. Cases were 25 to 74 years of age and were not residents of
a nursing home, to avoid misclassification as to cause of death.
Furthermore, cases were restricted to married individuals to obtain
spousal information on risk factors and comorbidities. The spouses
of ?85% of eligible case patients agreed to participate in an
in-person interview. Control subjects, matched to cases in age and
sex with the same eligibility criteria, were randomly selected from
the community by random-digit dialing. Spouses completed a ques-
tionnaire on comorbidities and cardiac risk factors for case and
control subjects. Details of the CABS recruitment experience are
described elsewhere.12We further restricted our present study of
genetic variants to white participants, because we had too few
participants of other ethnicity to perform meaningful analyses. A
sample of 155 case and 144 control white subjects with DNA
available was genotyped for B2AR gene variants.
For both studies, institutional review board approval was obtained,
and study subjects and/or spouses (CABS) provided informed consent.
SNP Selection and Genotyping
Common variants of the B2AR gene were identified from complete
sequence information obtained by Drysdale et al8in 23 whites and 19
blacks. In whites, this number of individuals allows for ?99%
probability of identifying a variant with an allele frequency of
?5%.13Of the 12 haplotypes identified, only 3 were common in
whites, accounting for 95% of the haplotypes seen in this popula-
tion.8A haplotype tree of these 3 common haplotypes was con-
structed with the MEGA program based on the number of differences
between haplotypes by UPGMA clustering method (Figure 1).14We
selected 2 informative variants, Gly16Arg and Gln27Glu, that
differentiate the 3 common haplotypes defined by Gly16-Glu27,
Arg16-Gln27, and Gly16-Gln27. Among blacks, 3 haplotypes ac-
count for ?95% of the variation seen in the coding and promoter
regions of the B2AR gene. The Arg16-Gln27 allele is further
differentiated into 2 haplotypes, both common in blacks, by SNPs in
the upstream regions at nucleotide positions ?1023 and ?654.8The
Thr164Ile variant was not examined because it is rare (allele
frequency, 1% to 2% in whites and blacks)8; its effect on SCD risk
would have to be large for our study to have adequate power to detect
Details of the blood collection protocol and sample storage for CHS
and CABS are described elsewhere.10,15In CHS, unphased genotyping
of the B2AR gene was performed after PCR amplification using 2
methods. Initially, the Gly16Arg and Gln27Glu variants were detected
on a subset of 2166 participants using 2 restriction enzyme digestions.
Genotyping was completed on the remainder of the cohort using a
high-throughput TaqMan assay (Applied Biosystems, Foster City,
Calif).16Both methods were used to genotype a sample of 222 subjects
representing all diplotypes (ie, haplotype pairs) with 99.6% intermethod
Figure 1. Haplotype tree of the B2AR gene. Ten SNPs differ between the 3 common haplotypes. Two evolutionary distant clades are
identified that completely segregate at 6 SNPs (italics). Gln27Glu (bold, italics) tags the first clade, which contains only the H1 haplo-
type. Arg16Gly (bold) differentiates the H2 and H3 haplotypes in the second clade. A variant in the leader cistron (LC) region of the
B2AR gene, Cys19Arg, is found only in the H1 haplotype. The remaining SNPs either are in noncoding regions or are synonymous.8
Sotoodehnia et alB2AR Variants and SCD
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agreement. In CABS, unphased genotyping was performed using direct
sequencing after PCR amplification. Oligonucleotide primers were
designed to amplify the coding sequence of B2AR to include SNPs for
both Arg16Gly and Gln27Glu in a single amplicon. The PCR product
sequencer.17All genotyping was performed by researchers blinded to
To investigate the potential for population admixture, 4 markers were
examined in the full CHS cohort (apolipoprotein E alleles 2, 3, and 4;
angiotensin type 1 receptor C1166A SNP; adducin Gly460Trp SNP) or
C825T SNP) using restriction-fragment-length polymorphism and/or
TaqMan allelic discrimination system on the basis of protocols detailed
Hardy-Weinberg equilibrium was assessed by ?2test. Haplotypes
and their frequencies were estimated from genotypes by the expec-
tation maximization method using the Arlequin program (University
of Geneva, Geneva, Switzerland).22Differences in participant char-
acteristics by genotype were assessed with ?2and Student’s t tests.
In CHS, the genotype-SCD association was assessed using the Cox
proportional hazards regression model with age as the time axis. The
overall association of genotype with SCD risk was assessed using Cox
regression with indicator variables representing the heterozygous and
each of the respective homozygous genotypes. For the SNP (Gln27Glu)
and haplotype (H1) with significant effects, we then assessed autosomal
dominant, recessive, and additive models. Nested models were com-
pared by likelihood ratio tests. Conservative likelihood ratio tests were
done for nonnested models using critical values appropriate for a larger
nested model. The model comparing Gln27 homozygotes with Glu27
carriers was the best fit and is the model presented. Most analyses were
stratified by ethnicity. Analyses of the combined cohort were adjusted
for ethnicity. Secondary analyses were performed stratified by clinic
site, gender, median age and body mass index, history of myocardial
infarction, congestive heart failure, hypertension, diabetes, and smoking
status at baseline, and interactions were assessed with the likelihood
ratio test. Multivariable analyses were performed with adjustment for
these covariates. The odds ratios (ORs) for total mortality and mortality
by specific cause of death by genotype were calculated by logistic
regression. To investigate the possibility of genetic admixture among
whites, allele frequencies of 4 unrelated markers were compared by
B2AR genotype using the ?2test. Among whites, the association of
diplotype with SCD risk was assessed using Cox regression with
indicator variables comparing each diplotype with the most common
diplotype. Similar analyses were not performed in blacks because of
small event numbers.
The CABS case-control study was used to validate the findings in
CHS. In CABS, genotype-SCD association was assessed with logistic
regression adjusted for the sampling variables of age, gender, and event
date. Further analysis was done with adjustment for spousal report of
study subject hypertension, diabetes, and smoking status. Analyses were
performed with Stata 8.0 SE (Stata Corp, College Station, Tex).
The authors had full access to the data and take full responsibility for
its integrity. All authors have read and agree to the manuscript as
CHS: SNP Analysis
Gly16Arg and Gln27Glu were in Hardy-Weinberg equilib-
rium in both white and black participants. The 2 SNPs were
in strong linkage disequilibrium, resulting in 3 common
haplotypes (Table 1). SNP and haplotype frequencies differed
between the 4441 white and 808 black study participants
(P?0.001). Within each ethnicity, there were no significant
differences by genotype in baseline characteristics (Table 2).
Over the median follow-up of 11.2 and 8.2 years, 156 and 39
SCD events occurred in white and black subjects, respectively.
The Gln27Glu variant was associated with SCD risk (P?0.008
for general model). A recessive model was the best-fitting
model. SCD risk was higher in Gln27 homozygous participants
than in participants with ?1 Glu27 alleles (ethnicity adjusted
hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.17 to
2.09) (Table 3). This increased SCD risk did not differ signifi-
(HR, 1.23; 95% CI, 0.61 to 2.48) participants (interaction
P?0.48), although the CI was wide and crossed 1.0 in blacks.
and history of myocardial infarction, congestive heart failure,
diabetes, and hypertension at study entry did not affect this
association (adjusted HR, 1.50; 95% CI, 1.12 to 2.00). The
association of SCD with genotype was not notably different in
subgroups defined by these covariates (interaction P?0.10 for
To determine whether the association was influenced by
survival bias, the risks of total mortality and mortality by cause
of death were compared by genotype. During follow-up, 1838
deaths occurred in white and 280 in black subjects. Gln27
homozygous participants had the same risk of total mortality as
Glu27 carriers among whites (OR, 1.06; 95% CI, 0.93 to 1.20)
and blacks (OR, 1.00; 95% CI, 0.73 to 1.37). Non-SCD
atherosclerotic death and noncardiac death risk were not associ-
ated with genotype.
We further examined the association of the B2AR Gln27Glu
variant with other ischemic heart disease events among whites.
Compared with Glu27 carriers, Gln27Gln27 participants did not
have a significantly increased risk of nonfatal myocardial infarc-
tions (n?384 non-fatal myocardial infarctions; HR, 1.17; 95%
CI, 0.95 to 1.44) or non-SCD atherosclerotic deaths (n?345
deaths; HR, 0.90; 95% CI, 0.71 to 1.13), suggesting that this
variant may play a role in SCD specifically rather than in
ischemic heart disease in general.
The possibility that genetic admixture could have resulted in
a spurious association among white participants was explored by
several methods. First, 4 polymorphic markers (apolipoprotein E
Haplotype Structure and Frequency in White and Black CHS
Participants and White CABS Control Subjects
B2AR Gene Polymorphism Allele Frequencies and
CHS, %CABS, %
Codon 16 polymorphism
Codon 27 polymorphism
*A single white CHS participant had an H4 Arg16-Glu27 haplotype, yielding
a haplotype frequency of 0.0001%.
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alleles 2, 3, and 4; angiotensin type 1 receptor C1166A SNP;
adducin Gly460Trp SNP; and G-protein ?-subunit C825T SNP)
were genotyped. Allele frequencies for all 4 markers differed
between CHS white and black subjects (P?0.001). Among
whites, there were no significant differences in the frequencies
of these markers by B2AR genotype and no association of these
markers with SCD risk (all P?0.15), suggesting that admixture
is less likely to account for our findings. Furthermore, adjusting
for each of these markers did not change the association of SCD
with B2AR variants. Second, the analysis was repeated, restrict-
ing the sample to each of the 4 clinic sites. The association in all
4 clinic sites was in the same direction (reaching statistical
significance in 2 of 4 sites) and did not significantly differ
between sites. Finally, we repeated these analyses in a second
white study population (see CABS results below).
The Gly16Arg variant was not associated with SCD risk
among white and black participants (P?0.66).
CHS: Haplotype Analysis
We next investigated whether the Gly16Arg and Gln27Glu
variants in combination identified those at increased SCD
risk. Because the Glu27 variant is found almost exclusively in
the H1 haplotype, analyses of the H1 haplotype yielded
results nearly identical to those obtained with the Glu27
variant. Participants who lack an H1 haplotype (Gln27
homozygous) had a higher SCD risk than H1 haplotype
(Glu27) carriers (ethnicity-adjusted HR, 1.56; 95% CI, 1.17
to 2.09; P?0.003). The H2 (P?0.66) and H3 (P?0.08)
haplotypes were not associated with SCD risk.
We further analyzed SCD risk among whites by diplotype.
Compared with the most common diplotype, H1H2, SCD risk
was not different in participants with either the H1H1 or H1H3
diplotype but was increased in participants without an H1 allele
SNP and haplotype analyses, which suggest that Gln27 homozy-
Baseline Characteristics of 4441 White and 808 Black CHS Participants by
White Participants Black Participants
Prior MI, %
Prior CHF, %
Current smoker, %
Heart rate, bpm
Carotid intima-media thickness, mm
MI indicates myocardial infarction; CHF, congestive heart failure; and BMI, body mass index. Numbers in
parentheses are SD. Within each ethnic group, there were no significant differences in baseline characteristics by
genotype (all P?0.05).
in Whites and Blacks According to Gln27Glu Genotype
Risk of SCD Among All CHS Participants (Adjusted for Ethnicity) and
Genotype Events/Total, n
Rate*Person-Years HR95% CIP
Ref indicates reference.
*Incidence rate per 1000 person-years.
†Glu27 carrier has either 1 or 2 copies of the Glu27 allele.
‡NS ? P?0.05.
Sotoodehnia et alB2AR Variants and SCD
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gous (H2H2, H2H3, H3H3) individuals are at higher risk than
Glu27 carriers (H1H1, H1H2, H1H3).
To validate these initial results, we replicated the study in a
population-based case-control study of SCD. Traditional risk
factors of hypertension and smoking status were more prev-
alent among the 155 cases than the 144 controls (Table 4).
Given the sampling, mean age and sex distribution were
similar in cases and controls. All subjects were white. Among
controls, Gly16Arg and Gln27Glu were in Hardy-Weinberg
equilibrium, and allele frequencies were similar to those
found among CHS whites (Table 1).
Similar to the findings in CHS, the odds of SCD were higher
in Gln27 homozygous CABS subjects (those without the H1
haplotype) than in Glu27 carriers (OR, 1.64; 95% CI, 1.02 to
2.63; P?0.040, adjusted for the sampling variables of age, sex,
and index year). This association remained after further adjust-
ment for cardiovascular risk factors of hypertension, diabetes,
and smoking status (adjusted OR, 1.83; 95% CI, 1.11 to 3.04).
(P?0.65) haplotypes were not associated with SCD risk.
The results of this study show that specific common B2AR
genetic variants are associated with increased risk of SCD. In
a prospective study (CHS), Gln27 homozygous participants
had a 58% higher SCD risk than participants with ?1 Glu27
alleles (ethnicity-adjusted HR, 1.56; 95% CI, 1.17 to 2.09).
This increased SCD risk did not differ significantly between
white (HR, 1.62; 95% CI, 1.18 to 2.23) and black (HR, 1.23;
95% CI, 0.61 to 2.48) participants, although the confidence
interval was wide in blacks. The study was replicated in a
separate population-based case-control study of cardiac arrest
in which Gln27 homozygous individuals had a 64% higher
risk of SCD among whites (OR, 1.64; 95% CI, 1.02 to 2.63).
We investigated this gene as a candidate risk factor for SCD
because of basic and clinical studies suggesting that B2AR may
play an important role in SCD. In ischemic dog models,
selectively blocking B2AR prevents ventricular fibrillation.6
Treatment with nonselective ?-blockers (that block both the ?1-
and ?2-adrenergic receptors) decreases SCD incidence in ran-
domized clinical trials23and may be associated with lower SCD
incidence than treatment with ?1-selective agents alone,24,25
underscoring the importance of B2AR in SCD. Our findings
provide support that the B2AR plays a role in SCD in humans.
The B2AR haplotypes are evolutionarily distant and function-
ally different. In transfected cell lines, these molecular haplo-
types defined by the amino-terminus SNPs lead to differential
agonist-promoted receptor downregulation.9A variant in the
leader cistron, Cys19Arg, found primarily in the H1 (Gly16-
Glu27) haplotype, alters receptor translation, hence affecting
B2AR protein expression.8Human beings with varying B2AR
alleles respond differently to administration of ?-adrenergic
In the heart, B2AR is located on the myocardium and
presynaptically on sympathetic nerve terminals.27Presynaptic
B2AR stimulation upregulates cardiac norepinephrine release.
Sympathetic activation and higher serum norepinephrine levels
are associated with SCD and ventricular fibrillation.2–4,27,28On
cardiac cells, B2AR activation modulates cardiac chronotropy,
inotropy, and ion channel function.6,29,30Higher heart rate, the
presence of heart failure, and abnormal ion channel function are
risk factors for SCD.31–33Variability in response to ?2-
adrenergic stimulation resulting from receptor allelic differences
may account for our findings.
B2AR also is located on a number of noncardiac tissues,
including vasculature, lung parenchyma, adipocytes, and plate-
lets; its effects on these tissues may influence SCD risk. For
instance, in adipocytes, catecholamine stimulation leads to
lipolysis and release of nonesterified fatty acids. Higher nones-
terified fatty acid levels are associated with ventricular ectopy
and SCD.34In a sibling study, Gln27 was associated with higher
nonesterified fatty acid levels, consistent with our finding that
Gln27 is associated with higher risk of SCD.35
The association of these common B2AR variants with other
SCD risk factors such as diabetes, hypertension, myocardial
Figure 2. Risk of SCD in CHS whites according to B2AR diplotype.
TABLE 4.Baseline Characteristics of CABS Study Participants
Current smoker, %†
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infarction, and heart failure has been examined in prior studies,
and consistent associations have not been found.35–38The pres-
ent study showed no association of B2AR variants with these
SCD risk factors at study entry.
Previously, we showed in CHS that Gln27 homozygous
participants had a higher risk of coronary events (combined
nonfatal and fatal myocardial infarction and coronary death)
compared with Glu27 carriers.39In the present study, we
hypothesized that B2AR variants would be associated with SCD
in particular and carefully classified all cardiac deaths in CHS
for the occurrence of SCD. Nineteen percent (n?133) of the
coronary event cases in our previous report had SCD and are
included in the present analysis of SCD. In this analysis, Gln27
is associated with increased risk of SCD but not with nonsudden
atherosclerotic death, suggesting that this variant may play a role
in fatal arrhythmia specifically rather than in ischemic heart
disease in general.
Several limitations to the interpretation of our findings de-
serve consideration. First, although both are population based,
the design of and populations in the 2 studies differ. CHS is a
cohort study of older adults with and without heart disease at
baseline. In contrast, CABS is a case-control study of younger
adults without clinically recognized heart disease. Because of
these eligibility restrictions in the CABS study, a large propor-
tion of SCD events in Seattle and King County were not
included. Nonetheless, the similar associations observed in the 2
studies suggest that the association of genetic variation in the
B2AR gene with SCD risk is present in different populations.
Second, these studies were performed in white and black adults.
The findings among whites may not be generalizable to other
ethnic groups. Moreover, because of low Glu27 allele frequency
and few SCD events, we had limited power to detect an
association in blacks. Additionally, population admixture is a
potential concern with genetic association studies. To minimize
this problem, the analyses were stratified by ethnicity. Further-
more, among whites, the 4 unrelated markers examined showed
similar allele frequencies by B2AR genotype, suggesting that
there was not unequal genetic admixture in the groups. How-
ever, fine population stratification that may result in a spurious
association cannot be excluded. Importantly, 2 different white
populations showed similar findings. Conditions that permit
major bias are unlikely to be repeated in a second population.40
Furthermore, although biological plausibility exists for the role
of the B2AR in SCD, it is possible that the association observed
reflects another susceptibility locus in linkage disequilibrium
with the Gln27Glu variant. Finally, the possibility remains that
the associations of B2AR variants and SCD risk identified in
these 2 study populations may be due to chance.
The strengths of this report lie in the rigorous methods used to
populations were used to replicate these findings. One of the
studies, CHS, was a large population-based cohort followed up
prospectively. Furthermore, we have examined a gene with
strong biological rationale and with functionally important
common variants. Because the disease association or functional
effect of a specific SNP may be dependent on its cis interactions
with other SNPs within the gene, we used haplotype analysis to
assess genotype-phenotype associations, in addition to focusing
on individual SNPs.
In summary, this is the first study to demonstrate an associ-
ation of a common functionally important genetic variant with
SCD in a large cohort followed up prospectively and to replicate
for 10% of all adult deaths.41It frequently presents as the first
and only manifestation of previously unrecognized ischemic
health challenge. The findings of this investigation suggest that
common genetic markers may help identify those at increased
risk of SCD in the general population and support the need for
further investigation of genomic variation in the B2AR gene.
Additionally, larger studies are needed to assess more fully the
potential interactions with modulators of the adrenergic nervous
system such as exercise, stress, and treatment with ?-blocking
medications. Ultimately, the goal of these studies is to improve
risk stratification and the identification of those who may benefit
from preventive measures.
This research was funded by grants from the National Heart, Lung, and
Blood Institute (K08-HL-074293, 5-R01-HL-041993-12, R21-
HL077706, contracts N01-HC-85079 through N01-HC-85086, N01-
HL-35129, and NO1-HL-15103), the National Institute of Aging (R01-
AG-15366), the Medic One Foundation (Seattle, Wash), the Sandra A.
Daugherty Foundation (Tampa, Fla), and the DW Reynolds Foundation
(Las Vegas, Nev). We appreciate the assistance of the paramedics of the
Seattle Medic One Program and Seattle-King County Health Depart-
ment Emergency Medical Services Divisions with this project.
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Sudden cardiac death (SCD) is a major public health concern, accounting for 450 000 deaths in the United States each year.
It frequently presents as the first and only manifestation of previously unrecognized ischemic heart disease. Identifying
those at increased risk remains a public health challenge. In 2 study populations, we show that individuals who are
homozygous for the Gln27 allele of the ?2-adrenergic receptor (B2AR) gene are at ?60% increased risk of SCD. The
findings of this investigation suggest that common genetic markers may help identify those at increased risk of SCD in the
general population and support the need for further investigation of genomic variation in the B2AR gene. Additionally,
larger studies are needed to more fully assess potential interactions with modulators of the adrenergic nervous system such
as exercise, stress, and treatment with ?-blocking medications. Ultimately, the goal of these studies is to improve risk
stratification and the identification of those who may benefit from preventive measures.
April 18, 2006
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Lumley, Lewis H. Kuller, Gregory L. Burke and Susan R. Heckbert
A. Towbin, Rozenn N. Lemaitre, Thomas D. Rea, J. Peter Durda, Joel M. Chang, Thomas S.
Nona Sotoodehnia, David S. Siscovick, Matteo Vatta, Bruce M. Psaty, Russell P. Tracy, Jeffrey
2-Adrenergic Receptor Genetic Variants and Risk of Sudden Cardiac Death
Print ISSN: 0009-7322. Online ISSN: 1524-4539
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