Published online before print July 18, 2005, doi: 10.1161/01.HYP.0000175842.19266.95
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(Hypertension. 2005;46:301.)
© 2005 American Heart Association, Inc.
Original Articles |
Interactive Effects of Common ß2-Adrenoceptor Haplotypes and Age on Susceptibility to Hypertension and Receptor Function
From the Departments of Medicine (X.B., F.R., M.M., D.O., M.G.Z.) and Psychiatry (P.J.M., B.K.R., J.E.D., N.J.S.), and the Division of Biologic Science (D.W.S.), University of California, San Diego.
Correspondence to Michael G. Ziegler, MD, Department of Medicine UCSD Medical Center, 200 W Arbor Dr, San Diego, CA 92103-8341. E-mail mziegler{at}ucsd.edu
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Abstract |
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Few studies have examined to what extent genetic variants of the ß2-adrenoceptor (ADRB2) are involved in the development of hypertension with age, although ß2-adrenergic receptor responsiveness declines in older subjects. To investigate this, 10 common single-nucleotide polymorphisms (SNPs) in the promoter and coding regions of the ADRB2 gene were genotyped in an unrelated population consisting of 2 ethnic groups: European American (EA; n=610) and African American (AA; n=420). ADRB2 haplotypes were estimated by expectation maximization (EM) algorithm–based methods. In the general population for EAs and AAs, the variants of the ADRB2 gene, including the individual SNPs and their haplotypes, were not associated with hypertension. However, there was a significant interaction between age and one of the common haplotypes (haplotype 1) in EAs (P=0.01). Haplotype 1 was associated with protection against hypertension in young (
50 years of age) but not in old (>50 years of age) EAs (odds ratio, 0.5; 95% confidence interval, 0.27 to 0.91; P=0.02). This age-specific effect was further supported by the observations that young subjects carrying 
1 copy of haplotype 1 had significantly lower diastolic blood pressure and nearly 2-fold higher ADRB2 binding density than the noncarriers (P<0.05). With aging, their ADRB2 numbers decreased to the level of the noncarriers, along with increased body mass index (7%; P<0.05) and decreased heart rate (7%; P<0.001). Our study suggests that age is an important modifier for the effects of ADRB2 polymorphisms on ADRB2 function and the development of hypertension.
Key Words: receptors, adrenergic beta • polymorphism • age • genetics
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Introduction |
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Genetic linkage and gene association studies have implicated several loci and genes in the predisposition to hypertension.1–3 The G-protein–coupled ß2-adrenoceptor (ADRB2) gene at chromosome 5q31/32 is one of these candidate genes.4 In the peripheral vasculature, ADRB2 agonists promote a rise in intracellular cAMP concentration, which, through smooth muscle relaxation, leads to vasodilation. Blunted ADRB2-mediated vasodilation has been implicated in the pathogenesis of hypertension.5,6 To date, 20 single-nucleotide polymorphisms (SNPs) have been identified in the promoter and coding regions of the ADRB2 gene.7,8 Because of the evidence of functional relevance,9 2 common nonsynonymous polymorphisms A46G (or Arg16Gly) and C79G (or Gln27Glu) have been examined extensively for their association with hypertension over the last decade.10–16 However, the reports are largely contradictory, with results of increased, decreased, or no risk of hypertension for the same ADRB2 polymorphism. Although ethnic divergence of gene polymorphisms could account for some of the inconsistent associations,17 the conflicting results may also reflect the problems inherent in studies using isolated SNPs in a gene in which multiple SNPs exhibit linkage disequilibrium (LD) with each other.7
One way to overcome the limitations of previous association studies is to look for susceptible haplotypes of the ADRB2 gene for hypertension rather than focusing on the Arg16Gly or Gln27Glu solely. Recently, the complex promoter and coding region haplotype structures of the human ADRB2 gene and the deep divergence in the distribution of some common haplotypes among different populations have been demonstrated.7 Haplotype-based analysis could be a more powerful approach to dissect the genetic architecture of complex diseases.18 The human genome is comprised of haplotype blocks, which are chromosomal segments that are preserved intact over many generations, interspersed by recombination hotspots.19 Alleles within such ancestrally preserved haplotype blocks tend to be in strong LD with one another. Relatively few haplotypes may account for the majority of diversity,20 and variations in haplotypes may be powerful predictors of diseases.
On the other hand, hypertension is a complex disorder resulting from the combined effects of genetic, environmental, and demographic factors.21 Because individual genes play a modest role in the pathogenesis of hypertension, confounding influences of nongenetic factors may decrease (or increase) the chance of identifying a causative relationship between the genes and hypertension, depending on the population studied. It has been well established that human ADRB2 responsiveness declines with age.22 Thus, an age-related decline in human ADRB2 responsiveness may obscure the influence of ADRB2 polymorphisms on the development of hypertension in elderly people. Although it has been noted that genetic variants in the ADRB2 gene correlate better with blood pressure regulation in younger subjects,23–25 most studies have paid little attention to the potential interaction of age and ADRB2 polymorphisms in the development of hypertension.
High-throughput genotyping allows the efficient investigation of the role of many genetic polymorphisms in a large study.26 Furthermore, the development of methods to estimate haplotype frequencies from unrelated cases and controls now allows the study of the combined effects of a number of polymorphisms that are in LD with one another.27,28 In this study, 10 common SNPs in the promoter and coding regions of the ADRB2 gene were genotyped, and their haplotypes were estimated in a large unrelated population consisting of 2 ethnic groups: European Americans (EAs) and African Americans (AAs). To determine the relevance of genetic variants in the ADRB2 gene to essential hypertension, we undertook extensive association and function studies. First, to elucidate the relationship between ADRB2 polymorphisms, age, and hypertension, we examined the role of age in the association of common ADRB2 haplotypes with hypertension in a case-control study (380 hypertensives and 650 normotensives) consisting of the aforementioned 2 ethnic groups. Second, to define the physiological basis of the potential association between ADRB2 haplotype and hypertension, we also directly examined the effect of ADRB2 haplotype and age on ex vivo and in vivo function of the ß2-adrenergic receptor.
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Subjects |
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A cohort of 1031 hypertensive and normotensive subjects (610 EAs and 420 AAs; mean age 48, ranging from 18 to 89 years) were recruited for this study by advertisement and referral from a general population in the San Diego area. Subjects had a history and physical examination along with chemical, hematologic, and urine studies to exclude secondary causes of hypertension. The diagnosis of hypertension was based on a previous diagnosis of hypertension by a physician and use of prescription antihypertensive medication, or having a systolic blood pressure (SBP)
140 mm Hg or diastolic blood pressure (DBP) 90 mm Hg measured 3x on 2 occasions after they had been seated resting for 5 minutes. Patients with diabetes mellitus or renal diseases were excluded. Hypertensive subjects taking medication were slowly tapered off medications under supervision and were drug-free for 2 weeks before ex vivo ß2-adrenergic receptor function measurements. Normotensive subjects were apparently healthy on the basis of their clinical history and laboratory tests and all had blood pressure <140/90 mm Hg. Ethnicity was classified as described previously.24 The study protocol was approved by the human subjects committee of the University of California, San Diego, and informed consent was obtained from each subject.
Genomic DNA Preparation and Genotyping
Genomic DNA was extracted from a whole blood sample (
1 mL) with PURE GENE DNA purification kit (Gentra Systems, Inc.). DNA samples were then genotyped by using a high-throughput MassArray technique (Sequenom). All polymerase chain reaction and MassEXTEND reactions were conducted by using standard conditions, and both alleles were analyzed to calculate allele frequencies as described previously.26
Of the 13 SNPs used previously for ADRB2 haplotype analysis,7 1 (T-20C) was found in absolute LD with C79G (or Gln27Glu),7,16 and 2 (C-709A and C491T) were rare in all ethnic groups. To be more economic while not losing much genetic information, the other 10 common SNPs at promoter and coding regions of the ADRB2 gene were genotyped and analyzed in this study (see Table 2).
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Lymphocyte ADRB2 Assay
Lymphocyte ADRB2 parameters were measured as described previously.29 In brief, density receptor (Bmax) and receptor binding affinity (Kd) were determined in lymphocyte membranes by ligand binding with [125I]iodopindolol at 6 concentrations from 10 to 320 pmol/L for 1 hour at 37°C. The basal level of cAMP and the maximal cAMP response (Emax) to stimulation with isoproterenol (10 µmol/L for 2 minutes) were measured using a radioimmunoassay technique.
Statistics
Statistical analysis was performed in 2 ethnic groups separately using SAS 6.1. Hardy–Weinberg equilibrium for the genotype distribution of every SNP was tested in controls by 
2 test with 1 df. A pairwise LD coefficient was estimated in controls and reported as r2. High values of LD were defined as r2 more than one third, as suggested by Ardlie et al.30 The allele frequencies and genotype distribution of the 10 SNPs were assessed between the hypertensive and normotensive subjects by 2 test. The associations of the ADRB2 genotype with blood pressure and body mass index (BMI) were tested in normotensive controls by ANOVA. Potential associations between the set of haplotypes and hypertension were examined by using a likelihood ratio test with permutation-based hypothesis testing procedures, as described by Fallin et al.28 To compare the consistency, haplotype frequencies and diplotype distribution were estimated using 2 other expectation maximization (EM) algorithm–based software programs: Arlequin27 and SNPAlyze 3.0. Maximum likelihood estimates of odds ratios and their 95% confidence intervals were obtained, and the significance was assessed using logistic regression to adjust for the effects of age and sex. Student’s t test was performed to compare the lymphocyte ADRB2 activity. Data are expressed as mean±SE, and a P value of <0.05 on a 2-sided test is considered statistically significant.
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Results |
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Characteristics of the 1030 participants are included in Table 1. In EA and AA groups, the hypertensive subjects were more likely to be male, older, and heavier compared with the normotensives (P<0.01 for all).
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As shown in Table 2, all 10 alleles are common (>15%) except for C-406T in EAs (<1%). Judged by 2 test, none of these SNPs showed significant associations with hypertension in EA or AA groups in the comparison of allele frequencies (df=1; Table 2) and genotype distribution under an additive genetic model (df=2; data not shown).
Among normotensive controls, subjects heterozygous for C/T at C-406T had a significantly higher BMI than those with homozygous C/C or T/T among EAs (48±4.6 kg/m2 for C/T versus 28±0.3 kg/m2 for C/C or 28±2.1 kg/m2 for T/T; P=0.001) and AAs (38±5.5 kg/m2 for C/T versus 28±0.3 kg/m2 for C/C or 29±0.8 kg/m2 for T/T; P=0.003). There were no other ADRB2 polymorphisms associated with BMI. None of these polymorphisms were related to SBP or DBP (data not shown).
All alleles were found to be in concordance with Hardy–Weinberg equilibrium except for C-406T in EA and AA controls (P<0.001), with an excess of homozygosity (-406TT). The estimated LD value, as measured by r2 (or 
), suggested that except for C-406T, which was not associated with any other alleles studied, the other 9 alleles were in strong LD with 1 allele in EAs (Table 3, upper diagonal entries), and AAs (Table 3, lower diagonal entries), although some pairs of close sites had reduced levels of LD relative to more distantly spaced pairs of sites. Overall, many of these allelic associations were stronger in EAs than in AAs.
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Of the 210 (1024) possible combinations of the above 10 SNPs, 47 haplotypes were found in our study population by using a maximum likelihood method. The overall distribution of these haplotypes was significantly different between EAs and AAs (P<0.001). Of these total haplotypes, 11 were unique in EAs, and 20 were only observed in AAs, and these race-specific haplotypes were very rare (overall frequency <2% for all). Of the 13 common haplotypes (found in both ethnic groups), the 6 most common haplotypes (frequency >2% in any ethnic group) and their distribution in hypertensive and normotensive subjects within 2 ethnic groups are shown in Table 4. These 6 common haplotypes accounted for 95% of all haplotypes in the EAs and 90% in AAs, respectively. Haplotype frequencies estimated using Arlequin and SNPAlyze were consistent with the frequencies we obtained and presented in Table 4. Judged from the likelihood ratio test, none of these 6 haplotypes were associated with hypertension (Table 4), and the set of haplotypes was not associated with hypertension in EAs (2=42.16; df=22; P=0.23) and AAs (2=38.11; df=32; P=0.53).
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To determine whether there is any evidence for population stratification, logistic regression analyses of each common haplotype for the risk of hypertension were further conducted to explore the potential interactions between the studied haplotype and the other nonlifestyle risk factors such as age and gender. Only 1 significant interaction between age and haplotype 1 was found in the EA group (ß=–2.193; 
=0.038; P=0.01). As demonstrated in the Figure, the overall trend of odds ratios for the development of hypertension in subjects carrying 1 copy of haplotype 1 was increased with age. However, when age was 50 years, the odds of the risk were <1, suggesting a reduced risk in the young group. There was no evidence for any interaction in the AA group.
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x(age).
To further illustrate the effect of this interaction on the association of haplotype 1 with hypertension, we divided the EAs into 2 groups by age, and their characteristics by haplotype 1 are shown in Table 5. In the 50 age group, only DBP was significantly lower in haplotype 1 carriers than in noncarriers (P=0.02). With aging, haplotype 1 carriers’ DBP and BMI increased significantly (P<0.05), but their heart rate decreased dramatically (P<0.001). Although SBP significantly increased with aging for carriers and noncarriers, SBP and its change with age were not associated with ADRB2 haplotype 1.
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Furthermore, in the 50 age group, the risk of hypertension was reduced by half for those with 1 copy of haplotype 1 (P=0.02) after adjusting for age and sex, but there was no association between haplotype 1 and hypertension in the older group (>50 years of age; Table 6). A set of ADRB2 haplotypes was borderline-associated with hypertension in younger EAs (2=34.55; df=17; P=0.08 based on 1000 permutations).
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To further investigate the effect of haplotype 1 on ADRB2 function, measurements of lymphocyte ADRB2 were made for Bmax, Kd, basal cAMP, and maximal cAMP response to isoproterenol (Emax) in EAs, and the results were summarized in Table 7. Receptor binding density was increased by nearly 2-fold in young subjects carrying 1 copy of haplotype 1 (50 years of age) but did not differ in old subjects between carriers and noncarriers for haplotype 1. Older subjects who carried haplotype 1 had only half the receptor binding density of the young carriers. Other lymphocyte ADRB2 parameters showed no differences between carriers and noncarriers within or between the 2 age groups.
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Discussion |
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We investigated 10 known SNPs of the ADRB2 gene, especially their common haplotypes, as candidate genetic variants predisposing to hypertension. Our study revealed that in a general population for EAs and AAs, the variants in the ADRB2 gene including individual SNPs and their chromosomally phased SNPs (haplotypes) were not associated with development of hypertension. However, there was a significant interaction between age and one of the common ADRB2 haplotypes (haplotype 1) in EAs, and this haplotype was significantly associated with a protective effect on hypertension development in young subjects (
50 years of age) but not in old subjects (>50 years of age). This distinct age-specific effect was further supported by the observations that young subjects carrying haplotype 1 had significant lower DBP and higher lymphocyte ADRB2-binding density than the noncarriers. With aging, their ADRB2 density was reduced significantly to the level equivalent to that for the noncarriers, along with increased BMI and decreased heart rate. Our findings suggest that age is an important modifier for the effect of ADRB2 polymorphisms on ADRB2 function and the development of hypertension. To our knowledge, this is the first such multiallele-haplotype (n=10) association study on the ADRB2 gene variants and hypertension. The structures and frequencies of the ADRB2 haplotypes in our study, particularly the 6 common haplotypes, were consistent with those delineated by Drysdale et al using a laboratory-based molecular method.7 Similar to that previous study, we also found a deep divergence in the distribution of these haplotypes between EAs and AAs, with more diversified haplotypes in AAs. In addition, the pair estimates of LD of the 10 SNPs studied in our EA population, as measured by r2, were also consistent with the previous study.7 The overall weaker LD in AAs compared with EAs reflects the more diversified ADRB2 haplotypes observed in this population. Because a large fraction of these haplotypes were rare, on the basis of the theory of "common disease, common variants," we restricted our examination to the common haplotypes (>5%; ie, n=3 in EAs, and n=5 in AAs).
Whether aging leads to downregulation of ADRB2 density has been controversial. A parallel line of research on rat heart suggests the number of ADRB2s decreases with age.31,32 However, ADRB2 density has not changed with age in a number of studies on human tissues including heart and lung.33–35 Our results show that age selectively modulates the density of lymphocyte ADRB2 because only haplotype 1 carriers had a significant (48%) age-associated decline in ADRB2 density. When these same data were examined without considering the ADRB2 haplotype (ie, grouping only according to age), there was no age difference in ADRB2 density. Therefore, it may be that the previous inconsistent finding on human tissues resulted from not attending to the interaction of age and ADRB2 polymorphisms. Although a 48% decrease in ADRB2 number may not be functionally significant in lymphocytes, because there was no proportional decrease in adenylyl cyclase activities found in our study (Table 7), such a decrease in ADRB2s is considered highly significant in physiologically relevant cell types.36 The above age-associated decline in ADRB2 density is consistent with the in vivo findings, in which older individuals carrying haplotype 1 had a significant increase (7%) in BMI and decrease (7%) in heart rate (Table 5), perhaps because of reduced metabolic and cardiac responses to decreased ADRB2 number.
To date, the mechanisms by which age interacts with multiple alleles in the ADRB2 haplotype 1 and ultimately affects the expression of ADRB2 are not clear. However, recent in vitro studies on the effect of the ADRB2 haplotypes on the ADRB2 transcript and protein expression provide some molecular clue for the association of haplotype 1 with increased lymphocyte ADRB2 density in younger subjects found in our study. Comparisons of the sequence of haplotype 1 and haplotype 2, the second common haplotype in EAs, reveal 7 differences in the 10 SNP positions. As discussed previously,7 these 7 SNPs may alter ADRB2 receptor expression by changing amino acids or by regulating transcriptional activity. When the constructs of these 2 haplotypes were transfected into a human embryonic kidney cell line, the expressions of ADRB2 mRNA and protein were 50% higher with haplotype 1 than haplotype 2.7 These in vitro data are consistent with our ex vivo findings, in which young individuals with haplotype 1 had nearly doubled ADRB2 density on the lymphocyte membrane compared with those without haplotype 1. We also found an inverse relationship between ADRB2 density and DBP in the same subjects, which is supportive of the notion of ADRB2 regulation of vasodilation. Furthermore, the 2-fold increase in ADRB2 density correlates well with the 50% decrease in the risk of hypertension in young EAs. This may indicate that the increase in ADRB2 number associated with haplotype 1 contributes to the protective effect of ADRB2 gene on the development of hypertension.
Unlike other common ADRB2 haplotypes, haplotype 1 occurs at markedly different frequencies in diverse populations (ranging from 6% to 48%).7 The greatest frequency contrast is between EAs and AAs. Attenuated ADRB2-mediated vasodilation and the prevalence of hypertension are more prominent in AAs than in EAs.37 Because haplotype 1 is less frequent in AAs than in EAs, this may provide a potential explanation for this racial difference in vasodilation and hypertension prevalence, as suggested by others.6,13,14 In the present study, we were not able to find the same association of ADRB2 haplotypes with hypertension in AAs as observed in EAs. However, this requires careful interpretation. First, statistical power is affected by population frequencies of the genetic variants.38 With less frequent haplotype 1 subjects and a relatively small sample size in our AA cohort, our study may not have enough power to detect an association, if there are any. Second, the racial difference in vasodilator response to ß-agonists could be attributable to a difference in ADRB2 activity29 or events distal to the receptor itself, such as adenylyl cyclases,39 which catalyze the synthesis of cAMP. The blunted vasodilator response to ß-agonists in AAs, if not the result of genetic variants of the ADRB2 gene, could potentially obscure the influence of ADRB2 polymorphisms on blood pressure regulation.
Perspectives
Our study revealed the interactive effects of age and ADRB2 haplotype 1 on ß2-adrenergic receptor binding density and hypertension. These results provide substantial evidence for future study to take into account age-related change in ß2-adrenergic receptor function when analyzing phenotypic effects of the ADRB2 genetic variants. In addition, our study demonstrated the utility of using a number of polymorphisms in LD to assess the association between specific haplotypes and essential hypertension in a study of unrelated individuals. Our LD analysis suggests there is >1 haplotype block within these 10 SNPs of the ADRB2 gene. Further identification of haplotype tags to discover which SNPs are primarily responsible for the interaction with age as well as the expressed phenotype is necessary to minimize genotyping effort and also relevant to the eventual clinical applications such as pharmacogenetics.
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Acknowledgments |
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This study was supported by National Institutes of Health (NIH) K23 award to X.B. (5K23RR17639-2), NIH grant HL36005 to J.E.D., NIH grant HL69758 to D.T.O., and by National Center for Research Resources grant M01RR00827. We thank Jiaxing Ding for handling the computer database and Alex Joyner for haplotype analysis.
Received April 18, 2005; first decision May 2, 2005; accepted June 21, 2005.
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