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(Hypertension. 2001;37:286.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Association Analysis of ß2-Adrenergic Receptor Polymorphisms With Hypertension in Japanese
From the Department of Internal Medicine, Teikyo (Japan) University School of Medicine (N.K., T. Sato); The Institute for Adult Diseases Asahi Life Foundation, Tokyo, Japan (T. Sugiyama); the Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo (Japan) (H.M., H.K); the Graduate School of Human and Environmental Studies, Kyoto (Japan) University (Y. Yamori); and The Hospital International Medical Center of Japan, Tokyo (Y. Yazaki).
Correspondence to Norihiro Kato, MD, PhD, Department of Internal Medicine, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan. E-mail nkato{at}med.teikyo-u ac.jp
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Abstract |
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Significant evidence has been provided for the pathophysiological involvement of the ß2-adrenergic receptor (ADRB2) in hypertension. Among ADRB2 polymorphisms identified to date, 2 amino acid substitutions, Arg16Gly and Gln27Glu, and a promoter variant, T-47C, are considered functionally important. In particular, Arg16Gly was shown to be associated with hypertension in black and white subjects. To investigate the relevance of ADRB2 polymorphisms to hypertension, we undertook an extensive association study in a Japanese population. An association was tested in 2 ways. First, a case-control study was conducted in 842 hypertensive and 633 normotensive subjects. In addition to the overall comparison between case and control groups, each was stratified by body mass index and compared with an independent panel of 525 diabetic subjects. Second, ANOVA and multivariate analyses were performed to test the significance of an association between ADRB2 genotype and the level of blood pressure within the entire population except for 395 subjects who had been under treatment for hypertension. Although no significant association was observed for Arg16Gly and T-47C, 2 analytical methods indicated a marginal association (P=0.01 to 0.04) between the Glu27 variant and lower blood pressure levels. Given such a normotensive propensity, the odds ratio for Glu27 versus Gln27 allele frequencies was estimated to be 0.74, with a wide confidence interval (95% CI, 0.55 to 0.99) reflecting the low Glu27-allele frequency (6% to 8%) in Japanese. There were no apparent confounding influences of obesity and diabetes on the postulated association. Our data suggest that 3 ADRB2 polymorphisms tested are unlikely to confer principal genetic susceptibility for hypertension in the Japanese population. However, further investigation is warranted to clarify the relevance of ADRB2 polymorphisms to blood pressure regulation.
Key Words: hypertension, essential • receptors, adrenergic • obesity • genetics
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Essential hypertension is considered to be a complex trait to which genetic, environmental, and demographic factors contribute interactively. Recently, studies of molecular genetics have achieved remarkable success in the elucidation of causative mutations in several mendelian hypertensive disorders in which single-nucleotide polymorphisms (SNPs) disrupt the function of single genes, thereby leading to unambiguous phenotypes.1 However, such a simple view may not be pertinent to a common type of hypertension, even if SNPs modify the relevant gene function to some extent. Although enormous efforts have been made to explore genetic susceptibility for essential hypertension, consistent results have rarely been found for particular candidate genes.2 One plausible explanation is that 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 relation between the genes and hypertension, depending on the populations studied. Accordingly, considerable care should be exercised when evaluating in one population the relevance of certain gene polymorphisms to hypertension that has been implied in another population.
Among candidate genes thus investigated to date, the
ß2-adrenergic receptor
(ADRB2) gene has drawn
substantial
attention.3 4 5 6 7 8 9
The sympathetic nervous system represents a major regulator of
blood pressure (BP) through alterations in sodium handling, vascular
resistance, and cardiac
output.10 In consideration
of physiological importance of the
ADRB2 gene, "functional"
molecular variations of the gene might cause attenuated vasodilatation,
leading to increased total peripheral resistance and hence
ultimately resulting in hypertension. In the promoter and coding
regions of ADRB2, a total of 17
SNPs have been reported,11
of which 2 amino-terminal polymorphisms were shown to impart
distinct agonist-mediated regulatory
properties.12 That is, an
Arg16
Gly substitution exaggerates agonist-mediated receptor
downregulation, whereas Gln27Glu reduces it. Moreover, a variant in
the promoter region (T-47C) was shown by an in vitro study to regulate
receptor expression at the translational
level.13 Interestingly, it
has been reported that the Gly16 variant is associated with the
presence of hypertension in African
Caribbeans,3 whereas the
alternate allele, Arg16, is associated with increased BP values in
the Bergen Blood Pressure
Study7 and the German twin
study.8 Also, a few studies
have provided suggestive evidence of linkage and association at (or
near) the ADRB2 locus in
black4 and white
subjects,5 6
whereas the lack of association has been recently reported in a black
African
population.9
Under these circumstances, further replications in different
populations, especially in a nonblack and nonwhite ethnic group, would
help to establish a causative relation between the
ADRB2 gene and hypertension.
Therefore, we undertook an extensive association study in a Japanese
population by using 3 aforementioned
ADRB2 polymorphisms. The
relevance of ADRB2
polymorphisms to hypertension was tested in 2 ways. First, a
case-control study was conducted in 842 hypertensive and 633
normotensive subjects, with the 
2
statistic used to test the significance of an association between
ADRB2 genotype and the
presence of hypertension. Second, ANOVA and
multivariate analyses were used to test the
significance of an association between
ADRB2 genotype and the
level of BP within an extended panel of 2088 individuals. Furthermore,
because some studies showed a significant association between the Glu27
variant and body mass index (BMI) and the presence of diabetes
mellitus,14 15 we
tested whether the postulated association between
ADRB2 genotype and
hypertension was influenced by these confounding
phenotypes.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Study Population
This study was approved by an institutional review committee. All participants were of Japanese origin and recruited at the Institute for Adult Diseases Asahi Life Foundation, Tokyo. Among those who gave informed consent for participation and provided blood samples for DNA analysis, a total of 1475 individuals were initially selected for a case-control study. Within the entire study population (n=2088), 554 individuals, who had not been selected because of BP criteria and/or the presence of diabetes mellitus, were additionally used to test the significance of an association between ADRB2 genotype and the level of BP. Hypertensive subjects were sequentially enrolled from outpatients on the basis of the classification criteria described below. Normotensive subjects were selected from (1) outpatients who had noncardiac symptoms and (2) hospital staff undergoing annual medical examinations, based on the BP criteria and the absence of diabetes mellitus. Two BP measurements were taken with a sphygmomanometer on separate visits and averaged for each subject.
Hypertension was defined according to the following
criteria: (1) systolic BP 
160 mm Hg,
diastolic BP 95 mm Hg, or both on 2 consecutive
visits for untreated subjects; (2) patients receiving long-term
antihypertensive treatments; (3) no secondary form of hypertension as
evaluated by extensive workup including serum creatinine
and electrolytes, chest radiography, ECG, urinalysis,
and other hematological screening tests; and (4) subjects with a
history of diabetes mellitus or kidney failure were excluded. Subjects
with a systolic BP <140 mm Hg and a
diastolic BP <90 mm Hg were assigned to the control
group. Because criteria for the classification of hypertension are only
arbitrarily definable, the evaluation of hypertensive patients selected
according to more stringent criteria would increase the chance of
detecting genetic susceptibility. Hence, the case group was subdivided
on the basis of the following criteria: subgroup 1, age of onset <60
years and BP readings clearly documented in hospital records
(systolic BP 160 mm Hg and/or diastolic BP
95 mm Hg) before establishing medication; subgroup 2, the
remaining hypertensive subjects. The control group was also subdivided
by the age of enrollment: subgroup 1, age 60 years; subgroup 2, age
>30 years and <60 years. Subgrouping within the case and control
groups was the result of a post hoc
analysis.
Genotyping of
ADRB2 Polymorphisms
The Arg16Gly polymorphism was genotyped
by the mutagenically separated polymerase chain reaction (PCR)
technique.16 To amplify 2
allelic PCR products with nearly equal intensity in heterozygous
individuals, we designed PCR primers such that the 2 allelic PCRs had a
3-bp difference, which was clearly resolved in a 6% denaturing
polyacrylamide gel. The following primer sets were used:
FP16Arg (21 mer),
5'-CCTTCTTGCTGGCACCCATTA-3'; FP16Gly (24 mer),
5'-GCGAGTTCTTGCTGGCACCCTATG-3';
RP-codon16 (25 mer), 5'-ACAGGCCAGTGAAGTGATGAAGTAG-3', in which
deliberate differences and base substitutions are underlined. PCR was
performed in PTC-100 (MJ Research Inc) in a 15-µL reaction volume
containing 200 nmol/L of RP-codon16, 160 nmol/L each of FP16Arg and
FP16Gly, 10 mmol/L Tris HCl (pH 8.3), 50 mmol/L KCl, 25
µmol/L each of dNTPs, 0.4U Ampli-Taq DNA Polymerase (Perkin Elmer),
and 1.5 mmol/L MgCl2. The initial
denaturation for 3 minutes at 95°C was followed by 35 cycles of
denaturation for 20 seconds at 94°C, annealing for 30 seconds at
60°C, and extension for 20 seconds at 72°C. PCR products were
electrophoresed in 6% polyacrylamide/7 mol/L urea gels on the
model S2 Sequencing apparatus (Life Technologies Inc) and
blotted onto nylon membranes (Pall Inc). The membranes were hybridized
in 7% polyethylene glycol/10% SDS at 42°C for 3 hours with the
RP-codon16 primer labeled with 32P-
dCTP
by terminal transferase (Boehringer Mannheim). After
hybridization, the membranes were rinsed in 2x SSC, 0.1% SDS, washed
in 2x SSC, 0.1% SDS at room temperature for 15 minutes, wrapped in
plastic, and exposed directly to film for 2 hours at
-80°C.
The Gln27Glu polymorphism was genotyped by using the PCR restriction fragment length polymorphism (RFLP) analysis. The designed primers were 5'-CGCTTACCTGCCAGACTGC-3' and 5'-GGCCAGTGAAGTGATGAAGTAGT-3'. PCR was performed in the same way as described for the Arg16Gly polymorphism except that 160 nmol/L each of the primers was used in a reaction. After the PCR amplification, the products were digested by Fnu4HI (New England Biolab) and clearly resolved in a 2% agarose gel (SeaKem agarose, FMC Bioproducts).
The T-47C polymorphism was also genotyped by RFLP analysis, as reported previously.13 The primers were 5'-GCTGAATGAG- GCTTCCAGGC-3' and 5'-CGCATGGCTTCTATTGGGTG-3'. PCR was performed in the presence of 10% dimethylsulfoxide, and the products were digested by MspA1I (Promega).
Genotype identity was confirmed by direct sequencing for 3 randomly selected individuals per genotype class.
Statistical Analysis
For hypertensive individuals, an initial value for BP
at the onset of hypertension was used in the association study.
Statistical analysis was performed in 2 ways. First, the
2 test statistic was calculated in the
case-control panel between the genotype distribution (or
allele frequencies) and hypertension status as defined above.
Further analysis was conducted between subgroups of cases and
control subjects to test the influences of disease severity, gender,
and age of control subjects on the postulated association. Second, BP
was considered a continuous variable, and association of the
ADRB2 polymorphisms with BP
was tested by ANOVA and multivariate analysis,
with all the individuals typed except for 395 individuals (336
hypertensive and 59 diabetic subjects) who had already received some
antihypertensive medication when initially referred to the institution.
Confounding influences of age, BMI, smoking status, and serum lipid
profile (total cholesterol, triglycerides, and
HDL-cholesterol levels) were assessed in a multiple
regression model. A backward elimination procedure was used to
determine important predictors of systolic BP and
diastolic BP, in which gender (male scored as 1, female as
0), smoking status (smoker scored as 1, nonsmoker as 0),
genotype of Arg16Gly (Arg/Arg scored as 0, Arg/Gly as 1,
Gly/Gly as 2), genotype of Gln27Glu (Gln/Gln scored as 1,
Gln/Glu+Glu/Glu as 0, considering the small number of subjects with
Glu/Glu), the presence of diabetes mellitus, age, BMI, and lipid
profile were regarded as independent variables. Here, the T-47C
polymorphism was genotyped only in the hypertension
case-control panel and was not used in either ANOVA or
multivariate analysis because we found it to be
in almost complete linkage disequilibrium with Gln27Glu and to be less
significantly associated with hypertension status than Gln27Glu.
Because a total of 3 polymorphisms were tested in the present
study, the nominal significance level was reduced to
P=0.05/3, that is, 0.017, with
the Bonferroni correction. Differences in clinical variables
between case and control groups were examined by ANOVA. Approximate
95% confidence intervals (CIs) of the odds ratio were calculated by
Woolf’s method.17 Values
are given as mean±SD unless otherwise
indicated.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Table 1 shows clinical characteristics in hypertensive (case) and normotensive (control) subjects and patients with impaired glucose tolerance or overt diabetes mellitus who were typed in addition to the case-control panel (see Methods). Aside from BP measurements, current age, and BMI, serum cholesterol and triglyceride levels were significantly higher in hypertensive than in normotensive subjects. When compared between the 2 study groups, serum total cholesterol levels (mmol/L) were 5.53±1.01 versus 5.30±0.94; likewise, triglyceride and HDL-cholesterol levels were 1.55±0.95 versus 1.28±1.07 and 1.44±0.39 versus 1.61±0.44, respectively. No significant differences were observed for smoking status, serum creatinine, and fasting plasma glucose levels between case and control groups. When confined to a hypertensive subgroup meeting stringent criteria, that is, subgroup 1, age differences were almost diminished.
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In the case-control analysis
(Table 2), there was no significant association between
either of the Arg16Gly and T-47C polymorphisms and hypertension
status, whereas there was a marginally significant association between
the Gln27Glu polymorphism and hypertension status. As for the T-47C
polymorphism, we found it to be in a close linkage disequilibrium
with Gln27Glu (a linkage-disequilibrium coefficient,
D’=0.97) when
genotyped in the hypertension case-control panel
(Table 2). Thus, we chose not to genotype T-47C in
the remaining subjects because it did not help clarify the indefinable
situation of the Gln27Glu polymorphism, as will be discussed later.
The Glu27 allele was more frequent in normotensive (7.8%) than in
hypertensive subjects (5.9%). Because only a small number of subjects
carried the Glu/Glu genotype in our population (5 subjects each
in case and control groups), the Gln/Glu and Glu/Glu genotypes
were analyzed together. The significance of an association
appeared borderline in the comparison of genotype distribution
(2=4.17,
df=1,
P=0.04) and allele
frequencies (2=4.12,
df=1,
P=0.04). Assuming a disposition
to protect the development of hypertension, the odds ratio for Glu27
versus Gln27 allele frequencies was 0.74 (95% CI, 0.55 to 0.99).
There was no apparent synergistic effect of 2 polymorphisms,
Arg16Gly and Gln27Glu, on hypertension status
(Table 3). However, a proper haplotype analysis was
difficult because of the presence of a significant linkage
disequilibrium (D’=0.1, which
is different from 0 at
P<10-5)
between these 2 polymorphisms and because of the small number of
individuals with the Glu27 allele in the Japanese population. As
for the Arg16Gly and Gln27Glu polymorphisms, to assess confounding
influences of obesity and diabetes on the postulated association
between ADRB2 genotype
and hypertension, the case-control study panel was subdivided according
to BMI (BMI =26.0 and BMI <26.0) and compared with an independent
panel comprising diabetic patients. Fasting plasma glucose levels in
this panel (7.24±2.63 mmol/L) were significantly higher than
those in hypertensive (5.14± 0.56 mmol/L) and normotensive
(5.06±0.56 mmol/L) groups of the case-control study panel. The
2 test statistic, however, showed no
significant interaction between these phenotypes and
hypertension
(Tables 2 and 4).
Three
cohorts used in the pairwise comparison (hypertensive, normotensive,
and diabetic groups) were in Hardy-Weinberg equilibrium for each
polymorphism.
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We additionally tested the significance of an association between ADRB2 genotype and the level of BP within the entire study population (n=2088), from which 395 individuals who had already received some antihypertensive medication when initially referred to the institution were excluded. The multivariate analyses revealed that genotype of Gln27Glu, the presence of diabetes mellitus, current age, BMI, and total cholesterol levels were predictors of both systolic and diastolic BP, whereas gender was a predictor of systolic BP alone at the level of P=0.05. An association between Gln27Glu and the level of BP was, again, marginally significant, as observed in the case-control comparison (Table 5). According to the estimation of R2, the Gln27Glu polymorphism could account for at most 0.29% and 0.28% of variances in systolic and diastolic BP, respectively.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This study investigated 3 SNPs of ADRB2 as candidate molecular variants predisposing to essential hypertension. In the Japanese population, we were not able to reproduce an association of the Arg16Gly polymorphism with either hypertension status or elevated BP measurements, as previously reported.3 7 8 On the other hand, we found a marginal association between the Glu27 variant and decreased BP measurements, which appears in accordance with the in vitro observation that a Gln27
Glu substitution reduces
agonist-mediated downregulation of the
ß2-adrenergic receptor, leading to depressed
receptor degradation during agonist exposure and presumably resulting
in sustained
vasodilatation.10 12
Such speculation is tempting, but we should be careful in the
interpretation of our data.
It appears to be notable that 2 analytical methods showed a
marginally significant association between the Glu27 variant and
normotension (or low values for BP). That is, on the basis of
dichotomous classification, the Glu27-allele frequency was higher
in normotensive subjects than in hypertensive subjects. When BP was
considered as a continuous variable, subjects carrying the Glu27
variant (Gln/Glu plus Glu/Glu genotype) had lower BP values
than those without Glu27 (Gln/Gln genotype). Several issues
must be discussed concerning this marginal association. First, the
statistical significance level is critical in the marker-disease
association study. Although some people believe that significance
levels much lower than P=0.05
are appropriate in candidate gene approaches to reduce the risk of
false-positive claims, an initial threshold may as well be not so
stringent to pick up genes with modest effects. In this context, we
adopted an arbitrary criterion of
P=0.05/3 because of 3
polymorphisms tested, but further adjustment for multiple testing
would be necessary because 2 types of analysis were attempted;
for example,
P=0.05/(3x2)
0.008.
(Although T-47C was not actually used for the quantitative association
analysis in our study, the a priori hypothesis could have
led to 6 types of analysis.) Strictly, because part of subjects
in the case-control study (n=1139) constituted an extended panel used
in the quantitative association study (n=1693), results produced by
both analytical methods could not be independent of each other.
Probability values of 0.007 and 0.013, which were attained by the
multivariate analyses for systolic and
diastolic BPs, respectively, are thus regarded as
borderline. Statistical power should be also taken into consideration.
According to our calculation, a relative risk of >1.30 (for Arg16Gly),
<0.57 (for Gln27Glu), and <0.60 (for T-47C) could have been detected
in the available sample of 842 cases and 633 control subjects, with
80% power at a 5% type I error probability. However, if the estimated
odds ratio for Glu27 (0.74) is indicative of the overall relative risk
in the target population, our case-control study has only a 30% chance
of finding that the sample estimate will be significantly
(P=0.05) different from unity,
as the result of the low Glu27-allele frequency in the Japanese
(6% to 8%). In addition, the number of subjects with homozygous
Glu/Glu genotype was not large enough for us to evaluate the
mode of inheritance in the studied population. Furthermore, among
diabetic patients, the Glu27-allele frequency was not increased in
normotensive subjects compared with hypertensive subjects. Considering
this, we cannot but set a limited potential value on the Glu27 variant
in the Japanese.
The absence of an observed association between the Gly16 variant and hypertension in the Japanese also requires careful interpretation. One frequently proposed but as-yet unproved hypothesis is the existence of ethnic differences among populations studied in hypertension genetics, in which at least 2 distinct possibilities are postulated. First, differences in population frequencies of a given gene variant may produce inconsistent claims for an association, mainly because statistical power is affected by population frequencies of the variant.18 In the case of the Gly16 variant, population frequencies were reported to fall within a relatively narrow range (41.3% to 54.3%) among black, white, and Asian subjects19 and unlikely to explain the discrepancy between the Japanese and black populations. Second, a given susceptibility gene may exert detectable BP-regulating effects in one ethnic group but not in another. In other words, some "intermediate" phenotypes representing the relevant gene function would differ between ethnic groups in question. This could be the case with a gene (or genes) underlying the pathophysiology of attenuated vasodilator responses to ß-agonists, which are known to be prominent in blacks.20 These arguments will lead to the necessity of comprehensive genetic approaches to differentiate "net" contribution of individual susceptibility genes from statistical noise such as selection bias.
One particular problem in investigating several candidate variants of the same gene is the occasional presence of a strong linkage disequilibrium. In the studied population, a significant degree of linkage disequilibrium was found among the 3 ADRB2 polymorphisms, especially between Gln27Glu and T-47C. Accordingly, it is possible that the borderline association between the Glu27 variant and normotension would rather result from the -47C variant, should it exist. Nevertheless, the low frequencies of both uncommon alleles in the Japanese population preclude a proper haplotype analysis and require extremely large trial size to determine which variant would exert primary effects on the postulated association.
In summary, we examined 3 SNPs of ADRB2 in an extensive association study; 2 SNPs not only involve amino acid substitutions but also alter in vitro expression levels of mRNA and the other SNP regulates receptor expression at the translational level. Although this type of strategy is theoretically practicable in finding mutations responsible for complex traits such as hypertension,21 compelling results have rarely been attained so far. In fact, even for 2 well-known candidate genes, angiotensin I–converting enzyme and angiotensinogen, consistent results have not always been observed among studies.22 23 Supposing that the uncertain picture of the molecular genetics of essential hypertension is attributed to uncontrollable factors (or factors difficult to sufficiently control) to a substantial extent, it is intricate to make definitive claims regarding a particular SNP on the basis of the results of a single study. Further investigation in a variety of ethnic groups is certainly warranted to clarify the relevance of ADRB2 polymorphisms to BP regulation.
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Acknowledgments |
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This work was supported in part by a research grant from the Uehara Memorial Foundation.
Received June 16, 2000; first decision June 29, 2000; accepted August 5, 2000.
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M. Tomaszewski, N. J.R. Brain, F. J. Charchar, W. Y.S. Wang, B. Lacka, S. Padmanabahn, J. S. Clark, N. H. Anderson, H. V. Edwards, E. Zukowska-Szczechowska, et al. Essential Hypertension and {beta}2-Adrenergic Receptor Gene: Linkage and Association Analysis Hypertension, September 1, 2002; 40(3): 286 - 291. [Abstract] [Full Text] [PDF]
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