(Circulation. 2000;101:2877.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Positional Genomic Analysis Identifies the ß2-Adrenergic Receptor Gene as a Susceptibility Locus for Human Hypertension
From the Institute of Molecular Medicine (M.S.B., J.K., L.L., E.B.) and Human Genetics Center (M.S.B., E.B.), The University of Texas–Houston Health Science Center, Houston, Tex; the Department of Human Genetics (R.F.), Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pa; the Departments of Epidemiology (S.K.) and Human Genetics (C.F.S.), University of Michigan, Ann Arbor, Mich; and the Division of Hypertension and Department of Internal Medicine (S.T.T.), Mayo Clinic, Rochester, Minn.
Correspondence to Eric Boerwinkle, PhD, Human Genetics Center, The University of Texas–Houston Health Science Center, PO Box 20334, Houston, TX 77225. E-mail eboerwin{at}gsbs.gs.uth.tmc.edu
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background—After genome-wide linkage analyses of blood pressure levels, we resequenced 5 positional candidate genes in a linkage region on chromosome 5 and genotyped selected variants in several family samples from Rochester, Minn.
Methods and Results—In a sample of 55 pedigrees containing 
1
sibling-pair(s) discordant for systolic blood pressure,
polymorphisms within the ß2-adrenergic receptor
gene (Arg16Gly, P=0.009) and the glutathione
peroxidase 3 gene (-302G
A, P=0.037; -623AC,
P=0.013) were significantly related to blood pressure
levels. In a second sample of 298 nuclear families (n=1283
individuals), the Arg16Gly polymorphism was significantly
associated with diastolic blood pressure in family-based
analyses (P=0.016) and with both
diastolic (P=0.009) and mean
arterial blood pressure (P=0.038) in
analyses of the parental generation only. Neither
polymorphism in the glutathione peroxidase 3 gene was associated
with blood pressure levels in this sample. An additional 291 families
(n=1240 individuals) were added to the nuclear family sample, and the
Gln27Glu polymorphism in the ß2-adrenergic receptor
gene was significantly associated with both systolic
(P=0.034) and mean arterial blood pressure
(P=0.035) in the parental generation of the combined 589
families. The frequencies of both the Gly16 and Glu27 alleles were
higher in hypertensives than in normotensives (0.649 versus 0.604 and
0.490 versus 0.429, respectively), and the odds ratio for the
occurrence of hypertension was 1.80 (95% confidence interval, 1.08 to
3.00; P=0.023) for the Glu27 allele.
Conclusions—The results of this study provide support for further detailed investigations of the mechanistic pathways by which variations in the ß2-adrenergic receptor gene may influence blood pressure levels.
Key Words: linkage (genetics) • genetics • polymorphism (genetics) • blood pressure
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Hypertension, or persistently elevated blood pressure, is a major risk factor for coronary artery disease, stroke, and renal disease.1 High blood pressure exacerbates atherogenesis,2 3 and sustained hypertension increases the long-term risk for myocardial infarction to levels comparable to those associated with smoking and elevated serum cholesterol.4 Although multiple studies have documented that genetic factors influence interindividual variation in blood pressure levels,5 6 the identity of the contributing genes remains largely unknown. In an effort to localize blood pressure–influencing genes, Krushkal et al7 8 recently performed a genome-wide linkage analysis of systolic blood pressure (SBP) levels in a sample of highly discordant Caucasian siblings from Rochester, Minn. Results from this study identified the long arm of human chromosome 5 (5q33.3 to 34) as a region putatively containing a gene or genes influencing blood pressure levels in this population.
We report the results of further investigations designed to identify candidate genes in this linked region, to catalogue DNA sequence variation in these positional candidate genes, and to establish the association of this genetic variation with blood pressure levels and hypertension. These analyses have identified polymorphisms in the ß2-adrenergic receptor gene (ADRB2) as significantly contributing to interindividual variations in blood pressure and the diagnosis of hypertension in this population.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Subjects
All subjects in this study were participants in the Rochester Family Heart Study (RFHS), an investigation that was begun in 1984 to determine the genetics of cardiovascular disease and hypertension.9 10 Briefly, non-Hispanic white families participating in the RFHS were selected without regard to health status on the basis of having
2 children enrolled in the public or parochial
schools in Rochester, Minn. In 1984, 298 three-generation pedigrees
were ascertained and examined; subsequently, an additional 291
three-generation pedigrees were examined in 1989. All subjects gave
written, informed consent before participation.9 From
these 2 large data sets, 55 families containing 1 sibling-pair(s)
discordant for SBP (ie, one sibling in the upper 20th percentile and
1 sibling in the lower 20th percentile of the SBP distribution) were
selected for linkage analysis of genes influencing blood
pressure. Results of the linkage analyses and details of the
discordant siblings were reported by Krushkal et al.7
Subsequent to the linkage analyses, 5 candidate genes within
the chromosome 5 linkage region were selected for resequencing. DNA
samples from 7 sibling-pairs discordant for SBP and sharing no
alleles identical by descent in the chromosome 5 linkage region
were used for the resequencing of these genes.
The initial analyses of DNA sequence variation within the
positional candidate genes and blood pressure levels were first
conducted using the families described by Krushkal et
al7 8 as containing 1 sibling-pair discordant for SBP
level. This was done to test the association in the same sample as that
in which significant linkage was found. This sample consisted of a
total of 427 individuals within 55 multigeneration pedigrees.
Polymorphisms demonstrating a consistent association in the discordant-sibling families were then genotyped in the initial sample of 298 pedigrees (n=1867) ascertained in 1984 as part of the RFHS. For analyses of quantitative measures of blood pressure levels, subjects in the grandparent generation (n=552) and subjects with type II diabetes or who were taking antihypertensive medications (n=32) were excluded. After exclusions, a total of 443 parents and 840 offspring remained in the data set. After analysis of the nuclear families within this initial data set, we expanded the subject sample to include an additional 291 families (n=1889) ascertained from the same population in 1989. After excluding 598 grandparents and 51 subjects with type II diabetes or who were taking antihypertensive medication in the additional sample, the expanded sample consisted of a total of 589 families with 975 parents and 1548 offspring.
For logistic regression analyses of hypertension status, all
nondiabetic subjects in the parental generation of the expanded sample
(n=1048) were used, and hypertensive individuals were defined as those
subjects with an SBP >140 mm Hg, a diastolic blood
pressure (DBP) >90 mm Hg, and/or currently taking blood
pressure–lowering medication. A total of 111 hypertensive and 937
normotensive individuals were included in this sample. Descriptive
statistics for the initial and expanded sets of families used in the
quantitative analyses of blood pressure levels are
presented in Table 1
.
|
Identification of Candidate Genes
Multiple online databases were searched for identified genes and
expressed sequence tags in the chromosome 5 linkage region. Information
about the location of the candidate genes was obtained by integrating
linkage, physical, radiation hybrid, sequencing, and cytogenetic
mapping data (Marshfield Medical Research Foundation, the Genome
Database, National Center for Biotechnology Information, and the
Genetic Location Database), as well as data from the chromosome 5
genome center (Human Genome Research Center at the University of
California, Irvine). Candidate genes were prioritized on the basis of
assigned biological function, and 5 genes that span the region of
interest were selected for resequencing. These 5 genes included the
1B-adrenergic receptor gene (ADRA1B), ADRB2,
the dopamine receptor 1A gene (DRD1A), the vascular
endothelial growth factor receptor 3 precursor gene
(FLT4), and the glutathione peroxidase 3 gene (GPX3).
Polymerase Chain Reaction and Direct Sequencing of Candidate
Genes
Primers for polymerase chain reaction (PCR) and sequencing were
designed to amplify 
1000 bp immediately 5' of the start site and all
exons and neighboring intron/exon boundaries within each published
candidate gene sequence (Genbank). DNA sequencing was performed in both
forward and reverse directions using PCR or internal primers and the
BigDye Terminator cycle-sequencing protocol (Perkin-Elmer).
Sequence variation was identified with the assistance of the POLYPHRED suite of programs from the University of Washington Genome Center.11 Contig assembly of overlapping sequence fragments within each gene was performed using the computer program PHRAP, and sequences from multiple individuals were then compared with each other and with published sequences using the program CONSED.
Genotyping of Candidate Gene Variants
Variant sites within each gene were prioritized for their likely
effect on the biological function of the gene or protein, with the
highest priority assigned to amino acid–altering substitutions and/or
promoter region variants. When no such polymorphisms were
present, as in the case of the ADRA1B and FLT4 genes, a synonymous
coding region or intronic variants were selected for
genotyping. Polymorphisms were
genotyped by PCR amplification of the variant site followed by
restriction enzyme digestion and detection on 2% agarose gels or by
using an allele-specific oligonucleotide-ligation
assay.12
Statistical Analysis
Hardy-Weinberg equilibrium for each polymorphic site was
verified for all markers. Association and linkage between each
polymorphism and blood pressure in the 55 families with discordant
sibling-pairs were determined using the transmission-disequilibrium
test (TDT) and sibling transmission-disequilibrium test
(S-TDT).13 For the purpose of these TDT analyses,
affected individuals were defined as those individuals in the upper
20th percentile of the SBP distribution, as described by Krushkal et
al.7 Analyses were performed using all available
offspring, with and without parents in the model.
Before the analyses of SBP, DBP, and mean arterial pressure, these traits were first adjusted for the concomitant effects of age, age-squared, and body mass index, within sex and generation. To relate the fixed effects of the marker loci to adjusted blood pressure levels while simultaneously accounting for the nonindependence among the nuclear family members, we used the "measured genotype approach"14 15 as implemented in the ASSOC algorithm of the SAGE computer package.16 Conventional ANOVA was used to test for an association between the selected polymorphisms and blood pressure levels in the parental generation only.
Logistic regression was used to test for an association between selected variants and hypertension diagnosis in the parental generation. Each allele of the 2 ADRB2 polymorphisms was tested separately and jointly in logistic regression models, which included age, age-squared, body mass index, and sex as covariates.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
All variants identified within the positional candidate genes selected for resequencing are presented in Table 2
. Details of the gene structure and
sequence variation within the FLT4 gene can be found in the article by
Ferrell et al.17 All 3 polymorphisms identified in the
ADRA1B gene were synonymous nucleotide substitutions in the
coding sequence. Of the 11 variants found within the ADRB2 gene, 2
change an amino acid, 3 are synonymous changes in coding sequence, 4
are in the 5' regulatory region, and 2 are in the 3' untranslated
region. Two of the 4 variants found within the DRD1A gene are in the 5'
regulatory region: one is a synonymous change within the coding region,
and the other is a nucleotide substitution in the 3'
untranslated region of the gene. Two variant sites were identified in
the 5' regulatory sequence of the GPX3 gene.
|
Results of the TDT/S-TDT analyses for the 10 selected
polymorphic sites identified for genotyping in the sample of 55
discordant-sibling families are presented in Table 3.
When only offspring were included in the analysis (S-TDT),
significant relationships were observed between blood pressure levels
and the Ile178Ile polymorphism in the ADRA1B gene, the Arg16Gly
variant in the ADRB2 gene, and both of the promoter variants in the
GPX3 gene. When parents were also included in the analysis (a
combined TDT/S-TDT), only the Arg16Gly and the 2 GPX3 variants remained
significantly related to blood pressure levels.
|
On the basis of the consistency of results for the ADRB2
and GPX3 genes in the TDT/S-TDT analyses for the 55
discordant-sibling families, both functional variants within the ADRB2
gene (Arg16Gly and Gln27Glu) and the 2 promoter region variants in the
GPX3 gene (-623AC and -302GA) were selected for genotyping and
analysis in the initial sample of 298 nuclear families from the
RFHS. In the family-based analyses, a significant association
was observed between the Arg16Gly variant and DBP
(
2=5.74, df=1, P=0.016) in a
dominant model for the Gly16 allele. ANOVA in the parental
generation only indicated significantly lower DBPs (62.22±9.0
mm Hg versus 65.60±8.5 mm Hg, P=0.009) and lower
mean arterial pressure levels (79.21±9.0 mm Hg
versus 82.1±9.3 mm Hg, P=0.038) in Arg16/Arg16
homozygotes compared with individuals with either Arg16/Gly16 or
Gly16/Gly16 genotypes (Table 4).
In this sample, the Arg16Gly polymorphism accounted for 2.3% of
the variance in DBP and 1.35% of the variance in mean
arterial pressure. Although the Gln27Glu polymorphism
was not significantly associated with blood pressure levels in this
sample, there was a consistent trend of increasing blood
pressure levels with increasing number of Glu27 alleles. Linkage
disequilibrium between the 2 ADRB2 variants was highly significant
(P<0.00001). Neither of the GPX3 polymorphisms was
significantly associated with blood pressure level in either the
nuclear family or parent samples.
|
To further validate our initial findings, we genotyped the 2
ADRB2 variants in an additional 291 nuclear families from Rochester and
analyzed the combined sample of 589 families. In this expanded
family sample, the Arg16Gly polymorphism was no longer
significantly associated with any measure of blood pressure (Table 4
). In contrast, however, the Gln27Glu polymorphism was
significantly associated with both SBP and mean arterial
pressure in the parental generation of the expanded family sample.
There was a linear trend for increasing blood pressure levels with
increasing number of Glu27 alleles, and individuals with the
Glu27/Glu27 genotype exhibited significantly greater SBPs
(116.76±13.1 mm Hg versus 114.58±11.3 mm Hg,
P=0.034) and mean arterial blood pressure levels
(84.10±9.9 versus 82.49±8.3 mm Hg, P=0.035) and
greater (but not significantly so) DBP levels (67.77±9.4 versus
66.43±8.1 mm Hg, P=0.070) than individuals with
either 1 or 2 Gln27 alleles. These results were consistent
with the analyses conducted in the combined nuclear family
sample (data not shown).
In addition to analyses of blood pressure level, we used logistic regression to investigate the association of the Arg16Gly and Gln27Glu polymorphisms with the diagnosis of hypertension in the parental generation of the expanded sample. The frequencies of both the Gly16 and Glu27 alleles were higher in hypertensive than in normotensive individuals (0.649 versus 0.604 and 0.490 versus 0.429, respectively), but these differences did not reach statistical significance. Both the Arg16Gly and Gln27Glu variants were associated with the occurrence of hypertension in the expanded sample. The Gly16 allele and the Glu27 allele were associated with an increased risk for hypertension, with the association being significant for the Glu27 allele (odds ratio, 1.80; 95% confidence intervals, 1.08 to 3.00; P=0.023) and approaching significance for the Gly16 allele in models that also included the Gln27 allele (odds ratio, 1.95; 95% confidence interval, 0.957 to 3.98; P=0.066).
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
In the current study, we expanded linkage results previously obtained in a sample of discordant-sibling families, which identified the long arm of chromosome 5 as a candidate region for genes influencing blood pressure. Multiple lines of investigation indicate that the Arg16Gly and Gln27Glu polymorphisms in the ADRB2 gene significantly influence interindividual blood pressure variation and the occurrence of hypertension.
Although family-based genome-wide linkage analyses are
currently being conducted for several clinically important
multifactorial traits, identification of the specific genes and genetic
variations contributing to such traits remains a formidable challenge.
That the ADRB2 variants were not significantly associated with blood
pressure in every sample considered is not surprising. Certainly, many
genes and environments are important in influencing interindividual
blood pressure variation, and the alleles of the responsible genes
are likely to be common in frequency and have small to moderate
effects. Analysis of genetic variation at the population level
must rely on statistical association of the genetic variant(s) with the
trait of interest. Statistical association may result from a number of
factors, including true biological effects of functional mutations,
linkage disequilibrium with the functional mutations, population
substructure, or a type I error, and they may be influenced by both the
study sample and the size of the effect. The ADRB2 polymorphisms
account for 2% of the total variation in blood pressure in this
sample from Rochester, Minn. This effect, although modest in size, is
consistent with the oligogenic nature of blood pressure levels
and hypertension status and is within the range expected for most genes
contributing to chronic diseases.18 This effect size does
not preclude the possibility, however, that ADRB2 polymorphisms may
have a larger impact in subsets of the population. Phenotypic and
environmental heterogeneity from sample to sample may
critically influence the ability to detect associations with factors of
such small effect, and such heterogeneity may likely
limit our ability to consistently detect the effects of
variation at the ADRB2 locus in the various samples we considered.
Analysis of the combined sample indicated that both the Arg16Gly and Gln27Glu polymorphisms were significantly associated with the diagnosis of hypertension. The Glu27 allele was more frequent among hypertensives and was significantly associated with the occurrence of hypertension compared with the Gln27 allele. The Gly16 allele was also more frequent among hypertensive individuals than the Arg16 allele. Furthermore, when conditioned on genotype at the Gln27Glu locus, the Gly16 allele was associated with the occurrence of hypertension in the presence of the Gln27 allele, suggesting an epistatic effect of the 2 loci. As reported above, both the Gly16 and the Glu27 alleles were associated with increased blood pressure in quantitative trait-association analyses.
Functional studies of these ADRB2 variants have provided some evidence that they may work synergistically to influence cellular physiology and function. Mice lacking a functional ADRB2 gene have elevated blood pressure levels in response to epinephrine or treadmill exercise, although resting blood pressure levels remain unchanged.19 Green et al20 reported that both the Arg16Gly and Gln27Glu polymorphisms play a role in ß2-adrenergic receptor downregulation. In cellular transfection assays, the Gly16 isoform showed significantly greater downregulation in response to the ß2-agonist isoproterenol compared with the Arg16 isoform. Such a response could likely produce an increase in blood pressure due to decreased agonist sensitivity, as was observed in quantitative analyses of our initial sample of 298 families. Conversely, the Glu27 isoform was completely resistant to downregulation relative to the Gln27 isoform in cell transfection experiments, suggesting an increased sensitivity to adrenergic agonists for cells carrying this allele. Nevertheless, this effect was only evident in the presence of the Arg16 allele. Cells transfected with both substitutions (Gly16 and Glu27) displayed increased downregulation relative to the wild-type form of the receptor, similar to cells with the Gly16 mutation only. Concordant with these observations in cell culture systems, the Glu27 allele was consistently associated with elevated blood pressure in individuals homozygous or heterozygous for the Gly16 allele in our analyses of the expanded sample, but this relationship was less consistent among Arg16/Arg16 homozygotes (ie, heterozygotes rather than homozygotes for the Glu27 allele had the highest blood pressure). These data provide evidence for an individual effect of the 2 ADRB2 polymorphisms and for the possibility that their effects may interact with one another to influence ß2-adrenergic receptor function and, ultimately, blood pressure levels.
Similar to the results described in the current study, Kotanko and colleagues21 reported that the frequency of the Gly16 allele was significantly greater among hypertensives than nonhypertensives in a sample of African-Caribbean men and women (0.85 versus 0.66, respectively; P<0.0001), and the odds ratio of the hypertension and Gly16 allele association was 2.74 (95% confidence interval, 1.44 to 4.36). In a study of normotensive Austrian men, Gly16/Gly16 homozygotes had a significantly higher resting blood pressure compared with subjects homozygous for the Arg16 allele (81.6±6.14 versus 75.2±4.93 mm Hg, respectively).22 Variation in the ß2-adrenergic receptor has also been associated with nocturnal and non-nocturnal asthma and, more importantly, with other phenotypes associated with hypertension, including obesity, impaired lipid metabolism, salt sensitivity, abdominal fat accumulation, and cardiac failure.23 24 25 26 27 28 29 It is likely that the variation in the ADRB2 gene has pleiotropic effects that may influence blood pressure levels in the population through multiple pathways, and it is reassuring that a variety of sources have provided support for the contribution of the ADRB2 gene in blood pressure regulation.
This study represents an important success in identifying genetic variation contributing to a multifactorial phenotype (ie, blood pressure) after genome-wide linkage analyses. Our investigation of the candidate genes within the chromosome 5 linkage region was not exhaustive, however, and this region of chromosome 5 has not yet been sequenced in its entirety by the human genome project. There may be additional genetic polymorphisms contributing to variation in blood pressure levels in this region that we have not yet identified. Nevertheless, on the basis of our findings in the current study, we believe that the significant evidence for linkage we observed in the chromosome 5 region is due, at least in part, to variation within the ADRB2 gene.
Identification of the ADRB2 gene as contributing to interindividual variation in blood pressure levels opens new opportunities for research. Prospective epidemiological studies may help determine whether the Arg16Gly polymorphism predicts the onset of clinical hypertension above and beyond that afforded by established predictors such as race, sex, age, and measures of body size. These studies can also be used to determine whether the clinical course of hypertension and its complications is influenced by variations in the ADRB2 gene. Because the ß-adrenergic receptors are frequent drug targets for therapeutic interventions, it will also be important to determine the contribution of ADRB2 polymorphisms to interindividual variation in the responses to these pharmaceutical agents.
|
Acknowledgments |
|---|
This research was supported by National Institutes of Health grants HL54481, HL54526, HL54457, and HL54464 and by grant UR6/CCU617218-01 from the Centers for Disease Control and Prevention.
|
Footnotes |
|---|
This article originally appeared Online Only with the May 30, 2000 issue of Circulation (Circulation. 2000;r9–r15).
Received May 10, 2000; accepted May 17, 2000.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. JNC. Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med. 1997;157:2413–2446.
2.
Chobanian A, Alexander R. Exacerbation of
atherosclerosis by hypertension: potential mechanisms
and clinical implications. Arch Intern Med. 1996;156:1952–1956.
3.
Alexander R. Theodore Cooper memorial lecture:
hypertension and the pathogenesis of atherosclerosis:
oxidative stress and the mediation of arterial inflammatory
response: a new perspective. Hypertension. 1995;25:155–161.
4.
Wilson P, D’Agostino R, Levy D, et al.
Prediction of coronary heart disease using risk factor
categories. Circulation. 1998;97:1837–1847.
5. Williams R, Hunt S, Hopkins P, et al. Genetic basis of familial dyslipidemia and hypertension: 15-year results from Utah. Am J Hypertens. 1993;6:319S–327S.[Medline] [Order article via Infotrieve]
6. Rice T, Vogler G, Perusse L, et al. Cardiovascular risk factors in a French Canadian population: resolution of genetic and familial environmental effects on blood pressure using twins, adoptees, and extensive information on environmental correlates. Genet Epidemiol. 1989;6:571–588.[Medline] [Order article via Infotrieve]
7.
Krushkal J, Xiong M, Ferrell R, et al. Linkage and
association of adrenergic and dopamine receptor genes in the distal
portion of the long arm of chromosome 5 with systolic blood
pressure variation. Hum Mol Genet. 1998;7:1379–1383.
8.
Krushkal J, Ferrell R, Mockrin S, et al. Genome-wide
linkage analyses of systolic blood pressure using
highly discordant siblings. Circulation. 1999;99:1407–1410.
9.
Turner ST, Michels VV. Sodium-lithium countertransport
and hypertension in Rochester, Minnesota. Hypertension. 1991;18:183–190.
10. Turner S, Sing C. Erythrocyte sodium transport and the probability of having hypertension. J Hypertens. 1996;14:829–837.[Medline] [Order article via Infotrieve]
11.
Nickerson DA, Tobe VO, Taylor SL. PolyPHRED: automating
the detection and genotyping of single nucleotide
substitutions using fluorescence-based resequencing.
Nucleic Acids Res. 1997;25:2745–2751.
12.
Nickerson D, Kaiser R, Lappin S, et al. Automated DNA
diagnostics using an ELISA-based
oligonucleotide ligation assay. Proc Natl Acad
Sci U S A. 1990;87:8923–8927.
13. Spielman R, Ewens W. A sibship test of linkage in the presence of association: the sib transmission/disequilibrium test. Am J Hum Genet. 1998;62:450–458.[Medline] [Order article via Infotrieve]
14. Boerwinkle E, Chakraborty R, Sing C. The use of measured genotype information in the analysis of quantitative phenotype in man. Ann Hum Genet. 1986;50:181–194.[Medline] [Order article via Infotrieve]
15. George V, Elston R. Testing the association between polymorphic markers and quantitative traits in pedigrees. Genet Epidemiol. 1987;4:193–201.[Medline] [Order article via Infotrieve]
16. SAGE: Statistical Analysis for Genetic Epidemiology. New Orleans, La: Department of Biometry and Genetics, LSU Medical Center; 1994.
17.
Ferrell R, Levinson K, Esman J, et al. Hereditary
lymphedema: evidence for linkage and genetic
heterogeneity. Hum Mol Genet. 1998;7:2073–2078.
18. Weiss K. Genetic Variation and Human Disease: Principles and Evolutionary Approaches. New York, NY: Cambridge University Press; 1993.
19.
Chruscinski A, Rohrer D, Schauble E, et al. Targeted
disruption of the ß2 adrenergic receptor gene. J Biol
Chem. 1999;274:16694–16700.
20. Green S, Turki J, Innis M, et al. Amino-terminal polymorphisms of the human ß2-adrenergic receptor impart distinct agonist-promoted regulatory properties. Biochemistry. 1994;33:9414–9419.[Medline] [Order article via Infotrieve]
21.
Kotanko P, Binder A, Tasker J, et al. Essential
hypertension in African Caribbean associates with a variant of the
ß2-adrenoceptor. Hypertension. 1997;30:773–776.
22.
Gratze G, Fortin J, Labugger R, et al. ß-2
adrenergic receptor variant affect resting blood pressure and
agonist-induced vasodilation in young adult caucasians.
Hypertension. 1999;33:1425–1430.
23. Turki J, Pak H, Green S, et al. Polymorphisms of the ß2 adrenergic receptor in nocturnal and non-nocturnal asthma: evidence that Gly 16 correlates with the nocturnal phenotype. J Clin Invest. 1995;95:1635–41.
24. Martinez F, Graves P, Baldini M, et al. Association between genetic polymorphisms of the beta2-adrenoceptor and response to albuterol in children with and without a history of wheezing. J Clin Invest. 1997;100:3184–3188.[Medline] [Order article via Infotrieve]
25. Hall I, Wheatley A, Wilding P, et al. Association of the Glu27 b2-adrenoceptor polymorphism with lower airway reactivity in asthmatic subjects. Lancet. 1995;345:1213–1214.[Medline] [Order article via Infotrieve]
26. Mori Y, Kim-Motoyama H, Ito Y, et al. The Gln27Glu beta2-adrenergic receptor variant is associated with obesity due to subcutaneous fat accumulation in Japanese men. Biochem Biophys Res Commun. 1999;258:138–140.[Medline] [Order article via Infotrieve]
27. Meirhaeghe A, Helbecque N, Cottel D, et al. Beta2-adrenoceptor gene polymorphism, body weight, and physical activity. Lancet. 1999;353:896.[Medline] [Order article via Infotrieve]
28. Large V, Hellstrom L, Reynisdottir S, et al. Human beta-2 adrenoceptor gene polymorphisms are highly frequent in obesity and associate with altered adipocyte beta-2 adrenoceptor function. J Clin Invest. 1997;100:3005–3013.[Medline] [Order article via Infotrieve]
29.
Dorn GN, Tepe N, Lorenz J, et al. Low- and high-level
transgenic expression of ß2-adrenergic receptors differentially
affect cardiac hypertrophy and function in
Gq-overexpressing mice. Proc Natl Acad Sci U S A. 1999;96:6400–6405.
This article has been cited by other articles:
 |
|
 |
|
  M. L. Miranda, P. Maxson, and S. Edwards Environmental Contributions to Disparities in Pregnancy Outcomes Epidemiol. Rev., November 1, 2009; 31(1): 67 - 83. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. K. Arnett, A. E. Baird, R. A. Barkley, C. T. Basson, E. Boerwinkle, S. K. Ganesh, D. M. Herrington, Y. Hong, C. Jaquish, D. A. McDermott, et al. Relevance of Genetics and Genomics for Prevention and Treatment of Cardiovascular Disease: A Scientific Statement From the American Heart Association Council on Epidemiology and Prevention, the Stroke Council, and the Functional Genomics and Translational Biology Interdisciplinary Working Group Circulation, June 5, 2007; 115(22): 2878 - 2901. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. M. Snyder, K. C. Beck, S. T. Turner, E. A. Hoffman, M. J. Joyner, and B. D. Johnson Genetic variation of the beta2-adrenergic receptor is associated with differences in lung fluid accumulation in humans J Appl Physiol, June 1, 2007; 102(6): 2172 - 2178. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. M. Snyder, S. T. Turner, and B. D. Johnson {beta}2-Adrenergic Receptor Genotype and Pulmonary Function in Patients With Heart Failure. Chest, November 1, 2006; 130(5): 1527 - 1534. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Pojoga, N. S. Kolatkar, J. S. Williams, T. S. Perlstein, X. Jeunemaitre, N. J. Brown, P. N. Hopkins, B. A. Raby, and G. H. Williams {beta}-2 Adrenergic Receptor Diplotype Defines a Subset of Salt-Sensitive Hypertension Hypertension, November 1, 2006; 48(5): 892 - 900. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. M. Snyder, S. T. Turner, M. J. Joyner, J. H. Eisenach, and B. D. Johnson The Arg16Gly polymorphism of the {beta}2-adrenergic receptor and the natriuretic response to rapid saline infusion in humans J. Physiol., August 1, 2006; 574(3): 947 - 954. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. H. Eisenach, D. R. Schroeder, T. L. Pike, C. P. Johnson, W. G. Schrage, E. M. Snyder, B. D. Johnson, V. D. Garovic, S. T. Turner, and M. J. Joyner Dietary sodium restriction and {beta}2-adrenergic receptor polymorphism modulate cardiovascular function in humans J. Physiol., August 1, 2006; 574(3): 955 - 965. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Gu, S. Su, D. Ge, S. Chen, J. Huang, B. Li, R. Chen, and B. Qiang Association Study With 33 Single-Nucleotide Polymorphisms in 11 Candidate Genes for Hypertension in Chinese Hypertension, June 1, 2006; 47(6): 1147 - 1154. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. J. Mullins, M. A. Bailey, and J. J. Mullins Hypertension, Kidney, and Transgenics: A Fresh Perspective Physiol Rev, April 1, 2006; 86(2): 709 - 746. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. M. Snyder, K. C. Beck, N. M. Dietz, M. J. Joyner, S. T. Turner, and B. D. Johnson Influence of {beta}2-Adrenergic Receptor Genotype on Airway Function During Exercise in Healthy Adults Chest, March 1, 2006; 129(3): 762 - 770. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. C. Poole, H. Snieder, H. C. Davis, and F. A. Treiber Anger suppression and adiposity modulate association between ADRB2 haplotype and cardiovascular stress reactivity. Psychosom Med, March 1, 2006; 68(2): 207 - 212. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Metra, C. Zani, L. Covolo, S. Nodari, N. Pezzali, U. Gelatti, F. Donato, G. Nardi, and L. D. Cas Role of {beta}1- and {alpha}2c-adrenergic receptor polymorphisms and their combination in heart failure: A case-control study Eur J Heart Fail, March 1, 2006; 8(2): 131 - 135. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. L. Riddle, B. K. Rana, K. K. Murthy, F. Rao, E. Eskin, D. T. O'Connor, and P. A. Insel Polymorphisms and Haplotypes of the Regulator of G Protein Signaling-2 Gene in Normotensives and Hypertensives Hypertension, March 1, 2006; 47(3): 415 - 420. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Jacob, E. M. Garland, F. Costa, C. M. Stein, H.-G. Xie, R. M. Robertson, I. Biaggioni, and D. Robertson {beta}2-Adrenoceptor Genotype and Function Affect Hemodynamic Profile Heterogeneity in Postural Tachycardia Syndrome Hypertension, March 1, 2006; 47(3): 421 - 427. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. M. Snyder, K. C. Beck, N. M. Dietz, J. H. Eisenach, M. J. Joyner, S. T. Turner, and B. D. Johnson Arg16Gly polymorphism of the {beta}2-adrenergic receptor is associated with differences in cardiovascular function at rest and during exercise in humans J. Physiol., February 15, 2006; 571(1): 121 - 130. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. R. Keys, R.-H. Zhou, D. M. Harris, C. A. Druckman, and A. D. Eckhart Vascular Smooth Muscle Overexpression of G Protein-Coupled Receptor Kinase 5 Elevates Blood Pressure, Which Segregates With Sex and Is Dependent on Gi-Mediated Signaling Circulation, August 23, 2005; 112(8): 1145 - 1153. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Bao, P. J. Mills, B. K. Rana, J. E. Dimsdale, N. J. Schork, D. W. Smith, F. Rao, M. Milic, D. T. O'Connor, and M. G. Ziegler Interactive Effects of Common {beta}2-Adrenoceptor Haplotypes and Age on Susceptibility to Hypertension and Receptor Function Hypertension, August 1, 2005; 46(2): 301 - 307. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Covolo, U. Gelatti, M. Metra, S. Nodari, A. Piccichè, N. Pezzali, C. Zani, A. Alberti, F. Donato, G. Nardi, et al. Role of {beta}1- and {beta}2-adrenoceptor polymorphisms in heart failure: a case-control study Eur. Heart J., September 1, 2004; 25(17): 1534 - 1541. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. L. Kirstein and P. A. Insel Autonomic Nervous System Pharmacogenomics: A Progress Report Pharmacol. Rev., March 1, 2004; 56(1): 31 - 52. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. H. Eisenach, A. M. McGuire, R. M. Schwingler, S. T. Turner, and M. J. Joyner The Arg16/Gly {beta}2-adrenergic receptor polymorphism is associated with altered cardiovascular responses to isometric exercise Physiol Genomics, February 13, 2004; 16(3): 323 - 328. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. C. Pereira, M. S. Floriano, G. F.A. Mota, R. S. Cunha, F. L. Herkenhoff, J. G. Mill, and J. E. Krieger {beta}2 Adrenoceptor Functional Gene Variants, Obesity, and Blood Pressure Level Interactions in the General Population Hypertension, October 1, 2003; 42(4): 685 - 692. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W J Yang, J F Huang, C L Yao, Z J Fan, D L Ge, W Q Gan, G Y Huang, R T Hui, Y Shen, B Q Qiang, et al. Evidence for linkage and association of the markers near the LPL gene with hypertension in Chinese families J. Med. Genet., May 1, 2003; 40(5): e57 - 57. [Full Text] [PDF]
|
|
|
|
|
|
H. Izawa, Y. Yamada, T. Okada, M. Tanaka, H. Hirayama, and M. Yokota Prediction of Genetic Risk for Hypertension Hypertension, May 1, 2003; 41(5): 1035 - 1040. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. R. Heckbert, L. A. Hindorff, K. L. Edwards, B. M. Psaty, T. Lumley, D. S. Siscovick, Z. Tang, J. P. Durda, R. A. Kronmal, and R. P. Tracy {beta}2-Adrenergic Receptor Polymorphisms and Risk of Incident Cardiovascular Events in the Elderly Circulation, April 22, 2003; 107(15): 2021 - 2024. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. D Garovic, M. J Joyner, N. M Dietz, E. Boerwinkle, and S. T Turner {beta}2-Adrenergic receptor polymorphism and nitric oxide-dependent forearm blood flow responses to isoproterenol in humans J. Physiol., January 15, 2003; 546(2): 583 - 589. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 A. D. Eckhart, T. Ozaki, H. Tevaearai, H. A. Rockman, and W. J. Koch Vascular-Targeted Overexpression of G Protein-Coupled Receptor Kinase-2 in Transgenic Mice Attenuates beta -Adrenergic Receptor Signaling and Increases Resting Blood Pressure Mol. Pharmacol., April 1, 2002; 61(4): 749 - 758. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. A. Doris Hypertension Genetics, Single Nucleotide Polymorphisms, and the Common Disease:Common Variant Hypothesis Hypertension, February 1, 2002; 39(2): 323 - 331. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Multi-Center Genetic Study of Hypertension: The Family Blood Pressure Program (FBPP) Hypertension, January 1, 2002; 39(1): 3 - 9. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Rankinen, P. An, T. Rice, G. Sun, Y. C. Chagnon, J. Gagnon, A. S. Leon, J. S. Skinner, J. H. Wilmore, D. C. Rao, et al. Genomic Scan for Exercise Blood Pressure in the Health, Risk Factors, Exercise Training and Genetics (HERITAGE) Family Study Hypertension, July 1, 2001; 38(1): 30 - 37. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. J. Lefkowitz and J. T. Willerson Prospects for Cardiovascular Research JAMA, February 7, 2001; 285(5): 581 - 587. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. I Amos and M. de Andrade Genetic linkage methods for quantitative traits Statistical Methods in Medical Research, February 1, 2001; 10(1): 3 - 25. [Abstract] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||