@article {711, title = {Angiotensin II type 1 receptor polymorphisms in the cardiovascular health study: relation to blood pressure, ethnicity, and cardiovascular events.}, journal = {Am J Hypertens}, volume = {15}, year = {2002}, month = {2002 Dec}, pages = {1050-6}, abstract = {

BACKGROUND: The angiotensin II type 1 receptor A1166C polymorphism has been associated with increased risks of hypertension and myocardial infarction in several small studies. We examined the association between this polymorphism and new-onset hypertension, blood pressure (BP) control, and incident cardiovascular events in a large population-based cohort of older adults.

METHODS: Eight hundred self-identified African Americans and 1,371 randomly selected white participants in the Cardiovascular Health Study were genotyped. The median duration of follow-up was 8.1 years.

RESULTS: The A1166C polymorphism was not associated with new-onset hypertension, with BP control, or with incident cardiovascular events in the overall population. In white participants, the CC genotype was associated with higher baseline systolic BP and pulse pressure, compared to the AC or AA genotype. In whites with treated hypertension at baseline, compared to the AA genotype, the CC genotype was associated with increased risks of incident congestive heart failure (hazard ratio = 2.5, 95\% confidence interval [CI] 1.3-4.9) and incident ischemic stroke (hazard ratio = 2.6, 95\% CI 1.1-6.0). These associations were not observed among white participants without treated hypertension, but the interaction of genotype with treated hypertension on ischemic stroke and heart failure was only marginally significant.

CONCLUSIONS: On the whole, in this large cohort of older adults, the A1166C polymorphism was not associated with BP control or incident cardiovascular events. The subgroup findings in treated hypertensives need to be confirmed in additional studies.

}, keywords = {African Continental Ancestry Group, Aged, Blood Pressure, Cardiovascular Diseases, European Continental Ancestry Group, Female, Gene Frequency, Humans, Hypertension, Male, Polymorphism, Genetic, Receptor, Angiotensin, Type 1, Receptors, Angiotensin, United States}, issn = {0895-7061}, doi = {10.1016/s0895-7061(02)03063-7}, author = {Hindorff, Lucia A and Heckbert, Susan R and Tracy, Russell and Tang, Zhonghua and Psaty, Bruce M and Edwards, Karen L and Siscovick, David S and Kronmal, Richard A and Nazar-Stewart, Valle} } @article {733, title = {Beta2-adrenergic receptor polymorphisms and risk of incident cardiovascular events in the elderly.}, journal = {Circulation}, volume = {107}, year = {2003}, month = {2003 Apr 22}, pages = {2021-4}, abstract = {

BACKGROUND: Genetic polymorphisms at codons 16 and 27 of the beta2-adrenergic receptor have been associated with altered response to sympathetic stimulation. We examined these polymorphisms in relation to cardiovascular event risk in the Cardiovascular Health Study.

METHODS AND RESULTS: A total of 808 black and 4441 white participants (mean age, 73 years) were genotyped for the Arg16Gly and Gln27Glu polymorphisms of the beta2-adrenergic receptor. There were 702 incident coronary events, 438 ischemic strokes, and 1136 combined cardiovascular events during 7 to 10 years of follow-up. Allele frequencies differed by race but not by age or hypertension status. Glu27 carriers had a lower risk of coronary events than Gln27 homozygotes (hazard ratio, 0.82; 95\% CI, 0.70 to 0.95), and there was a suggestion of decreased risk among Gly16 carriers compared with Arg16 homozygotes (hazard ratio, 0.88; 95\% CI, 0.72 to 1.07). There was no association of beta2-adrenergic receptor genotype with ischemic stroke or combined cardiovascular events.

CONCLUSIONS: The Glu27 allele of the beta2-adrenergic receptor was associated with a lower risk of incident coronary events in this elderly population.

}, keywords = {African Continental Ancestry Group, Aged, Alleles, Brain Ischemia, Cardiovascular Diseases, Cohort Studies, Comorbidity, Coronary Disease, European Continental Ancestry Group, Follow-Up Studies, Gene Frequency, Humans, Incidence, Linkage Disequilibrium, Polymorphism, Genetic, Receptors, Adrenergic, beta-2, Risk Assessment, Stroke, United States}, issn = {1524-4539}, doi = {10.1161/01.CIR.0000065231.07729.92}, author = {Heckbert, Susan R and Hindorff, Lucia A and Edwards, Karen L and Psaty, Bruce M and Lumley, Thomas and Siscovick, David S and Tang, Zhonghua and Durda, J Peter and Kronmal, Richard A and Tracy, Russell P} } @article {825, title = {beta(2)-Adrenergic receptor polymorphisms and determinants of cardiovascular risk: the Cardiovascular Health Study.}, journal = {Am J Hypertens}, volume = {18}, year = {2005}, month = {2005 Mar}, pages = {392-7}, abstract = {

BACKGROUND: Common Arg16Gly and Gln27Glu polymorphisms of the beta(2)-adrenergic receptor (beta(2)AR) have been associated with hypertension and coronary disease. This analysis of older adults in the Cardiovascular Health Study examined whether these polymorphisms were associated with blood pressure (BP), subclinical atherosclerosis, and, among treated hypertensive individuals, differences in coronary disease risk according to antihypertensive drug class.

METHODS: Altogether, 5249 participants (4441 white and 808 African American, median follow-up time 10.2 years) were genotyped for both polymorphisms. Ankle-arm index (AAI), carotid intima-media thickness (IMT), and brachial flow-mediated dilation were measured cross-sectionally. All estimates were adjusted for ethnicity.

RESULTS: Relative to Gln27 homozygotes, carrying the Glu27 allele was not associated with new-onset hypertension (hazard ratio [HR] = 1.01, 95\% confidence interval [CI] = 0.87 to 1.16), BP control (odds ratio [OR] = 0.97, 95\% CI = 0.89 to 1.06), AAI (mean difference 0.0042 +/- 0.0052), carotid IMT (mean difference 0.0044 +/- 0.02 mm), or brachial flow-mediated dilation (mean difference in baseline diameter -0.028 +/- 0.036 mm; the most marked of three measures). Among treated hypertensive individuals, coronary disease risk was similar in Glu27 carriers relative to Gln27 homozygotes in subgroups defined by use of beta-blockers (HR = 1.09, 95\% CI = 0.64 to 1.87) or other antihypertensive medications (HR = 1.00, 95\% CI = 0.78 to 1.28). Results were similar for the Arg16Gly polymorphism.

CONCLUSIONS: The association of beta(2)AR genotype with coronary disease previously reported in this older adult population is not likely to be explained by BP levels, subclinical atherosclerosis, or antihypertensive treatment. Other measures of vascular response, gene-gene or gene-environment interactions, or characteristics developing earlier in life may mediate the association between beta(2)AR genotype and coronary disease and merit further research.

}, keywords = {African Americans, Antihypertensive Agents, Arteriosclerosis, Coronary Artery Disease, European Continental Ancestry Group, Female, Genotype, Homozygote, Humans, Hypertension, Incidence, Male, Middle Aged, Polymorphism, Genetic, Receptors, Adrenergic, beta-2, Risk Factors}, issn = {0895-7061}, doi = {10.1016/j.amjhyper.2004.10.014}, author = {Hindorff, Lucia A and Heckbert, Susan R and Psaty, Bruce M and Lumley, Thomas and Siscovick, David S and Herrington, David M and Edwards, Karen L and Tracy, Russell P} } @article {883, title = {Genetic Susceptibility to Prostate Cancer: Prostate-specific Antigen and its Interaction with the Androgen Receptor (United States).}, journal = {Cancer Causes Control}, volume = {17}, year = {2006}, month = {2006 Mar}, pages = {187-97}, abstract = {

OBJECTIVE: To determine whether directly observed prostate-specific antigen (PSA) promoter diploid haplotype, either alone or in conjunction with androgen receptor (AR) genotype, is associated with prostate cancer risk.

METHODS: We conducted a case-control study nested within the US population-based Cardiovascular Health Study cohort. Incident prostate cancers were identified by linkage to cancer registry records for the years 1989-2000. We genotyped 193 cases and 391 controls for the PSA -252 G/A and -158 G/A SNPs and the AR CAG microsatellite, and developed methods to directly determine proximal PSA promoter haplotypes. Exact logistic regression was used to estimate odds ratios and significance levels.

RESULTS: No significant associations were observed between PSA diplotype and prostate cancer overall. Short (< 20) AR CAG repeat lengths were associated with modest increases in the risk of prostate cancer (OR, 1.46; 95\% CI, 0.97-2.19; p = 0.071) that were significant for advanced disease (OR, 1.82; 95\% CI, 1.02-3.26; p = 0.044). Men who possessed two copies of the PSA*2 (-252G/-158G) haplotype and short AR CAG repeat lengths had a 4-fold (95\% CI, 1.05-20.75; exact p = 0.040) increased risk of prostate cancer, and a 7-fold (95\% CI, 1.25-39.78; exact p = 0.026) increased risk of advanced disease.

CONCLUSIONS: We found evidence that the PSA*2*2 diplotype in combination with short AR CAG alleles increases a man{\textquoteright}s risk of developing prostate cancer. These findings support an etiologic role in prostate cancer of genetic interactions between polymorphisms that increase AR transactivation strength and those that alter the regulatory regions of target genes such as PSA that are responsive to androgen stimulation.

}, keywords = {Aged, Biomarkers, Tumor, Case-Control Studies, Cohort Studies, Genetic Predisposition to Disease, Genotype, Haplotypes, Humans, Male, Polymorphism, Genetic, Prostate-Specific Antigen, Prostatic Neoplasms, Receptors, Androgen, United States}, issn = {0957-5243}, doi = {10.1007/s10552-005-0454-8}, author = {Sieh, Weiva and Edwards, Karen L and Fitzpatrick, Annette L and Srinouanprachanh, Sengkeo L and Farin, Fred M and Monks, Stephanie A and Kronmal, Richard A and Eaton, David L} }