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Associations between polymorphisms of the G-protein coupled receptors and intermediate phenotypes in hypertensive families.

机译：G蛋白偶联受体的多态性与高血压家族的中间表型之间的关联。

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摘要

Background. Studies have demonstrated that variants of the polymorphisms of the G protein-coupled receptors are associated with hypertension and decreased vasodilation. No study, however, has investigated associations between all common polymorphisms of the candidate genes encoding these receptors and intermediate phenotypes of hypertension, controlling for population stratification in a family-based population.; Methods and results. A total of 608 subjects from 141 African-American and Caucasian families were selected on the basis of a hypertensive proband. An extensive re-sequencing of the candidate genes α 1B adrenergic receptor, β2 adrenergic receptor, and dopamine receptor D1 on chromosome 5q in 92 subjects identified all common single nucleotide polymorphisms that were subsequently genotyped in the entire population. Associations between polymorphisms and phenotypes were tested with the Quantitative Transmission Disequilibrium Test, a test that can model both allelic transmission and linkage. Intermediate phenotypes examined in this study included baroreceptor and α1 pressor sensitivity, autonomic responses to changes in blood pressure upon infusion of pharmacologic agents. Highly significant associations were found between α1 pressor sensitivity and 4 promoter polymorphisms (C-468G, T-367C, T-47C, T-20C (range of p-values: .0008–.017)), and 1 coding polymorphism (C79G, p-value = .005) in the β2 adrenergic receptor gene. Permutation tests confirmed these results, thus reducing the chance of type I errors potentially arising from violations of multivariate normality or multiple testing. Haplotypes were constructed from the polymorphisms in the β2 adrenergic receptor gene and analyzed for associations. A comparison of models developed from haplotypes and single nucleotide polymorphisms revealed similarities with the one notable exception Arg16Gly (p = .005). Consistent with our earlier findings, this highly publicized polymorphism was not associated with any of our traits.; Conclusion. Allelic variants of the β2 adrenergic receptor locus are associated with early functional alterations in baroreceptor sensitivity and α1 pressor responsiveness, and may thus play an important role in the pathogenesis of essential hypertension. Taken together with recent in vitro functional testing, the findings highlight the need for examining not just one, but multiple polymorphisms and their haplotypes in allelic association analyses.
机译：背景。研究表明，G蛋白偶联受体多态性的变异与高血压和血管舒张减少有关。然而，尚无研究调查编码这些受体的候选基因的所有常见多态性与高血压的中间表型之间的关联，这些高血压控制着基于家庭的人群中的人群分层。 方法和结果。根据高血压先证者，从141个非裔美国人和白种人家庭中选出了608名受试者。在92名受试者的5q染色体上对候选基因α 1B 肾上腺素能受体，β 2 肾上腺素能受体和多巴胺受体D1进行了广泛的重测序，发现了所有常见的单核苷酸多态性随后在整个人群中进行基因分型。多态性与表型之间的关联性通过定量传递不平衡测试进行了测试，该测试可以模拟等位基因的传递和连锁。在这项研究中检查的中间表型包括压力感受器和α 1 升压敏感度，输注药后对血压变化的自主反应。在α 1 升压敏感性和4个启动子多态性之间发现高度显着关联（C-468G，T-367C，T-47C，T-20C（p值范围：.0008–.017） ），以及β 2 肾上腺素能受体基因中的1个编码多态性（C79G，p值= 0.005）。排列检验证实了这些结果，从而减少了因违反多元正态性或多重检验而引起的I型错误的可能性。利用β 2 肾上腺素能受体基因的多态性构建单倍型，并进行关联分析。根据单倍型和单核苷酸多态性开发的模型的比较显示，与一个值得注意的例外Arg16Gly（p = .005）相似。与我们先前的发现一致，这种广为宣传的多态性与我们的任何特征均不相关。 结论。 β 2 肾上腺素能受体基因座的等位基因变异与压力感受器敏感性和α 1 升压反应性的早期功能改变有关，因此可能在必需的发病机理中起重要作用。高血压。结合最近的体外功能测试，这些发现强调了在等位基因关联分析中不仅需要检查一种多态性，还需要检查其多态性及其单倍型。

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  • 作者

    Timberlake, David Sommer.;

  • 作者单位

    University of California, San Diego and San Diego State University.;

  • 授予单位 University of California, San Diego and San Diego State University.;
  • 学科 Health Sciences Public Health.; Chemistry Biochemistry.
  • 学位 Ph.D.
  • 年度 2003
  • 页码 p.2151
  • 总页数 113
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 预防医学、卫生学;
  • 关键词

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