GWAS for Sleep Apnea and Endothelial Function Among Mexican Americans

描述（由申请人提供）：越来越多的证据表明，一系列不太传统的风险因素对高血压、心血管疾病和中风至关重要。这些因素包括阻塞性睡眠呼吸暂停、内皮功能受损、高中心血压和主动脉僵硬。此外，它们都与2型糖尿病及其并发症有关。这些非传统风险因素的出现提供了关键的生理目标，了解生物学基础可能对制定疾病预防和/或减缓几种慢性疾病进展的策略产生重大影响。已知这些因素中的每一个都具有实质性的遗传成分。因此，在全基因组关联研究的背景下，对每一种方法进行适当的测量，对于阐明那些基因和途径具有巨大的潜力，这些基因和途径的遗传变异介导了风险因素水平和随后疾病的差异。因此，我们建议在来自德克萨斯州斯塔尔县的1，200名先前特征化的墨西哥裔美国人中测量非传统风险因素的这一轴，我们已经从Affyestry Human Genome-Wide SNP Array 6.0平台进行了基因分型。这项工作建立在我们28年的经验，调查遗传学和流行病学的2型糖尿病，其并发症，并在斯塔尔县的相关条件。具体而言，我们建议：1）确定遗传变异对阻塞性睡眠呼吸暂停、内皮功能受损、中心血压、主动脉僵硬度及其概况的贡献; 2）确定2型糖尿病和糖尿病前期是否介导与非传统风险因素轴的基因组关联; 3）通过与包括西班牙裔健康队列在内的其他组的合作复制显著结果;以及4）通过利用网络理论和进化背景的深度重测序和分析，将因果多态性与那些简单地处于连锁不平衡的多态性区分开来。在西班牙裔人群中，这一轴的危险因素的流行病学数据很少。此外，尚未在任何人群中进行这些风险因素的全基因组关联研究。这些研究已被证明在识别以前与慢性疾病风险无关的基因方面非常有效，可能为干预开辟新的途径。我们希望我们提出的研究对这组非传统风险因素也能做到这一点。它们特别具有吸引力，因为它们在生理上相互关联，而且与造成大多数人口发病率和死亡率负担的一系列疾病有着一贯的联系。 公共卫生相关性：阻塞性睡眠呼吸暂停、内皮功能受损、高中心血压和主动脉僵硬越来越多地被证明是造成大多数人口发病率和死亡率负担的一系列疾病的风险因素。我们建议系统地评估人类基因组的遗传变异，改变这些因素的水平和它们之间的关系。这些研究应该确定以前没有涉及慢性疾病风险的基因，可能为干预开辟新的途径。

DESCRIPTION (provided by applicant): Accumulating evidence is establishing a series of less traditional risk factors as being critical for hypertension, cardiovascular disease and stroke. These factors include obstructive sleep apnea, impaired endothelial function, high central blood pressure and aortic stiffness. Furthermore, they are each associated with type 2 diabetes and its complications. The emergence of these non-traditional risk factors provides key physiologic targets where understanding the biological underpinnings could have substantial impact on developing strategies for disease prevention and/or slowing the progression of several chronic conditions. Each of these factors is known to have a substantial genetic component. Consequently, coupling appropriate measures of each in the context of a genome-wide association study has immense potential for elucidating those genes and pathways whose genetic variation mediates differences in risk factor levels and subsequently disease. Accordingly, we propose to measure this axis of non-traditional risk factors in 1,200 previously characterized Mexican Americans from Starr County, Texas, for whom we will already have genotyping from the Affymetrix Human Genome-Wide SNP Array 6.0 platform. This work builds on our 28 years of experience investigating the genetics and epidemiology of type 2 diabetes, its complications, and related conditions in Starr County. Specifically, we propose: 1) to determine the contribution of genetic variation to obstructive sleep apnea, impaired endothelial function, central blood pressure, aortic stiffness and their profile; 2) to determine whether type 2 diabetes and pre-diabetes mediate genomic associations with this axis of non-traditional risk factors; 3) to replicate significant results through collaboration with other groups including the Hispanic Health Cohort; and 4) to distinguish causal polymorphisms from those simply in linkage disequilibrium for identified genes through deep re-sequencing and analyses that exploit network theory and evolutionary contexts. There is a paucity of epidemiologic data for this axis of risk factors in the Hispanic population in general. Furthermore, genome-wide association studies of these risk factors in any population have not yet been conducted to any significant extent. Such studies have proven to be remarkably effective in identifying genes not previously implicated in chronic disease risk potentially opening new pathways for intervention. We expect our proposed study to do the same for this set of non-traditional risk factors. They are particularly attractive given their physiologic interrelatedness and their consistent associations with the constellation of diseases most responsible for the morbidity and mortality burden borne by most populations. PUBLIC HEALTH RELEVANCE: Obstructive sleep apnea, impaired endothelial function, high central blood pressure and aortic stiffness are increasingly being shown as risk factors for the constellation of diseases most responsible for the morbidity and mortality burden borne by most populations. We propose to systematically evaluate the human genome for genetic variation that alters the levels of these factors and their relationships. These studies should identify genes not previously implicated in chronic disease risk potentially opening new pathways for intervention.