Genetics of atherosclerosis in renal disease

描述(申请人提供)：动脉粥样硬化性心血管疾病(CVD)是一种具有复杂遗传基础的炎症性疾病。慢性肾脏疾病(CKD)是心血管疾病的一个主要危险因素，在美国正在迅速增加。这些疾病之间的机制联系在很大程度上仍未确定。最近的研究表明，胰岛素抵抗、肾功能障碍和心血管疾病有着共同的遗传基础。先天免疫和胰岛素抵抗在动脉粥样硬化中汇聚，是CKD的显著特征。我们假设，在这种情况下，先天性免疫和胰岛素抵抗途径基因的遗传变异将单独并通过多位点效应在CKD人群中对临床上重要的CVD风险做出贡献，而不是传统的危险因素。慢性肾功能不全队列研究(CRIC)是一项由国立卫生研究院赞助的关于CKD肾脏和心血管并发症的前瞻性多中心研究(n=3,000)，它为检验这些假设提供了一个独特的机会。我们将使用通过NIH赞助的计划获得的大多数候选基因(n=52)的重新测序数据，来选择定义先天免疫(AIM 1)和胰岛素抵抗(AIM 2)候选基因共同变异的标签SNPs。我们将测试TagSNPs和单倍型与炎症和胰岛素抵抗生物标记物、冠状动脉钙化(CAC)(动脉粥样硬化的直接指标)和临床CVD结果的关系。我们的统一假设(目标3)具有机械学、治疗学和公共卫生的含义，即候选基因的多位点组合将以临床重要的方式对CKD人群的归因风险或CVD做出贡献。这将是首批全面的前瞻性研究之一，这些研究将产生无偏见的基于人群的风险数据，解决这一重要的、基本上被忽视的遗传风险组成部分。我们将继续对被发现与心血管疾病相关的SNPs、单倍型和多位点基因类型进行功能研究，这最终可能改变我们如何将人类基因数据用于治疗、诊断和公共卫生目的的范式。

DESCRIPTION (provided by applicant): Atherosclerotic cardiovascular disease (CVD) is an inflammatory disorder with a complex genetic basis. Chronic kidney disease (CKD), a major risk factor for CVD, is rapidly increasing in the U.S. The mechanistic link between these diseases remains largely undetermined. Recent studies suggest that insulin resistance, kidney dysfunction and CVD share common genetic bases. Innate immunity and insulin resistance converge in atherosclerosis and are prominent features of CKD. We hypothesize that, in this setting, genetic variation in innate immune and insulin resistance pathway genes will contribute individually and through multi-locus effects, to clinically important risk of CVD in the CKD population beyond traditional risk factors. The Chronic Renal Insufficiency Cohort (CRIC) Study, a prospective NIH sponsored multi-center study (n=3,000) of renal and CVD complications of CKD, provides a unique opportunity to examine these hypotheses. We will use re-sequencing data, available for most of our candidate genes (n=52) through NIH- sponsored programs, to select tagSNPs that define the common variation in innate immune (Aim 1) and insulin resistance (Aim 2) candidate genes. We will test the relationship of tagSNPs and haplotypes with inflammatory and insulin resistance biomarkers, coronary artery calcification (CAC), a direct measure of atherosclerosis, and clinical CVD outcomes. Our unifying hypothesis (Aim 3), with mechanistic, therapeutic and public health implications, is that multi- locus combinations of candidate gene will contribute in a clinically important manner to the attributable risk or CVD in the CKD population. This will be one of the first comprehensive, prospective, studies that will generate unbiased population-based risk data addressing this important and largely neglected component of genetic risk. We will pursue functional studies of SNPs, haplotypes and multi-locus genotypes, found to be associated with CVD that may, ultimately, change the paradigm of how we utilize human genetic data for therapeutic, diagnostic and public health purposes.