Genetics of atherosclerosis in renal disease

描述（由申请人提供）：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CVD的主要危险因素，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具有共同的遗传基础。先天性免疫和胰岛素抵抗在动脉粥样硬化中汇合，是CKD的突出特征。我们假设，在这种情况下，先天免疫和胰岛素抵抗途径基因的遗传变异将单独或通过多位点效应对CKD人群中CVD的临床重要风险做出贡献，而不是传统的风险因素。慢性肾功能不全队列（CRIC）研究是一项前瞻性的NIH赞助的CKD肾脏和CVD并发症的多中心研究（n= 3000），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赞助的项目获得的大多数候选基因（n=52）的重测序数据，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snp。我们将测试标签snp和单倍型与炎症和胰岛素抵抗生物标志物、冠状动脉钙化（CAC）（动脉粥样硬化的直接指标）和临床心血管疾病结局的关系。我们的统一假设（Aim 3）具有机制、治疗和公共卫生意义，即候选基因的多位点组合将在临床上以重要的方式对CKD人群的归因风险或CVD做出贡献。这将是第一个全面的、前瞻性的研究之一，将产生无偏倚的基于人群的风险数据，解决这一重要的、在很大程度上被忽视的遗传风险组成部分。我们将继续进行与心血管疾病相关的单核苷酸多态性、单倍型和多位点基因型的功能研究，这可能最终改变我们如何利用人类遗传数据进行治疗、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.