Genetic Variants in Calcium Channel and Binding Proteins Underlying cIMT in HIV

 描述（申请人提供）：颈动脉内膜中层厚度（cIMT）是动脉粥样硬化的亚临床标志物，即使在调整传统风险因素后，HIV感染患者的cIMT始终高于HIV未感染的一般人群。我们推测，HIV相关因素直接或间接加剧了编码钙（Ca 2+）稳态的基因的遗传变异的影响，这可以加速和加重cIMT。然而，迄今为止，这一途径尚未完全阐明。导致这一应用，我们已经（a）鉴定了Ca 2+通道兰尼碱受体2和3中的SNP在HIV感染的脂肪再分布和代谢变化（弗拉姆）研究中，与颈总动脉（CCA）cIMT增加显著相关的RYR 2和RYR 3变体，（B）在多中心AIDS队列研究（MACS）中复制了RYR 3变体的关联，（c）在妇女机构间HIV研究（WIHS）中鉴定出与CCA cIMT相关的RYR 3中的其他变体，以及在高血压相关治疗遗传学研究中，与其他降压药物相比，GenHAT）研究。在本申请中，我们将测试与Ca 2+稳态调节基因与临床前动脉粥样硬化相关的创新假设，并在三个特征良好的HIV队列中系统地进行多阶段研究。在目标1-阶段I中，我们将对来自上尾（每个队列的1/3）的CCA cIMT分布（466个来自WIHS，312个来自MACS）和下尾（1/3）匹配的778个年龄和种族频率的受试者中编码Ca 2+通道和相关蛋白的9个基因进行测序，以发现遗传变异及其与cIMT的相关性。在目标1-阶段II中，我们将对MACS和WIHS中剩余的780名个体中来自阶段I的所有显著变异体进行基因分型（在所有队列个体或荟萃分析中p<0.05），并在所有2，336名HIV感染受试者中确认与定量cIMT的相关性，并估计效应量。在目标2中，我们将在独立队列弗拉姆的537名参与者中复制这些结果，该队列使用与WIHS和MACS不同的方法测量cIMT。在目标3中，我们将评估这些重复的关联是否也可以通过冠状动脉钙（CAC）来验证，CAC是MACS中938名参与者的亚临床动脉粥样硬化的替代指标，在目标4中，我们将检查这些变异是否影响1，014名HIV未感染对照（MACS中309名，WIHS中477名，弗拉姆中228名）的cIMT。我们提出的遗传学研究将有助于阐明在HIV背景下动脉粥样硬化的Ca 2+依赖机制，这可能用于开发新的遗传标记物用于筛选和预防HIV患者动脉粥样硬化的新药。(End摘要）

 DESCRIPTION (provided by applicant): Carotid intima-media thickness (cIMT), a subclinical marker of atherosclerosis, is consistently higher among HIV-infected patients than in the HIV non-infected general population, even after adjusting for traditional risk factors. We hypothesize that HIV-related factors exacerbate the effects of genetic variations of genes encoding calcium (Ca2+) homeostasis directly or indirectly, which can accelerate and accentuate cIMT. However, to date this pathway has not been fully elucidated. Leading to this application, we have (a) identified SNPs in Ca2+ channels ryanodine receptors 2 and 3 (RYR2 and RYR3) that are significantly associated with increased common carotid artery (CCA) cIMT in the Fat Redistribution and Metabolic Change in HIV infection (FRAM) study, (b) replicated the association of the RYR3 variant in the Multicenter AIDS Cohort Study (MACS), (c) identified other variants in RYR3 associated with CCA cIMT in Women's Interagency HIV Study (WIHS), and d) identified variants in RYR3 that increased risk of atherosclerotic cardiovascular outcomes, specifically heart failure, among hypertensive patients on Ca2+ channel blockers compared to other antihypertensive drugs in the Genetics of Hypertension Associated Treatment (GenHAT) study. In this application we will test the innovative hypothesis related to the association of genes involved in regulation of Ca2+ homeostasis with pre-clinical atherosclerosis and systematically conduct a multi-stage study in three well-characterized HIV cohorts. In Aim 1- stage I, we will sequence 9 genes encoding Ca2+ channels and related proteins in subjects from the upper tail (1/3rd of each cohort) ranked CCA cIMT distribution (466 from WIHS and 312 from MACS) and the 778 individuals age and race frequency matched in the lower tail (1/3rd), to discover genetic variants and their association with cIMT. In Aim 1- stage II, we will genotype all significant variants from stage I (p<0.05 in all cohorts individuall or in meta-analysis) in the remaining 780 individuals in MACS and WIHS and confirm the association with quantitative cIMT in all 2,336 HIV-infected subjects and estimate effect size. In Aim 2, we will replicate these findings in 537 participants in an independent cohort, FRAM, which measured cIMT with a different method than in WIHS and MACS. In Aim 3, we will assess whether these replicated associations can also be validated for coronary artery calcium (CAC), an alternate measure for subclinical atherosclerosis in 938 participants in MACS and in Aim 4, we will examine if these variants influence cIMT in 1,014 HIV non-infected controls (309 in MACS, 477 in WIHS and 228 in FRAM). Our proposed genetic study will help elucidate Ca2+- dependent mechanisms of atherosclerosis in the context of HIV, which potentially could be used to develop novel genetic markers for screening and new drugs for atherosclerosis prevention in HIV patients. (End of Abstract)