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)，动脉粥样硬化的一个亚临床标志，在艾滋病毒感染患者中始终高于未感染艾滋病毒的普通人群，即使在调整了传统的危险因素后也是如此。我们假设HIV相关因素直接或间接地加剧了编码钙(Ca~(2+))稳态基因的遗传变异的影响，从而加速和加重了CIMT。然而，到目前为止，这一途径还没有完全阐明。在这一应用中，我们已经(A)在脂肪再分布和HIV感染中的代谢变化(FRAM)研究中发现了与颈总动脉(CCA)cIMT增加显著相关的钙通道ryanodine受体2和3(RYR2和RYR3)中的SNPs，(B)在多中心艾滋病队列研究(MACS)中复制了RYR3变异的关联，(C)在女性机构间HIV研究(WIHS)中发现了RYR3中与CCA cIMT相关的其他变异，以及d)发现了RYR3中的变异，该变异增加了动脉粥样硬化结果的风险，特别是心力衰竭、心血管疾病在高血压遗传学相关治疗(GenHAT)研究中，比较服用钙通道阻滞剂与其他降压药的高血压患者。在这项应用中，我们将检验与钙离子稳态调节基因与临床前动脉粥样硬化相关的创新假说，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，我们将对来自上尾部(每个队列的1/3)的受试者(每个队列的1/3)、CCA CIMT分布排序的受试者(WIHS的466个和MACS的312个)和与下尾(1/3)匹配的778个个体的9个编码钙通道和相关蛋白的基因进行测序，以发现遗传变异及其与cIMT的关联。在目标1-阶段II中，我们将在MACS和WIHS的其余780名个体中对第一阶段的所有显著变异(在所有队列中个体或荟萃分析中P&lt；0.05)进行分型，并确认与所有2,336名HIV感染受试者的定量cIMT的相关性，并估计效应大小。在目标2中，我们将在独立队列FRAM的537名参与者中重复这些发现，FRAM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关联是否也可以用于冠状动脉钙化(CAC)，这是MACS中938名参与者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非感染对照(MACS中309人，WIHS中477人，FRAM中228人)的cIMT。我们提出的遗传学研究将有助于阐明HIV背景下动脉粥样硬化的钙依赖机制，这可能被用来开发新的遗传标记，用于筛选HIV患者的动脉粥样硬化预防新药。(摘要结束)

 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)