Genomic approaches to cardiometabolic risk and treatment in HIV

描述（由申请人提供）：摘要随着超过三分之一的艾滋病毒感染者（PLWH）超过50岁，并且PLWH中心血管疾病（CVD）的发生率更高，我们可能会在未来十年见证这一人群中CVD发病率的急剧上升。PLWH中心脏代谢并发症的潜在发病机制尚未完全阐明，独特的风险因素仅部分解释PLWH中CVD相关风险增加。近年来，人们对一般人群中CVD遗传基础的了解迅速增长;然而，关于PLWH中遗传对CVD影响的数据非常有限。大多数艾滋病毒研究的样本量小，缺乏匹配的艾滋病毒对照，以及与大规模遗传分析相关的成本，可能解释了这一知识上的根本差距。虽然先前在一般人群中建立的多个基因座也与HIV相关的CVD风险有关，但可能存在与HIV感染相互作用的其他变体。本申请的目的是评估遗传风险负担是否有助于解释暴露于抗逆转录病毒治疗（ART）的PLWH中CVD风险较高的原因，并确定使用共享的HIV/CVD分子网络减轻CVD相关并发症的治疗机会。核心假设是，HIV中CVD并发症的风险增加至少可以部分解释为与HIV本身相互作用和/或加剧ART效应的已知和新型易感基因座的负担。 在强有力的初步数据的指导下，并利用通过艾滋病研究中心（CFAR）综合临床系统网络（CNICS）项目招募的大型特征良好的前瞻性队列和三个独立的复制队列，我们将追求以下具体目标：1）识别与CVD相关性状相关的遗传变异 在5，000例艾滋病病毒感染者中，研究艾滋病病毒阳性和阴性个体之间心脏代谢并发症机制的差异和共性; 2）探索ART对心血管健康的恶化效应是否至少部分可以通过遗传基因座的变异来解释; 3）鉴定在艾滋病病毒感染和心血管疾病相关性状中具有重叠治疗活性的药物化合物。这是高通量基因分型在PLWH（包括功能变异体）中的最大应用。使用基因组学和系统生物学方法，我们提出的研究将能够解决以下问题：a）哪些生物学途径导致艾滋病毒的心脏代谢并发症，以及它们如何与普通人群中检测到的并发症进行比较，B）哪些遗传变异加剧或减轻与ART相关的心脏代谢风险，以及c）ART和CVD疗法的最有效组合是什么。这项拟议的研究有望促进我们对PLWH CVD并发症中涉及的HIV相关途径的理解，并确定有助于减轻CVD风险的替代治疗策略。最终，这些知识有可能加强护理，减少PLWH中日益严重的不良心脏代谢结果问题。

DESCRIPTION (provided by applicant): ABSTRACT With over a third of persons living with HIV (PLWH) being over 50 and cardiovascular disease (CVD) occurring at a higher rate in PLWH, we are likely to witness a dramatic rise in the incidence of CVD in this population over the next decade. The underlying pathogenesis of cardiometabolic complications in PLWH has not yet been fully elucidated with the unique risk factors only partially accounting for increased CVD-related risks among PLWH. In recent years, there has been rapid growth in understanding the genetic basis for CVD in the general population; however, there is very limited data related to the impact of genetics on CVD in PLWH. The small sample size and lack of matched HIV- controls for most HIV studies, as well as the cost associated with large-scale genetic analyses, likely explain this fundamental gap in knowledge. While multiple loci previously established in the general population have also been implicated in HIV-related CVD risks, other variants may exist that interact with HIV infection. The objectives of this application are to assess if the genetic risk burden can help explain a higher risk of CVD in PLWH with exposure to antiretroviral therapy (ART) and identify therapeutic opportunities to mitigate CVD-related complications using the shared HIV/CVD molecular networks. The central hypothesis is that the increased risk of CVD complications in HIV can be at least in part explained by a burden of known and novel susceptibility loci that interact with HIV itself and/or exacerbate effects of ART. Guided by strong preliminary data and taking advantage of the large well-characterized prospective cohort recruited though the Center for AIDS Research's (CFAR) Network of Integrated Clinical Systems (CNICS) project and three independent replication cohorts, we will pursue the following specific aims: 1) Identify genetic variants associated with CVD-related traits in the setting of HIV in 5,000 PLWH and investigate differences and commonalities in the mechanisms of cardiometabolic complications between HIV+ and HIV- individuals; 2) Explore whether exacerbating effects of ART on cardiovascular health can be at least in part explained by variation at genetic loci, and 3) Identify drugs compounds with overlapping therapeutic activity in HIV infection and CVD-related traits. This is the largest application of the high-throughput genotyping in PLWH, including functional variants. Using genomic and systems biology approaches, our proposed studies will be able to address the following questions: a) which biological pathways lead to cadiometabolic complications in HIV and how they compare to those detected in the general population, b) which genetic variants exacerbate or mitigate cardiometabolic risks associated with ART, and c) what are the most effective combinations of ART and CVD therapies. The proposed research is expected to advance our understanding of HIV-related pathways involved in CVD complications in PLWH and determine alternative therapeutic strategies that can help mitigate CVD risks. Ultimately, such knowledge has the potential to enhance the care and reduce the growing problem of adverse cardiometabolic outcomes in PLWH.