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携带者(PLWH)超过50岁，在PLWH中心血管疾病(CVD)的发病率更高，我们可能会看到这一人群在未来十年中心血管疾病的发病率急剧上升。PLWH的心脏代谢并发症的潜在发病机制尚未完全阐明，其独特的危险因素仅部分解释了PLWH中心血管疾病相关风险的增加。近年来，在普通人群中对心血管疾病的遗传基础的了解迅速增长，然而，关于遗传学对PLWH中心血管疾病的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，以及与大规模基因分析相关的成本，可能解释了知识方面的根本差距。虽然以前在普通人群中建立的多个基因座也与艾滋病毒相关的心血管疾病风险有关，但可能存在其他与艾滋病毒感染相互作用的变种。该应用程序的目的是评估遗传风险负担是否有助于解释接受抗逆转录病毒治疗(ART)的PLWH患者发生心血管疾病的更高风险，并利用共享的艾滋病毒/心血管疾病分子网络确定减轻心血管疾病相关并发症的治疗机会。中心假设是，艾滋病毒心血管并发症风险的增加至少部分可以由已知和新的易感基因的负担来解释，这些易感基因与艾滋病毒本身相互作用和/或加剧抗逆转录病毒疗法的影响。 在强大的初步数据的指导下，利用艾滋病研究中心(CFAR)的综合临床系统网络(CNICs)项目和三个独立的复制队列招募的大量具有良好特征的预期队列，我们将追求以下具体目标：1)识别与心血管疾病相关特征相关的基因变异 2)探索抗逆转录病毒疗法对心血管健康的恶化作用是否至少部分可以通过基因座的变异来解释，以及3)确定在艾滋病毒感染和心血管疾病相关特征中具有重叠治疗活性的药物化合物。这是包括功能变异在内的高通量基因分型在PLWH中的最大应用。利用基因组和系统生物学方法，我们拟议的研究将能够解决以下问题：a)哪些生物途径导致艾滋病毒的心脏代谢并发症，以及它们与在普通人群中检测到的那些途径相比如何；b)哪些基因变异加剧或减轻了与抗逆转录病毒治疗相关的心脏代谢风险；以及c)什么是抗逆转录病毒治疗和心血管疾病治疗的最有效组合。这项拟议的研究有望促进我们对与PLWH的CVD并发症有关的艾滋病毒相关途径的理解，并确定有助于降低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中日益严重的心脏代谢不良结局问题。

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.