Genomic approaches to cardiometabolic risk and treatment in HIV

随着超过三分之一的艾滋病毒感染者（PLWH）年龄在50岁以上，心血管疾病（CVD）在PLWH中的发病率更高，我们很可能在未来十年内见证这一人群中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，其独特的危险因素仅部分解释了PLWH中cvd相关风险的增加。近年来，对普通人群心血管疾病遗传基础的了解迅速增加；然而，遗传学对PLWH患者心血管疾病影响的相关数据非常有限。大多数艾滋病毒研究的小样本量和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，可能解释了这种知识上的根本差距。虽然先前在普通人群中建立的多个基因座也与HIV相关的心血管疾病风险有关，但可能存在与HIV感染相互作用的其他变异。本应用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CVD的风险较高，并确定利用共享的HIV/CVD分子网络减轻CVD相关并发症的治疗机会。中心假设是，艾滋病毒中心血管疾病并发症的风险增加至少可以部分解释为已知和新的易感位点的负担，这些易感位点与艾滋病毒本身相互作用和/或加剧抗逆转录病毒治疗的效果。

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.