Mitochondrial DNA Haplogroups and Diabetes-related Outcomes in MACS

描述（由申请人提供）：线粒体DNA（mtDNA）单倍型群可影响线粒体功能，并与一般人群中的糖尿病相关。IR和DM更常发生在HIV感染者中，并且是发病率和死亡率的重要原因，尽管进行了有效的抗逆转录病毒治疗（ART）。在多中心艾滋病队列研究（MACS）的分析中，HIV感染男性比HIV血清阴性男性有更大的IR和DM风险。这些并发症的病理生理学尚未完全确定。脂联素是一种脂肪细胞源性激素，具有多种有益特性，与线粒体功能有关。低脂联素与一般人群中的IR和DM相关，在HIV感染者中很常见。我们相信HIV感染和ART会造成线粒体损伤和糖代谢异常，从而建立一个富含糖尿病相关表型的人群，包括低脂联素血症和IR。线粒体DNA单倍型群与HIV和ART相关的不良结局相关。虽然没有研究评估HIV感染者mtDNA变异与DM之间的关系，但最近的研究发现mtDNA变异、IR和脂联素之间存在关联，表明脂联素失调可能是mtDNA变异影响IR和DM的一种新机制。该提案的共同研究者开发了使用来自通用平台的全基因组关联研究（GWAS）数据推导单倍型组的算法，使我们能够利用现有的全基因组基因型数据以及现有的mtDNA单倍型组数据，对MACS中单倍型组与糖尿病相关表型之间的关联进行二次分析。我们还将为大多数MACS参与者生成新的mtDNA单倍群数据，增加我们的分析样本量。我们的假设是IR和DM的风险：（a）与mtDNA单倍型群相关;（B）由慢性HIV感染和ART的额外线粒体“应激源”加重;（c）由脂联素和脂肪细胞线粒体功能介导。我们将在以下目标中检验这些假设：1）确定mtDNA单倍型群与MACS参与者中的流行和偶发DM之间的关联; 2）确定mtDNA单倍型群与欧洲血统的MACS参与者中的IR之间的关联; 3）探索HIV感染和未感染的MACS参与者中mtDNA单倍型群与循环脂联素水平之间的关联;以及4）探索HIV血清阳性临床试验参与者ART前和ART期间mtDNA单倍型群与脂肪线粒体功能、脂联素水平和IR之间的关联。本项目中拟议的二次分析将使用创新方法从现有的全基因组基因型数据中获得mtDNA单倍型群，将包括血清脂联素和脂肪线粒体功能的新分析，并将直接告知未来的干预研究，以预防和/或治疗艾滋病毒感染和未感染人群的IR和DM。

DESCRIPTION (provided by applicant): Mitochondrial DNA (mtDNA) haplogroups can affect mitochondrial function, and have been associated with diabetes in the general population. IR and DM occur more frequently in persons with HIV infection, and are important causes of morbidity and mortality despite effective antiretroviral therapy (ART). In analyses of the Multicenter AIDS Cohort Study (MACS), HIV-infected men had a significantly greater risk of IR and DM than HIV-seronegative men. The pathophysiology of these complications is not well established. Adiponectin is an adipocyte-derived hormone with diverse beneficial properties, and is related to mitochondrial function. Low adiponectin is associated with IR and DM in the general population, and is common in HIV-infected persons. We believe HIV-infection and ART create a milieu of mitochondrial damage and abnormal glucose metabolism, thus establishing a population enriched with diabetes-related phenotypes, including hypoadiponectinemia and IR. Mitochondrial DNA haplogroups have been associated with HIV- and ART-related adverse outcomes. Although no studies have assessed relationships between mtDNA variation and DM in HIV-infected persons, recent studies found associations between mtDNA variants, IR and adiponectin, suggesting that adiponectin dysregulation may be a novel mechanism by which mtDNA variation influences IR and DM. A co-investigator on this proposal has developed algorithms to derive haplogroups using genome-wide association study (GWAS) data from common platforms, enabling us to utilize available genome-wide genotype data in addition to existing mtDNA haplogroup data to perform secondary analyses of associations between haplogroups and diabetes-related phenotypes in MACS. We will also generate new mtDNA haplogroup data for the majority of MACS participants, increasing our analysis sample sizes. Our hypotheses are that the risk of IR and DM is: (a) associated with mtDNA haplogroups; (b) accentuated by additional mitochondrial "stressors" of chronic HIV infection and ART; and (c) mediated by adiponectin and adipocyte mitochondrial function. We will test these hypotheses in the following aims: 1) Determine associations between mtDNA haplogroups and prevalent and incident DM among MACS participants; 2) Determine associations between mtDNA haplogroups and IR among MACS participants of European ancestry; 3) Explore associations between mtDNA haplogroups and circulating adiponectin levels in HIV-infected and uninfected MACS participants; and 4) Explore associations between mtDNA haplogroups and adipose mitochondrial function, adiponectin levels, and IR in HIV seropositive clinical trial participants before and during ART. The proposed secondary analyses in this project will use innovative methods to obtain mtDNA haplogroups from existing genome-wide genotype data, will include novel analyses of serum adiponectin and adipose mitochondrial function, and will directly inform future studies of interventions to prevent and/or treat IR and DM in HIV-infected and uninfected populations.