Mitochondrial DNA Haplogroups and Diabetes-related Outcomes in MACS

描述(由申请人提供)：线粒体DNA(MtDNA)单倍群可以影响线粒体功能，并与普通人群中的糖尿病有关。尽管有效的抗逆转录病毒治疗(ART)，但IR和DM在艾滋病毒感染者中更常见，是发病率和死亡率的重要原因。在多中心艾滋病队列研究(MACS)的分析中，HIV感染的男性患IR和DM的风险明显高于HIV血清阴性的男性。这些并发症的病理生理学机制尚不清楚。脂联素是一种脂肪细胞来源的激素，具有多种有益性质，与线粒体功能有关。在普通人群中，低脂联素与胰岛素抵抗和糖尿病有关，在艾滋病毒感染者中很常见。我们认为，HIV感染和ART创造了线粒体损伤和糖代谢异常的环境，从而建立了一个富含糖尿病相关表型的人群，包括低脂联素血症和胰岛素抵抗。线粒体DNA单倍群与艾滋病毒和抗逆转录病毒治疗相关的不良后果有关。虽然还没有研究评估线粒体DNA变异与HIV感染者糖尿病的关系，但最近的研究发现线粒体DNA变异、IR和脂联素之间存在关联，提示脂联素失调可能是线粒体DNA变异影响IR和DM的新机制。这项提议的一位联合调查员已经开发了使用来自通用平台的基因组范围关联研究(GWAS)数据来推导单倍组的算法，使我们能够利用现有的mtDNA单倍组数据之外的现有基因组范围的基因型数据来对单倍组和Mac中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，从而增加我们的分析样本大小。我们的假设是，IR和DM的风险是：(A)与mtDNA单倍群相关；(B)因慢性HIV感染和ART的额外线粒体“应激源”而加重；以及(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单群与MACS参与者中流行和发生的DM之间的关联；2)确定欧洲血统的MACS参与者中mtDNA单群与IR之间的关联；3)探索HIV感染和未感染MACS参与者中mtDNA单群与循环脂联素水平之间的关联；以及4)探索mtDNA单群与抗逆转录病毒治疗前和期间HIV血清阳性临床试验参与者的脂肪线粒体功能、脂联素水平和IR之间的关联。该项目中拟议的二次分析将使用创新的方法从现有的全基因组基因数据中获得mtDNA单倍群，将包括对血清脂联素和脂肪线粒体功能的新分析，并将直接为未来预防和/或治疗艾滋病毒感染和未感染人群中的胰岛素抵抗和糖尿病的干预研究提供信息。

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.