Mitochondrial DNA Haplogroups and Diabetes-related Outcomes in MACS

MACS 中的线粒体 DNA 单倍群和糖尿病相关结果

• 批准号: 8731432
• 负责人: TODD T BROWN
• 金额: $ 24.83万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-23 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8731432
• 关键词: AIDS clinical trial group; Acquired Immunodeficiency Syndrome; Adipocytes; Adipose tissue; Affect; Algorithms; Antioxidants; Biogenesis; Cardiovascular Diseases; Chronic; Clinical Data; Clinical Trials; Cohort Studies; Data; Diabetes Mellitus; Disease Progression; European; Exposure to; Functional disorder; Future; General Population; Genomics; Genotype; Goals; HIV; HIV Infections; Haplogroup; Health; Hepatitis C virus; Hormones; Human Genetics; In Vitro; Inherited; Insulin Resistance; Intervention Studies; Knowledge; Lipoatrophy; Measures; Mediating; Mediator of activation protein; Metabolic; Metabolic Diseases; Methods; Mitochondria; Mitochondrial DNA; Morbidity - disease rate; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Participant; Pathogenesis; Persons; Phenotype; Population; Populations at Risk; Property; Regimen; Research; Research Personnel; Risk; Role; Sample Size; Sampling; Serum; Testing; Therapy Clinical Trials; Variant; Woman; Work; adiponectin; adverse outcome; antiretroviral therapy; genetic risk factor; genome wide association study; genome-wide; glucose metabolism; healthy volunteer; improved; innovation; men; mitochondrial dysfunction; mortality; novel; prevent; public health relevance; stressor

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.

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，并且与普通人群中的糖尿病有关。 IR 和 DM 在 HIV 感染者中更常见，尽管抗逆转录病毒治疗 (ART) 有效，但它们仍然是发病和死亡的重要原因。在多中心艾滋病队列研究 (MACS) 的分析中，感染 HIV 的男性患 IR 和 DM 的风险明显高于 HIV 血清阴性男性。这些并发症的病理生理学尚未明确。脂联素是一种脂肪细胞衍生的激素，具有多种有益特性，并且与线粒体功能相关。低脂联素与一般人群中的 IR 和 DM 相关，并且在 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葡萄糖代谢异常，从而形成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 单倍群与 HIV 和 ART 相关的不良后果有关。尽管没有研究评估 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 的新机制。该提案的一位共同研究员开发了算法，使用来自通用平台的全基因组关联研究 (GWAS) 数据来推导单倍群，使我们能够利用可用的全基因组基因型数据以及现有的 mtDNA 单倍群数据来进行关联的二次分析MACS 中单倍群和糖尿病相关表型之间的关系。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 的风险是： (a) 与 mtDNA 单倍群相关； (b) 慢性艾滋病毒感染和抗逆转录病毒疗法的额外线粒体“应激源”加剧； (c) 由脂联素和脂肪细胞线粒体功能介导。我们将按照以下目标测试这些假设：1）确定 mtDNA 单倍群与 MACS 参与者中流行和偶发 DM 之间的关联； 2) 确定欧洲血统的 MACS 参与者中 mtDNA 单倍群与 IR 之间的关联； 3) 探索 HIV 感染和未感染 MACS 参与者的 mtDNA 单倍群与循环脂联素水平之间的关联； 4) 探索 HIV 血清阳性临床试验参与者在 ART 之前和期间的 mtDNA 单倍群与脂肪线粒体功能、脂联素水平和 IR 之间的关联。该项目提出的二次分析将使用创新方法从现有全基因组基因型数据中获取 mtDNA 单倍群，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 IR 干预措施的研究提供信息艾滋病毒感染者和未感染者的糖尿病。