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

基本信息

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
项目类别：
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

项目摘要

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）单倍群会影响线粒体功能，并且与一般人群中的糖尿病有关。 IR和DM在患有HIV感染的人中更频繁地发生，尽管有效的抗逆转录病毒疗法（ART）是发病率和死亡率的重要原因。在对多中心艾滋病队列研究（MACS）的分析中，与HIV辅助男性相比，感染HIV的男性患IR和DM的风险明显更大。这些并发症的病理生理学尚未确定。脂联素是一种具有不同有益特性的脂肪细胞衍生的激素，与线粒体功能有关。低脂联素与普通人群中的IR和DM相关，在HIV感染者中很常见。我们认为，艾滋病毒感染和艺术创造了线粒体损害和异常葡萄糖代谢的环境，从而建立了富含糖尿病相关表型的人群，包括低脂肪核血症和IR。线粒体DNA单倍体与HIV和艺术相关的不良结果有关。尽管尚未评估艾滋病毒感染者中mtDNA变异与DM之间的关系，但最近的研究发现mtDNA变体，IR和脂联素之间的关联表明脂联素失调可能是mtDNA变异影响IR和DM的新型机制。该提案上的共同评估器已开发出使用全基因组关联研究（GWAS）数据来得出单倍型的算法，从而使我们能够利用现有的MTDNA单倍型数据除外，除了现有的MTDNA单倍体数据外，还可以执行单倍型和糖尿病和糖尿病的二倍分析的二级分析。我们还将为大多数MAC参与者生成新的mtDNA单倍群数据，从而增加分析样本量。我们的假设是IR和DM的风险是：（a）与mtDNA单倍群相关；（b）由慢性艾滋病毒感染和艺术的其他线粒体“压力源”强调；（c）由脂联素和脂肪细胞线粒体功能介导。我们将在以下目的中检验这些假设：1）确定MTDNA单倍群与MAC参与者之间普遍存在的DM和事件DM之间的关联； 2）确定欧洲血统参与者MTDNA单倍群与IR之间的关联； 3）探索MTDNA单倍群与艾滋病毒感染和未感染的MAC参与者中的脂联素水平之间的关联； 4）探索MTDNA单倍群与脂肪线粒体功能，脂联素水平和IR在ART之前和期间HIV血清阳性临床试验参与者中的关联。该项目中提出的二次分析将使用创新的方法从现有全基因组基因型数据中获得mtDNA单倍群，包括新的分析血清脂联素和脂肪线粒体功能，并将直接为预防和/或对HIV INIV INIV INIV INIV和DM IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN IN和DM IN IR和DM处理。