Mitochondrial Variation and risk of T2DM

描述(由申请人提供)：遗传因素强烈影响II型糖尿病的风险，这是一种复杂的特征，影响着5-10%的美国人口。多条证据表明线粒体变异在II型糖尿病风险中的作用。线粒体是胰岛β细胞胰岛素分泌途径的重要组成部分，也是肌肉和肝脏细胞胰岛素敏感性的重要组成部分。一种罕见的母系遗传型II型糖尿病是由线粒体基因突变引起的，差异表达研究表明糖尿病肌肉中氧化3-磷酸化途径基因水平较低。这项研究的主要目标是确定普通T2 DM中OXPHOS途径的任何遗传变异的因果作用。这项研究的目的是全面检查关键线粒体和核编码的OXPHOS基因的常见变异，并确定OXPHOS变异在RMR易感性和II型糖尿病易感性中的作用。RMR是一种反映细胞能量学的数量性状。线粒体谱系和OXPHOS途径基因的常见变异将被编目，并在良好的研究中单独和联合测试与RMR和T2 DM的遗传关联。

DESCRIPTION (provided by applicant): Genetic factors strongly influence the risk of type II diabetes, a complex trait affecting 5-10% of the US population. Multiple lines of evidence point to a role of mitochondrial variation in risk of type II diabetes. Mitochondria are essential components of insulin secretion pathways in pancreatic beta cells and of insulin sensitivity in muscle and liver cells. A rare, maternally inherited form of type II diabetes is caused by a mitochondrial gene mutation, and differential expression studies indicate lower levels of oxidative 3hosphorylation pathway genes in diabetic muscle. The broad goal of this research is to characterize the causal role, if any of inherited variations in the OXPHOS pathway in common T2DM. The objective of this research proposal is to comprehensively examine common variation in key mitochondrial and nuclear-encoded OXPHOS genes, and identify the role of OXPHOS variation on susceptibility to RMR, a quantitative trait reflecting cell energetics, and to type II diabetes. Common variation in mitochondrial lineages and OXPHOS pathway genes will be catalogued, and tested, both singly and in combination, for genetic association to RMR and to T2DM in well powered studies.