Mitochondrial Variation and risk of T2DM

描述（由申请人提供）：遗传因素强烈影响2型糖尿病的风险，这是一种影响5-10%美国人口的复杂特征。多种证据表明线粒体变异在II型糖尿病风险中的作用。线粒体是胰腺β细胞胰岛素分泌途径以及肌肉和肝细胞胰岛素敏感性的重要组成部分。一种罕见的母亲遗传型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磷酸化途径基因的水平较低。本研究的主要目的是确定常见T2DM中OXPHOS通路的遗传变异是否存在因果关系。本研究计划的目的是全面研究线粒体和核编码的关键OXPHOS基因的常见变异，并确定OXPHOS变异在RMR易感性（反映细胞能量学的数量性状）和II型糖尿病中的作用。将对线粒体谱系和OXPHOS通路基因的常见变异进行分类，并对其进行单独和组合的测试，以在有力的研究中确定与RMR和T2DM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.