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.
