Novel Mitochondrial DNA Variations Associated with Coronary Artery Disease in Type 2 Diabetes from an Asian Indian Population

摘要

Background: Mitochondrial dysfunction leading to insulin resistance may contribute to metabolic and cardiovascular abnormalities and subsequent increase in coronary artery disease. Since mitochondria are involved in generation of ROS, we aimed to investigate the association of mtDNA mutations with T2DM and CAD in our population. Methods: We analyzed the complete mtDNA of South Indian subjects which included patients with angiographically documented CAD [n = 120], subjects with Type 2 Diabetes Mellitus and CAD [n = 150] and healthy control subjects without clinical manifestations of atherosclerotic disease and Type 2 Diabetes [n = 100]. We detected the association of common variants of the mitochondrial genes with both T2DM and CAD, which raises the possibility of a shared mitochondrial genetic background of these metabolic disorders in our population. Results: The complete mitochondrial analysis of the control group revealed several sequence variations but did not show any novel mutations. Mitochondrial analysis of individuals with CAD and T2DM revealed a total of 36 novel variations. Mutations were more prevalent in NADH Dehydrogenase [ND] genes that encode mitochondrial enzyme Complex I. Among the 20 novel mutations in the ND genes, 17 were missense, 2 synonymous and 1 frame shift variant were observed. In Cytochrome b [Cytb] gene, 7 variations observed were novel that included 5 missense mutations in cytochrome c oxidase [CO2] were novel mutations including 1 missense mutation and 1 synonymous mutation. In rRNA genes, we identified 1 novel variant in 12s RNA and 3 in 16s rRNA. Among the CAD patient group without T2DM, 3 novel variants in ND region were identified of which 2 were synonymous and one was missense. The variants observed are not reported to have any disease association so far by any studies. Conclusions: Presence of pathogenic known and novel mutations suggests mtDNA variations have a role in the pathophysiology of CAD associated with T2DM in our population.