Assessing the role of the mitochondrial genome in type 2 diabetes mellitus and related traits in Finns

E.C. Peck, K.L. Mohlke, A.U. Jackson, Y. Suh, P.S. Chines, L.J. Scott, J. Tuomilehto, R.N. Bergman, M. Boehnke, F.S. Collins, FUSION Study Group

NHGRI, Bethesda, MD; U. Michigan, Ann Arbor, MI; National Public Health Institute, Helsinki, Finland; U. Southern California, Los Angeles, CA

Type 2 diabetes mellitus (T2DM), a complex gene disorder, accounts for approximately 90% of diabetes cases. T2DM has strong genetic and environmental components and is characterized by insulin resistance as well as pancreatic beta cell dysfunction. Since mitochondria play an integral role in ATP production in cells and are involved in glucose metabolism and insulin secretion, variants in the mitochondrial genome are plausible candidates for contributing to diabetes susceptibility. In our study of 793 Finnish families ascertained for T2DM, probands reported affected mothers three times more frequently than they reported affected fathers. To assess whether this apparent excess maternal transmission can be explained by mitochondrial variants, we selected single nucleotide polymorphisms (SNPs) based on phylogenetic networks. We selected 15 SNPs that define the major haplogroups and 18 that subdivide groups H and U, which are common in Finns. We genotyped the SNPs on one T2DM case per family and unaffected controls using primer extension MALDI-TOF mass spectrometry. We were able to assign haplogroups to 789 cases and 414 controls; in addition, we assigned the maternal haplogroup to 480 offspring of genotyped females. We evaluated association with both affected status and 8 to 14 diabetes-related traits for each of the cases, controls, and offspring. One of these traits was glucose effectiveness, which is the ability of glucose to enhance glucose disposal independent of an increment in insulin. The strongest evidence for phenotypic association was reduced glucose effectiveness in offspring from haplogroup V (p-value = 0.0003). No haplogroup, however, showed notable association with T2DM affected status (best p-value = 0.081 for haplogroup J). This study suggests that mitochondrial variants may play a modest role in glucose metabolism in the Finnish population.