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Aims/hypothesis: This multinational study was conducted to investigate the association between a mitochondrial DNA (mtDNA) T16189C polymorphism and type 2 diabetes in Asians. The mtDNA 16189C variant has been reported to be associated with insulin resistance and type 2 diabetes. However, a recent meta-analysis concluded that it is negatively associated with type 2 diabetes in Europids. Since the phenotype of an mtDNA mutant may be influenced by environmental factors and ethnic differences in the nuclear and mitochondrial genomes, we investigated the association between the 16189C variant and type 2 diabetes in Asians., Methods: The presence of the mtDNA 16189C variant was determined in 2,469 patients with type 2 diabetes and 1,205 non-diabetic individuals from Korea, Japan, Taiwan, Hong Kong and China. An additional meta-analysis including previously published Asian studies was performed. Since mtDNA nucleotide position 16189 is very close to the mtDNA origin of replication, we performed DNA-linked affinity chromatography and reverse-phase liquid chromatography/tandem mass spectrometry and chromatin immunoprecipitation to identify protein bound to the 16189 region., Results: Analysis of participants from five Asian countries confirmed the association between the 16189C variant and type 2 diabetes [odds ratio (OR) 1.256, 95% CI 1.08-1.46, p=0.003]. Inclusion of data from three previously published Asian studies (type 2 diabetes n=3,283, controls n=2,176) in a meta-analysis showed similar results (OR 1.335, 95% CI 1.18-1.51, p=0.000003). Mitochondrial single-stranded DNA-binding protein (mtSSB) was identified as a candidate protein bound to the 16189 region. Chromatin immunoprecipitation in cybrid cells showed that mtSSB has a lower binding affinity for the 16189C variant than the wild-type sequence., Conclusions/interpretation: The mtDNA 16189C variant is associated with an increased risk of type 2 diabetes in Asians.

Microsatellite markers are an essential tool for genetic linkage analysis because of their high polymorphism content. Four hundred commercially available markers covering the entire genome were genotyped from 578 sib individuals from 249 Korean families. Allelic frequencies and heterozygosities were determined for each marker loci and compared between Korean, Taiwanese, Japanese and Caucasian populations. In the three Asian populations, 10-13% of the markers had less than 0.6 heterozygosity, whereas in the Caucasian population, only 0.5% of the markers had less than 0.6 heterozygosity. Mean identical by descent (IBD) values were calculated for 578 sib individuals. Analysis of IBD values greater than 0.5 suggested that markers with low heterozygosity can also provide positive linkages, at least for the IBD sharing method of model-free linkage analysis. The data presented in this study will be a useful reference for genome-wide screens of Koreans and comparative studies with other ethnic populations.