Aims: Type 2 Diabetes (T2D) is characterized by insulin resistance and failure of the pancreatic beta cells to compensate for this defect. Several studies have demonstrated a link between insulin resistance and impaired mitochondrial oxidative phosphorylation (OxPhos) in skeletal muscle. Recently, mitochondrial defects have also been implicated in beta-cell dysfunction in T2D. We hypothesized that single nucleotide polymorphisms (SNPs) in OxPhos genes could contribute to the pathogenesis of T2D.
Methods: Exploring results from a meta-analysis of genome wide association studies (GWAS) published by the Diabetes Genetics Replication And Meta-analysis Consortium (DIAGRAM), we found that among 1284 SNPs in 119 OxPhos genes, 39 SNPs in 7 genes showed potential association with T2D (p<0.01). Tagging by Haploview was used to exclude 28 SNPs that were in high linkage disequilibrium (r>0.8). One SNP with an allele frequency below 0.05 was not genotyped. The resulting 10 SNPs in or near 6 OxPhos genes were genotyped in 3,139 T2D patients and 5,302 control individuals with normal glucose tolerance (NGT).-- page break --
Results: We found that rs1466100 in COX5B (OR=1.67, p=0.004) and rs9915302 in COX10 (OR=1.14, p=0.02) were significantly associated with T2D. In a subsequent meta-analysis combining our results with data from an avaliable subset of the DIAGRAM data, we demonstrated that three SNPs (rs10775377, rs8077302, rs9915302) in COX10 and a SNP (rs2267584) in a gene (UPK1A) next to COX6B1 were significantly associated with T2D. In particular, the rs9915302 variant in COX10 showed strong association with T2D in the meta-analysis (OR=1.14, p=7.7 x 10-6). Analysis of quantitative traits, applying an additive model and adjusting for age and sex, revealed significant associations (p<0.05) between a surrogate marker (BIG-AIR) for insulin secretion and variants in COX5B (rs11904110) and COX10 (rs10521253), and between fasting p-glucose and a variant in COX5B (rs11904110) and 2-h post-OGTT plasma glucose and a variant in NDUFV3 (rs8134542) (p<0.05).
Conclusions: Our data suggest that genetic variants in or near subunits in complex IV (COX5B, COX6B1, COX10) contribute to the pathogenesis of T2D. The association of other variants in COX5B and COX10 and a variant in the complex I gene, NDUFV3, with markers of insulin secretion and postprandial hyperglycaemia supports a role for mitochondrial defects in beta-cell dysfunction in T2D. It does, however, not exclude a role for variants in OxPhos genes in the link between mitochondrial dysfunction and insulin resistance in skeletal muscle in T2D.
|Number of pages||1|
|Publication status||Published - 2010|
|Event||Dansk Endokrinologisk Årsmøde - Herlev, København, Denmark|
Duration: 22. Jan 2010 → 23. Jan 2010
|Conference||Dansk Endokrinologisk Årsmøde|
|Period||22/01/2010 → 23/01/2010|
- Type 2 Diabetes Mellitus
- Mitochondrial dysfunction