Type 2 Diabetes (T2D) is a chronic disease, characterized by hyperglycaemia, caused by decreased insulin secretion by beta-cells and insulin resistance of target tissues of insulin. Several risk... Show moreType 2 Diabetes (T2D) is a chronic disease, characterized by hyperglycaemia, caused by decreased insulin secretion by beta-cells and insulin resistance of target tissues of insulin. Several risk factors are known, like decreased exercise, ageing and western diet. Also genetic variance can alter susceptibility to develop T2D. Until recently only four T2D susceptibility genes were identified (PPARG, KCNJ11, CAPN10 and TCF7L2). However, recent Genome Wide Association Studies (GWAS) have increased this number to at least 20. My thesis describes the search for additional T2D susceptibility genes. For this we used a classical candidate gene approach and we case/control studies from the Netherlands, Scandinavia and the UK. We selected 14 nuclear encoded candidate genes, all regarded essential for mitochondrial protein synthesis and biogenesis. Since mitochondrial function was shown to be associated with T2D, we hypothesized that genes in these pathways are good candidates. Tagging SNPs were selected, which should cover all known common variation (minor allele frequency (MAF) > 0.05) in the candidate genes. These tagging SNPs were measured in our first stage, comprising of the Dutch Hoorn study and significant associations were than taking forward for replication in our replication cohorts in the second stage of this study. However, after second stage genotyping non of the signals remained significant, indicating that the selected candidate genes do not play a major role in T2D susceptibility. Furthermore, nuclear encoded mitochondrial genes were not among the top hits of GWAS, which were made available online after completion of our study. Therefore, we conclude that nuclear encoded mitochondrial genes do not have a major contribution to the development of T2D. Next, we analyzed the association of mitochondrial DNA (mtDNA) content with T2D. First we estimated the heritability in Dutch twins and found a heritability of 35% (19%-48%). Next we analyzed the association with prevalent and incident T2D in a Dutch case control study and two prospective studies from the Netherlands and Finland. However, no associations were observed. Therefore, we conclude that mtDNA content does not play a major role in the development of T2D. Finally, we analyzed four known fasting plasma glucose (FPG) influencing genes (GCK, GCKR, G6PC2 and MTNR1B). In a Dutch population based sample we could replicate the association of these genes with FPG levels (except for GCKR). Furthermore, the combined risk alleles (ranging from 0 to 8 risk alleles) were strongly associated with FPG and HbA1C levels. This risk allele score was also associated with T2D susceptibility and age of diagnosis at T2D. We therefore conclude that the FPG influencing genes have a combined effect on FPG and are associated with T2D susceptibility and age at diagnosis of T2D. In conclusion, we could not find evidence that nuclear encoded mitochondrial proteins and mtDNA content are associated with T2D susceptibility. The four known FPG genes do not only influence FPG levels, but also have a combined effect on T2D susceptibility and age at diagnosis of T2D. Show less
