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Johan Holmkvist

Exploring Positional and Functional Candidate Genes for Type 2 Diabetes

Type 2 diabetes (T2D) is a complex, metabolic disorder characterized by hyperglycaemia because of defects in insulin secretion and sensitivity. The rapid increase in T2D is likely to reflect the influence of both genetic and environmental factors in disease development. However, the genetic aetiology of T2D remains largely unknown. Thus, the aim of this thesis was to study the role of genetic variation in positional and functional candidate genes for T2D. In the first study, we studied association between polymorphisms in the FXN gene and T2D. We excluded that polymorphisms in FXN have a role in T2D susceptibility. The ?common variation common disease? hypothesis suggests that common polymorphisms increase susceptibility to common disorders. Thus, it is reasonable to hypothesize that variants in genes causing rare monogenic forms of diabetes also harbours polymorphisms that increase susceptibility for the more common late onset T2D. Mutations in the HNF-1a gene cause Maturity Onset Diabetes of the Young (MODY) type 3, and this is the most frequent form of monogenic diabetes. We studied polymorphisms in this gene and observed that the I27L and A98V polymorphisms were associated with decreased insulin secretion and a modest increase in risk of future T2D, especially in overweight individuals. In a subsequent study polymorphisms in the HNF-4a, GCK and HNF-1b genes (causing MODY 1, 2 and 5 respectively) were studied. An HNF-4a P2 promoter variant was associated with elevated rates of hepatic glucose production during hyperinsulinaemic euglycaemic clamp and increased future risk of T2D. A polymorphism in the GCK promoter was associated with increased fasting plasma glucose levels that maintained unchanged during follow-up, but had no effect on risk of future T2D. Genetic variation in the HNF-1b gene did not confer increased risk of future T2D. Glucose stimulated insulin secretion is dependent on electrical activity in the beta-cells, hence ion-channels in the beta-cells are potential candidate genes for T2D. We also showed that polymorphisms in the CACNA1E gene, which encodes for the CaV2.3 pore forming subunit were associated with reduced second phase insulin secretion and increased risk of future T2D.

In conclusion, these results suggest that: 1) common variation in MODY genes confer an increased risk of future T2D, particularly in individuals with increased insulin demands; 2) variation in the CACNA1E gene is associated with T2D and contribute to regulation of second phase insulin secretion.

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