Genetics of type 2 diabetes and the metabolic syndrome
Abstract: Type 2 diabetes and the metabolic syndrome are highly prevalent disorders with severe complications such as cardiovascular disease. The aetiology of type 2 diabetes and the metabolic syndrome is not known, but the interaction between genetic factors and environmental triggers is important. The aim this thesis was to identify genetic factors that may increase susceptibility to these disorders by investigating candidate genes regulating lipolysis (hormone-sensitive lipase, HSL, lipoprotein lipase, LPL and phosphodiesterase 3B, PDE3B), thermogenesis (uncoupling protein 2, UCP2) and adipogenesis (peroxisome proliferator-activated receptor gamma, PPARG). Four of the genes were screened for mutations and identified variants were tested for association in large intra-familial and case-control association studies. Variability in the UCP2 gene was not associated with alterations in basal metabolic rate or with obesity. The gene encoding HSL was associated with type 2 diabetes in a case-control study, and the LIPE marker of the HSL gene showed distorted transmission to abdominally obese offspring. The PDE3B gene was associated with hyperinsulinaemia in genotype-discordant siblings. Haplotypes including several variants on chromosome 11 were unequally transmitted to offspring with abnormal glucose tolerance. The studies also provided evidence for an interaction between a variant in the LPL gene and insulin sensitivity. In a large, family-based multi-step study we could show that genetic variability in the gene encoding PPARG is associated with a reduced risk for diabetes, supported by the consistent results in a meta-analysis on the same variant. In conclusion, variability in genes regulating lipolysis and adipogenesis increase susceptibility to type 2 diabetes and the metabolic syndrome. Prospective studies will be helpful to establish the risk associated with the potential genetic riskfactors presented in this thesis.
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