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Marketa Sjögren

Genetics of Type 2 Diabetes and Metabolic Syndrome: From Genome Wide Linkage Scans and Candidate Genes to Genome Wide Association Studies

Type 2 diabetes (T2D) and metabolic syndrome (MetS) are major health problems associated with cardiovascular disease. Both diseases are influenced by a combination of genetic and environmental factors. The aim of this thesis was to identify genetic risk factors for T2D, particularly T2D associated with obesity, and for MetS. To achieve this goal, we 1) followed-up a region linked to obese T2D in an earlier genome wide linkage study; 2) studied IRS1 as a candidate gene for T2D and MetS and 3) studied the role of 28 genes, earlier identified in candidate gene- and genome wide association studies (GWAS) as susceptibility genes for T2D, in MetS.

In study I, extensive fine mapping by genotyping 501 haplotype tag SNPs in 27 genes within the 15 Mb region linked to obese T2D on chromosome 18p was undertaken in Botnia 2 family material. Nominal association (p < 0.05) between T2D, obese T2D and/or BMI in T2D patients and 74 SNPs was identified. Five of the strongest associated SNPs were selected for replication in a large Swedish T2D case-control material. In addition, six SNPs indicating strongest association in three GWAS (DGI, WTCCC and Mexican Americans) with T2D, obese T2D, BMI in T2D patients or fat mass as well as a SNP in the lipin 2 gene (LPIN2) showing association with T2D in a Dutch population (rs3745012, p = 0.03) were pursued further in the same cohort. However, no significant association was observed between the selected SNPs in the case-control material. These findings argue against common variation contributing to the observed linkage on chromosome 18p.

In studies II and III, the role of polymorphisms in IRS1 in T2D risk was investigated in

> 9 000 individuals. We found no association between T2D and G972R nor any of the 20 tag SNPs capturing 85% of the common variation in IRS1. These findings argue against any major involvement of common polymorphisms in IRS1 in the development of T2D.

In studies IV and V, we investigated the role of candidate or susceptibility genes for T2D or components of MetS in the development of MetS. In the family based Botnia prospective study (study IV) we found that polymorphisms in PPARG and ADRB1 predicted development of MetS, indicating a role of altered free fatty acid metabolism in the pathogenesis of MetS. In study V, polymorphisms in candidate genes for T2D (TCF7L2, WFS1, IGF2BP2) and obesity (FTO) predicted development of MetS and the risk to develop MetS seemed to be driven by associations with the previously reported phenotypes. These data do not support the view that the different components of MetS share a common genetic background.

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