Molecular genetics of type 2 diabetes (T2DM) in Germany: Genes / Polymorphisms for T2DM - Cloning of diabetes susceptibility sequence variants

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The overall aim of this project is to identify and characterize sequence variants that contribute to the development of type 2 diabetes mellitus (T2DM) in Germany. A total genome scan in 394 affected sib pairs (ASP) revealed two susceptibility loci on chromosomes 1 (D1S3669; NPL = 2.16; P = 0.003) and 16 (D16S403; NPL = 2.305; P = 0.003). By using advanced multilocus analyses assuming different inheritance models we identified an interaction between those two loci (LOD = 4.32). Other selected candidate genes were genotyped in the Augsburg family trio sample. Further, we collected two additional replication samples of 537 and 116 ASPs (WÜDC), and another 355 ASPs (AUGC). Those samples will be used for finemapping and locus confirmation. Then we will elucidate the families who were responsible for linkage in both, the initial and the replication samples. We will screen all available SNPs within the linked regions in those most contributing families. Associated SNPs will then be tested in all available ASPs from Würzburg and Augsburg as well as in another 2,000 cases and 4,000 controls from Augsburg (1,000 cases and 2,000 controls yet to be collected). This strategy should reveal sequence variants which are of functional importance for the development of T2DM in Germany. Our international collaborations with Nancy J. Cox in terms of combining genome-scan data will significantly increase the power of the study. The identification and functional characterization of the variants for T2DM will lead to a better understanding of the molecular basis of diabetes mellitus. It will provide the scientific foundation for new approaches for prevention and treatment including the identification of atrisk subjects before the onset of clinical disease and specific treatment modalities based on the nature of the underlying molecular defect.