Type 2 diabetes (T2D) is a major cause of morbidity and mortality in the USA and worldwide. Identification of genes increasing susceptibility to T2D would impact public health by providing basic biological and clinical data about development and treatment of T2D and by advising specific lifestyle changes in at-risk individuals. T2D is a complex disease with clear genetic and environmental risk factors, however few actual genes leading to this increased risk have been identified and the underlying mechanisms by which T2D develops remain obscure. Our goal is to identify genes increasing susceptibility to T2D and related quantitative traits (QTs) in a large sample of Finnish individuals collected both from at-risk families and from population cohorts. We have completed genome screens for T2D and related QTs in the 855 families. In the current proposal, we extend the scope of our genetic analysis to include carefully targeted genes spanning the genome. We will select genes with prior evidence of association with T2D and/or QTs and genes connected to T2D-related transcription factors/coactivators based on protein interaction and gene ontology. We will prioritize genes based on QT linkage signals. Recent technical advances in high-throughput genotyping, single nucleotide polymorphism (SNP) discovery and haplotype map (HapMap) construction provide unprecedented tools enabling more thorough analysis of targeted genes than was previously possible. We propose to perform in-depth analysis of 3072 SNPs in 181 selected genes by evaluating common and likely functional SNPs in a large, well-characterized sample set of 1185 cases, 1197 controls and 946 at-risk individuals. We will follow-up promising T2D and QT associations in a second large sample set of 1150 cases, 1000 controls and 781 at-risk individuals. We will identify potential susceptibility variants and test their functional roles. We strongly believe that a detailed study of genetic factors and their interactions is an essential step to identifying targeted prevention strategies and treatments.
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