Identification of NIDDM susceptibility genes in the Japanese population by candidate gene approach and whole genome mapping.

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1.Common NIDDM gene mapping.We attempt to employ affected sib pair analysis for the identification of common NIDDM genes. We have collected DNA sample from 250 affected sib pairs of NIDDM from outpatients clinic of Tokyo Unibersity Hospital. We have also gathered the detailed clinical information such as family history, obesity, age of onset, insulin secretory capacity and treatment modality for all of the affected sib pairs. We plan to initiate whole genome mapping using microsatellite markers located every 10cM on the genome. We Iso started analysis of candidate Ioci revealed in the similar studies in other ethnic groups such as NIDDM1 and NIDDM2. We found that these loci are not the major Ioci for NIDDM susceptibility in the Japanese population.2.Candidate gene approachWe studied several candidate genes for obesity, the most important risk factor for NIDDM in Japan. We identified several mutations in the genes for in the beta3 adrenergic receptor, UCP-1,3 and PPARgamma and are in the process of carrying out functional analysis and association studies. Among these, Trp64Arg mutation in the beta3 adrenergic receptor was found to be associated with higher BMI and increased visceral adiposity.