Identification of type 2 diabetes susceptibility genes in the Japanese population by linkage disequilibrium mapping in the chromosomal regions harboring type 2 diabetes susceptibility genes

我们在日本人群中定位了9个染色体区域（1p36-p32、2q34、3q26-q28、6p23、7p22-p21、9p、11p13p-p12、15q13-q21和20q12-q13）的2型糖尿病易感基因。在3q26-q28中，编码脂肪细胞衍生的胰岛素增敏激素脂联素的基因被定位。我们发现脂联素基因中的SNP276与血浆脂联素水平、胰岛素抵抗和2型糖尿病风险相关，提示脂联素基因是2型糖尿病的易感基因。在1q36-32中，AMPKα2亚基基因被定位，我们发现AMPKα2亚基基因多态性与胰岛素抵抗和2型糖尿病有关。在2012 - 2013年，我们发现了强有力的证据，证明2型糖尿病与HNF4A基因P2启动子区域的两个多态性组成的单倍型之间存在关联，尽管所检查的个体多态性均未显示与2型糖尿病有任何显著关联。相比之下，2型糖尿病与由不在P2启动子区域的多态性组成的单倍型之间没有关联，这表明2型糖尿病的易感位点位于HNF4A基因的P2启动子区域。本分析结果表明，HNF4A基因可能是不同民族共有的2型糖尿病易感基因。该研究还提示，在HNF4A基因的P2启动子区域可能存在一种尚未确定但具有功能的多态性，直接影响2型糖尿病的易感性。我们正在使用剩余6个染色体区域的SNP密集图谱进行关联研究，以确定日本人群中的2型糖尿病易感基因。

We have mapped type 2 diabetes susceptibility genes to the 9 chromosomal regions 1p36-p32, 2q34, 3q26-q28, 6p23, 7p22-p21, 9p, 11p13p-p12 15q13-q21, and 20q12-q13) in the Japanese population. In 3q26-q28, the gene encoding adiponectin which is adipocyte-derived insulin sensitizing hormone, is located. We found that SNP276 in the adiponectin gene was associated with plasma level of adiponectin, insulin resistance, and risk of type 2 diabetes, suggesting that the adiponectin gene is a type 2 diabetes susceptibility gene. In 1q36-32, the AMPKα2 subunit gene is located ant we found that polymorphism in the AMPKα2 subunit gene is associated with insulin resistance and type 2 diabetes. In 20q12-q13 we found we found very strong evidence of the association between type 2 diabetes and the haplotype consisting of two polymorphisms in the P2 promoter region of the HNF4A gene, although none of the individual polymorphisms examined showed any significant association with type 2 diabetes. In contrast, therse was no association between type 2 diabetes and haplotypes consisting of polymorphisms not located in the P2 promoter region, suggesting that the type 2 diabetes susceptibility loci are localized in the P2 promoter region of the HNF4A gene. The results of the present analysis revealed that the HNF4A gene might be a type 2 diabetes susceptibility gene common to different ethnic groups. The study also suggested the possible existence of an as yet unidentified but functional polymorphism in the P2 promoter region of the HNF4A gene directly influencing the susceptibility to type 2 diabetes. We are performing association studies using dense map of SNP in the remaining 6 chromosomal regions we have mapped to identify type 2 diabetes susceptibility genes in the Japanese population.