Molecular Epidemiological Study for Genetic Factors Susceptible for Type 2 Diabetes

我们调查了日本人群中与2型糖尿病(DM)相关的基因和多态(第一和第二样本集(第一和第二样本分别为72、75和NGT：227和DM：31、IGT：77和NGT：244))，发现2039个SNPs(704个基因)中有33个SNPs(29个基因)与DM显著相关。其中，我们通过对ATP结合盒转运蛋白A1(ABCA1)和Nephin基因的遗传多态性(包括连锁不平衡分析和单倍型分析)的研究，进一步详细地研究了这两个基因与DM的关联。结果-1。ABCA1：从启动子区域到ABCA1基因最后一个外显子的34个SNPs的基因分型显示，基因中有13个LD区块。位于5‘-区的LD区段在两组间的单倍型分布有显著差异(NGT与IGT+DM：总体p=0.0180；NGT与DM：0.0001)。Fisher‘s确切概率检验(NGT与DM)显示LD块的单倍型2显著相关(p=0.0001)，优势比(OR)为2.53(95%CI：1.62~4.12)。二倍型分析也显示二倍型与单倍型2显著相关(OR/p：2.59/0.0013)。2.肾小球蛋白：研究了三个SNP(C294T、-61C/G和C2289T)与糖尿病的相关性。在第一个样本集中，这些SNP显示出显著的关联性(分别为p=0.0028、0.0336和0.0007)。单倍型分析显示，6个单倍型中有一个区块。单倍型1(由每个SNP的保护等位基因组成)和双倍型1/1具有显著相关性(分别为0.42/0.0008和0.35/0.0005)。使用第二个样本集的分析也进一步证实了这种相关性，即使在调整了甘油三酯、体重指数和收缩压(0.38/&lt；0.0001)之后，这种相关性仍然显著。结论：ABCA1和Nephin基因与糖尿病相关，因此，这些基因可能在糖尿病的病理生理学中起重要作用。

We have investigated genes and polymorphisms that associate with type 2 diabetes (DM) in the Japanese population (first and second sample sets (DM:72, IGT:75, and NGT:227 and DM:31, IGT:77 and NGT:244, respectively)), and found 33 SNPs (29 genes) out of 2039 SNPs (704 genes) to be significantly associated with DM. Among them, we further examined the association of the ATP-binding cassette transporter Al (ABCA1) and Nephrin genes with DM in details by studying genetic polymorphisms of the genes including its linkage disequilibrium (LD) and haplotype analyses. Results-1. ABCA1 : Genotypes of 34 SNPs distributed from the promoter region to the last exon of the ABCA1 gene revealed 13 LD blocks in the genes. An LD block at the 5'-region showed a significant difference in the haplotype distribution between the study groups (NGT vs. IGT+DM : overall p=0.0180 ; NGT vs. DM : 0.0001). The Fisher's exact probability test (NGT vs. DM) showed a significant association of the haplotype 2 of the LD block (p=0.0001), with an odds ratio (OR) of 2.53 (95%CI : 1.62-4.12). Diplotype analysis also showed a significant association of the diplotypes with the haplotype 2 (OR/p : 2.59/0.0013). 2. Nephrin : The associations of three SNPs (C294T, -61C/G and C2289T) with DM were examined. In the first sample set, these SNPs showed a significant association (p=0.0028, 0.0336 and 0.0007, respectively). Haplotype analysis revealed one block with the six haplotypes. Haplotype 1 (composed of the protective alleles of each SNP) and Diplotype 1/1 showed significant associations (0.42/0.0008, and 0.35/0.0005, respectively). The association was further confirmed by analysis using the second sample set as well, and was significant even after the adjustment for TG, BMI and systolic blood pressure (0.38/<0.0001). Conclusions- The ABCA1 and the Nephrin genes were associated with DM ; thus, these genes may play an important role in the pathophysiology of DM.