Molecular Epidemiological Study for Genetic Factors Susceptible for Type 2 Diabetes

我们研究了日本人群中与2型糖尿病（DM）相关的基因和多态性（第一个和第二个样本集（DM:72, IGT:75， 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。我们进一步研究了atp结合盒转运蛋白Al （ABCA1）和Nephrin基因与糖尿病的关系，通过研究这些基因的遗传多态性，包括其连锁不平衡（LD）和单倍型分析。的查询结果,以下是第1。ABCA1：从ABCA1基因的启动子区域到最后一个外显子分布的34个snp的基因型显示，基因中有13个LD块。5'区域的LD块显示研究组之间单倍型分布的显著差异（NGT vs. IGT+DM：总体p=0.0180; NGT vs. DM: 0.0001）。Fisher精确概率检验（NGT vs. DM）显示LD区单倍型2显著相关（p=0.0001），比值比（OR）为2.53 （95%CI: 1.62-4.12）。双倍型分析还显示，双倍型与单倍型2显著相关（OR/p: 2.59/0.0013）。2. Nephrin：检测三个snp （C294T， -61C/G和C2289T）与DM的关系。在第一个样本集中，这些snp显示出显著的相关性（p分别=0.0028、0.0336和0.0007）。单倍型分析显示，其中一个片段具有6个单倍型。单倍型1（由每个SNP的保护性等位基因组成）和双倍型1/1的相关性显著（分别为0.42/0.0008和0.35/0.0005）。通过对第二组样本的分析，进一步证实了这种关联，即使在调整TG、BMI和收缩压后，这种关联仍然显著（0.38/<0.0001）。结论：ABCA1和Nephrin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.