| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2005: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2004: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
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.
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