Since SIRT1 could affect various metabolic activities, the effects of SIRT1 polymorphisms on susceptibility to diabetic nephropathy might be mediated by differences in the metabolic state among individuals, including glycemic control,
obesity, blood pressure, etc. We then examined the association between SNPs in SIRT1 and BMI, hemoglobin A1c (HbA1c), fasting plasma glucose, or systolic blood pressure in the present subjects with type 2 diabetes, but we could not observe any association between the SIRT1 SNPs and those quantitative traits (P > 0.05, Supplementary Table 4). In contrast to our present finding, SNPs within the SIRT1, rs7895833 and rs1467568, were MK-4827 manufacturer shown to be significantly associated with BMI in Dutch populations . We did not examine those SNPs, but the present study includes an SNP in high linkage disequilibrium (LD) to these
2 SNPs (rs10997868; r 2 = 1 and 0.64 to rs1467568 and rs7895833, respectively). Interestingly, there is a dramatic difference in the frequency of the reported protected allele (A allele of rs1467568) between European and Japanese populations (0.25 in the European population vs. 0.841 in MK-1775 datasheet the Japanese population, HapMap database, http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1467568). Since rs10997868 was not associated with either BMI or susceptibility to the disease, ethnic differences may contribute to the discrepancy between the Dutch and Japanese populations, and the contribution of SIRT1 SNPs to BMI, if it is present, is considered very minor in the Japanese population. It has been also reported that SNPs in SIRT1 were associated with energy expenditure in a small number of Finnish healthy nondiabetic offspring of patients with type 2 diabetes . The alleles associated with higher energy expenditure, supposed to be favorable alleles for glucose metabolism, are G for rs3740051, G for rs2236319, and C for rs2273773, respectively; although these
alleles increase the risk of diabetic nephropathy in the present Japanese population. From these observations, we speculate that the effects of SIRT1 gene polymorphisms on diabetic nephropathy are independent of these metabolic parameters; however, there are limitations to the present cross-sectional study and further longitudinal Bacterial neuraminidase prospective studies are required to obtain a precise conclusion. The association between individual SIRT1 SNPs and diabetic nephropathy did not attain statistically significant levels after correction for multiple-testing errors, and a haplotype consisting of 11 SIRT1 SNPs had a stronger association with the disease, suggesting the existence of other true causal variations within this locus. In addition, since nephropathy cases in the present study were at a more advanced stages of diabetic nephropathy, the findings on SNPs and the haplotype within SIRT1 may be applicable mainly to advanced diabetic nephropathy.