Familial clustering of diabetic nephropathy was also reported in both type 1 [4] and type 2 diabetes [6]; thus, the involvement of genetic factors in the development of diabetic nephropathy is strongly suggested. Both candidate gene approaches and genome-wide linkage analyses have suggested several candidate genes with a potential impact on diabetic nephropathy. These findings, however, have not been robustly replicated and many genes responsible for susceptibility
to diabetic nephropathy remain to be identified. To identify loci involved in susceptibility to BLZ945 manufacturer common diseases, we initiated the first round of a genome-wide association study (GWAS) using 100,000 single nucleotide polymorphisms (SNPs) from a Japanese SNP database (JSNP: http://snp.ims.u-tokyo.ac.jp/index_ja.html). BB-94 Through this JQEZ5 project, we have previously identified genes encoding solute
carrier family 12 (sodium/chloride) member 3 (SLC12A3, MIM 600968, Online Mendelian Inheritance in Man: http://www.ncbi.nlm.nih.gov/omim) [7]; engulfment and cell motility 1 (ELMO1, MIM 606420) [8]; neurocalcin δ (NCALD, MIM 606722) [9]; and acetyl-coenzyme A carboxylase beta gene (ACACB, MIM: 601557) [10] as being associated with susceptibility to diabetic nephropathy. The association between ELMO1 or ACACB and diabetic nephropathy has been confirmed in different ethnic populations [11–13]. The GWAS for diabetic nephropathy using European American populations (the Genetics of Kidneys in
Diabetes (GoKinD) collection) led to the identification of 4 distinct loci as novel candidate loci for susceptibility to diabetic nephropathy in European American subjects with type 1 diabetes [14]: the CPVL/CHN2 locus on chromosome 7, the FRMD3 locus on chromosome Thiamet G 9, the CARS locus on chromosome 11, and a locus near IRS2 on chromosome 13. Among those 4 loci, only one locus (near IRS2 in chromosome 13) could be replicated in Japanese subjects with type 2 diabetes [15]. Although these loci are considered as convincing susceptibility loci for diabetic nephropathy across different ethnic groups, a considerable number of susceptibility genes for diabetic nephropathy still remain to be identified. Sirtuins, the silent information regulator-2 (SIR2) family, is a member of NAD-dependent deacetylases, and the sir2 gene was originally identified as a gene affecting the malting ability of yeast. Mammalian sirtuins consist of seven members, SIRT1–SIRT7, and some of them, especially SIRT1, have been shown to play pivotal roles in the regulation of aging, longevity, or in the pathogenesis of age-related metabolic diseases, such as type 2 diabetes [16–18]. The expressions of sirtuin families have also been observed in the kidneys, and recently SIRT1 has been shown to mediate a protective role of calorie restriction (CR) in the progression of the aging kidney [19].