To identify genetic elements that might confer susceptibility to diabetic nephropathy, we performed a genome-wide analysis of gene-based single nucleotide polymorphisms (SNPs) in a large cohort of Japanese patients with diabetes. In case-control association studies, patients with type 2 diabetes were divided into two groups, one having retinopathy as well as overt nephropathy and the other (the control group) having diabetic retinopathy but with no signs of renal involvement. Genotyping of these patients at >55,000 SNP loci indicated a gene encoding solute carrier family 12 member 3 (SLC12A3) to be a good candidate for the susceptibility to diabetic nephropathy, in view of a significant association of one landmark SNP located in the 24th intron (chi(2) = 15.4, P = 0.000087, odds ratio = 2.53 [95% CI 1.57-4.09]). Subsequent analysis of additional genetic variations in this gene identified several SNPs that were significantly associated with nephropathy, especially one in exon 23 (+78 G to A: Arg913Gln, chi(2) = 18.5, P = 0.00002, odds ratio = 2.53 [95% CI 1.64-3.90]). The results implicated that substitution of Arg913 to Gln in the SLC12A3 gene might reduce the risk to develop diabetic nephropathy and suggested that the gene product might be a potential target for the prevention or treatment of this disease.