OBJECTIVE—To evaluate the effect of RANTES gene promoter polymorphism and RANTES receptor (CCR5 gene) promoter polymorphism on diabetic nephropathy in Japanese type 2 diabetic subjects.RESEARCH DESIGN AND METHODS—A total 616 Japanese subjects with type 2 diabetes were recruited. Polymorphisms of −28 C/G and −403 G/A in the RANTES gene promoter region, and of 59029 G/A in the CCR5 gene promoter region were detected by PCR-RFLP (restriction fragment length polymorphism). The association of these genotypes with nephropathy was analyzed.RESULTS—While the RANTES −403 genotype showed no association with nephropathy, the frequency of the −28G allele was significantly higher in the DN2 group (urinary albuminuria-to-creatinine ratio [ACR] ≧300 mg/g creatinine, serum creatinine <2.0 mg/dl) than in the DN0 (ACR <30 mg/g creatinine) and DN1 (ACR ≥30 mg/g creatinine and <300 mg/g creatinine) groups. The frequency of a RANTES −28G-positive genotype (C/G or G/G) was higher in the DN2 group than in the DN0 and DN1 groups (34% vs. 25 and 20%, P = 0.0268, χ2 = 4.905), and the frequency of a CCR5 59029 A-positive genotype (G/A or A/A) was higher in the DN1 and DN2 groups than in the DN0 group (84 and 85% vs. 76%, P = 0.0123, χ2 = 6.269). Discriminant analysis showed that the RANTES −28G-positive genotype and CCR5 59029A-positive genotype were independently associated with nephropathy. The percentage of macroalbuminuria was twofold higher in the subjects having −28G or 59029A and threefold higher in the subjects having −28G and 59029A than in the subjects without −28G and 59029A.CONCLUSIONS—The RANTES promoter −28G genotype and CCR5 promoter 59029A genotype may be independent risk factors for diabetic nephropathy in patients with type 2 diabetes and may have an additive effect on nephropathy.