RANTES Promoter Genotype Is Associated With Diabetic Nephropathy in Type 2 Diabetic Subjects
- Kunihiro Nakajima, MD,
- Yasushi Tanaka, MD,
- Takashi Nomiyama, MD,
- Takeshi Ogihara, MD,
- Fuki Ikeda, MD,
- Rei Kanno, MD,
- Noseki Iwashita, MD,
- Ken Sakai, MD,
- Hirotaka Watada, MD,
- Tomio Onuma, MD and
- Ryuzo Kawamori, MD
- From the Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo, Japan
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.
- ACR, albuminuria-to-creatinine ratio
- CCR5, chemotactic cytokine receptor 5
- IL-1β, interleukin-1β
- RFLP, restriction fragment length polymorphism
- SNP, single nucleotide polymorphism
- TNF-α, tumor necrosis factor-α;
Address correspondence and reprint requests to Yasushi Tanaka, Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, 2–1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. E-mail:.
Received for publication 4 June 2002 and accepted in revised form 8 December 2002.
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