Association of Solute Carrier Family 12 (Sodium/Chloride) Member 3 With Diabetic Nephropathy, Identified by Genome-Wide Analyses of Single Nucleotide Polymorphisms

  1. Nobue Tanaka123,
  2. Tetsuya Babazono2,
  3. Susumu Saito4,
  4. Akihiro Sekine4,
  5. Tatsuhiko Tsunoda5,
  6. Masakazu Haneda6,
  7. Yasushi Tanaka7,
  8. Tomoaki Fujioka8,
  9. Kohei Kaku9,
  10. Ryuzou Kawamori7,
  11. Ryuichi Kikkawa6,
  12. Yasuhiko Iwamoto2,
  13. Yusuke Nakamura34 and
  14. Shiro Maeda1
  1. 1Laboratory for Diabetic Nephropathy, SNP Research Center, the Institute of Physical and Chemical Research, Kanagawa, Japan
  2. 2Diabetes Center, Tokyo Women’s Medical University, Tokyo, Japan
  3. 3Laboratory for Molecular Medicine, Human Genome Center, the Institute of Medical Science, University of Tokyo, Tokyo, Japan
  4. 4Laboratory for Genotyping, SNP Research Center, the Institute of Physical and Chemical Research, Kanagawa, Japan
  5. 5Laboratory for Medical Informatics, SNP Research Center, the Institute of Physical and Chemical Research, Kanagawa, Japan
  6. 6Department of Medicine, Shiga University of Medical Science, Shiga, Japan
  7. 7Department of Medicine, Metabolism & Endocrinology, School of Medicine, Juntendo University, Tokyo, Japan
  8. 8Department of Urology, Iwate Medical University School of Medicine, Iwate, Japan
  9. 9Division of Endocrinology and Metabolism, Department of Internal Medicine, Kawasaki Medical School, Okayama, Japan
  1. Address correspondence and reprint requests to Shiro Maeda, Laboratory for Diabetic Nephropathy, SNP Research center, the Institute of Physical and Chemical Research, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. E-mail: smaeda{at}src.riken.go.jp

Abstract

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 (χ2 = 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, χ2 = 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.

Footnotes

    • Accepted July 22, 2003.
    • Received May 14, 2003.
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  1. doi: 10.2337/diabetes.52.11.2848 Diabetes November 2003 vol. 52 no. 11 2848-2853
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