Genetic Variation in the Gene Encoding Adiponectin Is Associated With an Increased Risk of Type 2 Diabetes in the Japanese Population

  1. Kazuo Hara123,
  2. Philippe Boutin4,
  3. Yasumichi Mori14,
  4. Kazuyuki Tobe12,
  5. Christian Dina4,
  6. Kazuki Yasuda5,
  7. Toshimasa Yamauchi12,
  8. Shuichi Otabe6,
  9. Terumasa Okada15,
  10. Kazuhiro Eto12,
  11. Hiroko Kadowaki4,
  12. Ryoko Hagura4,
  13. Yasuo Akanuma24,
  14. Yoshio Yazaki5,
  15. Ryozo Nagai7,
  16. Matsuo Taniyama8,
  17. Koichi Matsubara9,
  18. Madoka Yoda10,
  19. Yasuko Nakano10,
  20. Satoshi Kimura1,
  21. Motowo Tomita10,
  22. Satoshi Kimura1,
  23. Chikako Ito11,
  24. Philippe Froguel4 and
  25. Takashi Kadowaki12
  1. 1Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
  2. 2CREST, Japan Science and Technology Corporation (JST), Tokyo, Japan
  3. 3Institute for Diabetes Care and Research, Asahi Life Foundation, Tokyo, Japan
  4. 4Institute of Biology-Centre National de la Recherche Scientifique (CNRS) 8090, Institute Pasteur de Lille, Lille, France
  5. 5Department of Metabolic Disorder, Research Institute, International Medical Center of Japan, Tokyo, Japan
  6. 6Department of Endocrinology and Metabolism, Kurume University School of Medicine, Kurume, Japan
  7. 7Department of Cardiology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
  8. 83rd Department of Internal Medicine, Showa University, Tokyo, Japan
  9. 9Chugai Diagnostics Science, Tokyo, Japan
  10. 10Department of Physiological Chemistry, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan
  11. 11Hiroshima Atomic Bomb Casualty Council Health Management Center, Hiroshima, Japan

    Abstract

    An adipocyte-derived peptide, adiponectin (also known as GBP28), is decreased in subjects with type 2 diabetes. Recent genome-wide scans have mapped a diabetes susceptibility locus to chromosome 3q27, where the adiponectin gene (APM1) is located. Herein, we present evidence of an association between frequent single nucleotide polymorphisms at positions 45 and 276 in the adiponectin gene and type 2 diabetes (P = 0.003 and P = 0.002, respectively). Subjects with the G/G genotype at position 45 or the G/G genotype at position 276 had a significantly increased risk of type 2 diabetes (odds ratio 1.70 [95% CI 1.09–2.65] and 2.16 [1.22–3.95], respectively) compared with those having the T/T genotype at positions 45 and 276, respectively. In addition, the subjects with the G/G genotype at position 276 had a higher insulin resistance index than those with the T/T genotype (1.61 ± 0.05 vs. 1.19 ± 0.12, P = 0.001). The G allele at position 276 was linearly associated with lower plasma adiponectin levels (G/G: 10.4 ± 0.85 μg/ml, G/T: 13.7 ± 0.87 μg/ml, T/T: 16.6 ± 2.24 μg/ml, P = 0.01) in subjects with higher BMIs. Based on these findings together with the observation that adiponectin improves insulin sensitivity in animal models, we conclude that the adiponectin gene may be a susceptibility gene for type 2 diabetes.

    Footnotes

    • Address correspondence and reprint requests to Takashi Kadowaki, Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail: kadowaki-3im{at}h.u-tokyo.ac.jp.

      Received for publication 16 February 2001 and accepted in revised form 26 October 2001.

      Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org.

      EH, Estimation Haplotype; HOMA, homeostasis model assessment; HOMA-IR, HOMA of insulin resistance; OR, odds ratio; SNP, single nucleotide polymorphism.

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