Differences in the Contribution of HLA-DR and -DQ Haplotypes to Susceptibility to Adult- and Childhood-Onset Type 1 Diabetes in Japanese Patients

  1. Satoshi Murao1,
  2. Hideichi Makino2,
  3. Yukikazu Kaino3,
  4. Etsushi Konoue4,
  5. Jun Ohashi5,
  6. Kaichi Kida3,
  7. Yasuhisa Fujii6,
  8. Ikki Shimizu6,
  9. Eiji Kawasaki7,
  10. Masao Fujiyama8,
  11. Shiori Kondo4,
  12. Kiyonobu Tanaka9,
  13. Yoshinao Tarumi10,
  14. Isamu Seto11,
  15. Kenichi Kato7,
  16. Keizo Ohno6,
  17. Yukiko Kusunoki6,
  18. Osamu Ebisui6,
  19. Yasuharu Takada9,
  20. Katsuya Tanabe12,
  21. Koji Takemoto3,
  22. Hiroshi Onuma2,
  23. Tatsuya Nishimiya2 and
  24. Haruhiko Osawa2
  1. 1Matsuyama Shimin Hospital, Ehime, Japan
  2. 2Department of Laboratory Medicine, Ehime University School of Medicine, Ehime, Japan
  3. 3Department of Pediatrics, Ehime University School of Medicine, Ehime, Japan
  4. 4Matsuyama Red Cross Hospital, Ehime, Japan
  5. 5Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
  6. 6Ehime Prefectural Central Hospital, Ehime, Japan
  7. 7Department of Metabolism/Diabetes and Clinical Nutrition, Nagasaki University School of Medicine, Nagasaki, Japan
  8. 8Fujiyama Clinic, Ehime, Japan
  9. 9Saijo Central Hospital, Ehime, Japan
  10. 10Minami Matsuyama Hospital, Ehime, Japan
  11. 11BML, Tokyo, Japan
  12. 12Ehime Rousai Hospital, Ehime, Japan
  1. Address correspondence and reprint requests to Dr. Hideichi Makino, Department of Laboratory Medicine, Ehime University School of Medicine, Shigenobu, Ehime 791-0295, Japan. E-mail: hidemak{at}m.ehime-u.ac.jp

Abstract

To clarify heterogeneity in Japanese adult-onset type 1 diabetes, we analyzed the HLA-DR and -DQ haplotypes, depending on the clinical phenotype, and compared them with those in childhood-onset type 1 diabetes (CO). The patients in a previously reported Ehime Study were divided into subgroups by the mode of onset of diabetes: 68 acute-onset type 1 diabetic patients (AO) and 28 slowly progressive type 1 diabetic patients (SO). HLA haplotypes were compared with those of 80 CO patients and 190 control subjects. Two major susceptible HLA haplotypes in the Japanese, DRB1*0405-DQB1*0401 (DR4) and DRB1*0901-DQB1*0303 (DR9), were significantly increased in the AO and CO groups, but only DR9 was increased in the SO group. AO subjects had a higher frequency of DR9 than CO subjects. Accordingly, the DR9:DR4 frequency increased with increasing age of onset. Another susceptible haplotype, DRB1*0802-DQB1*0302 (DR8), was involved only in the CO group. Analysis of haplotype combinations revealed that DR4 and DR9 had significant dosage effects on the AO and CO groups (P < 0.0001), but only DR9 had such an effect in the SO group (P < 0.03). These results suggest differences in the contribution of HLA class II haplotypes to susceptibility of type 1 diabetes depending on the clinical phenotype and also indicate that HLA class II haplotypes may be associated with the onset age of type 1 diabetes.

Footnotes

    • Accepted July 19, 2004.
    • Received March 28, 2004.
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