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

• Published in: Diabetes (New York, N.Y.) Vol. 53; no. 10; pp. 2684 - 2690
• Main Authors: MURAO, Satoshi, MAKINO, Hideichi, KONDO, Shiori, TANAKA, Kiyonobu, TARUMI, Yoshinao, SETO, Isamu, KATO, Kenichi, OHNO, Keizo, KUSUNOKI, Yukiko, EBISUI, Osamu, TAKADA, Yasuharu, TANABE, Katsuya, KAINO, Yukikazu, TAKEMOTO, Koji, ONUMA, Hiroshi, NISHIMIYA, Tatsuya, OSAWA, Haruhiko, KONOUE, Etsushi, OHASHI, Jun, KIDA, Kaichi, FUJII, Yasuhisa, SHIMIZU, Ikki, KAWASAKI, Eiji, FUJIYAMA, Masao
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.10.2004
• Subjects: Adult; Age of Onset; Biological and medical sciences; Care and treatment; Child; Diabetes Mellitus, Type 1 - epidemiology; Diabetes Mellitus, Type 1 - genetics; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Gene Frequency; Genetic Predisposition to Disease - genetics; Haplotypes; HLA-DQ Antigens - genetics; HLA-DR Antigens - genetics; Humans; Japan - epidemiology; Medical sciences; Type 1 diabetes; Japan; Endocrinopathy; Human; HLA-System; Sensitivity; Type 1 diabetes; Haplotype; Japanese
• DOI: 10.2337/diabetes.53.10.2684
• ISSN: 0012-1797

Differences in the Contribution of HLA-DR and -DQ Haplotypes to Susceptibility to Adult- and Childhood-Onset Type 1 Diabetes in Japanese Patients Satoshi Murao 1 , Hideichi Makino 2 , Yukikazu Kaino 3 , Etsushi Konoue 4 , Jun Ohashi 5 , Kaichi Kida 3 , Yasuhisa Fujii 6 , Ikki Shimizu 6 , Eiji Kawasaki 7 , Masao Fujiyama 8 , Shiori Kondo 4 , Kiyonobu Tanaka 9 , Yoshinao Tarumi 10 , Isamu Seto 11 , Kenichi Kato 7 , Keizo Ohno 6 , Yukiko Kusunoki 6 , Osamu Ebisui 6 , Yasuharu Takada 9 , Katsuya Tanabe 12 , Koji Takemoto 3 , Hiroshi Onuma 2 , Tatsuya Nishimiya 2 and Haruhiko Osawa 2 1 Matsuyama Shimin Hospital, Ehime, Japan 2 Department of Laboratory Medicine, Ehime University School of Medicine, Ehime, Japan 3 Department of Pediatrics, Ehime University School of Medicine, Ehime, Japan 4 Matsuyama Red Cross Hospital, Ehime, Japan 5 Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan 6 Ehime Prefectural Central Hospital, Ehime, Japan 7 Department of Metabolism/Diabetes and Clinical Nutrition, Nagasaki University School of Medicine, Nagasaki, Japan 8 Fujiyama Clinic, Ehime, Japan 9 Saijo Central Hospital, Ehime, Japan 10 Minami Matsuyama Hospital, Ehime, Japan 11 BML, Tokyo, Japan 12 Ehime Rousai Hospital, Ehime, Japan 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. APC, antigen-presenting cell LADA, latent autoimmune diabetes in adults RPE method, relative predispositional effects method Footnotes Accepted July 19, 2004. Received March 28, 2004. DIABETES