Association of HLA-DQ Genotype in Autoantibody-Negative and Rapid-Onset Type 1 Diabetes
- Shoichiro Tanaka, MD12,
- Tetsuro Kobayashi, MD1,
- Koji Nakanishi, MD34,
- Rikako Koyama, MD3,
- Minoru Okubo, MD34,
- Toshio Murase, MD4,
- Masato Odawara, MD34 and
- Hidetoshi Inoko, MD2
- 1Third Department of Internal Medicine, Yamanashi Medical University, Yamanashi, Japan
- 2Department of Molecular Life Science, Tokai University School of Medicine, Isehara, Japan
- 3Department of Endocrinology and Metabolism, Toranomon Hospital, Tokyo, Japan
- 4Okinaka Memorial Institute for Medical Research, Tokyo, Japan
Abstract
OBJECTIVE—Some type 1 diabetic patients have a distinct phenotype characterized by the absence of pancreatic autoantibodies and fulminant clinical symptoms at onset, including marked hyperglycemia, severe diabetic ketoacidosis, and normal to near-normal HbA1c levels with complete destruction of β-cells. However, little is known about genetic factors of this distinct subtype of diabetes (fulminant autoantibody-negative type 1 diabetes).
RESEARCH DESIGN AND METHODS—We analyzed HLA-DQ genotypes in fulminant autoantibody-negative type 1 diabetes (n = 22) and autoantibody-positive type 1 diabetes (immune-mediated type 1 diabetes, n = 78) recruited from a cohort between 1980 and 2000.
RESULTS—Fulminant autoantibody-negative type 1 diabetes had a significantly high prevalence of the HLA-DQA1*0303-DQB1*0401 haplotype in a homozygous manner (RR 39) or in a heterozygous manner with the HLA-DQA1*0302-DQB1*0303 haplotype (RR 13). In contrast, autoantibody-positive type 1 diabetic patients had a high prevalence of the HLA-DQA1*0302-DQB1*0303 haplotype in a homozygous manner (RR 10) or in a heterozygous manner with the HLA-DQA1*0303-DQB1*0401 haplotype (RR 12).
CONCLUSIONS—Pathogenic roles of genotypic combinations of specific HLA-DQ haplotypes in a homozygous manner are suggested as causative mechanisms of aggressive β-cell damage in a subtype of autoantibody-negative type 1 diabetes with fulminant clinical features.
- GADAb, GAD autoantibody
- HNF-1α, hepatocyte nuclear factor-1α
- IA-2Ab, insulinoma-associated protein 2/islet cell antigen 512 autoantibody
- IAA, insulin autoantibody
- ICA, islet cell antibody
- OGTT, oral glucose tolerance test
Footnotes
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Address correspondence and reprint requests to Dr. Tetsuro Kobayashi, Third Department of Internal Medicine, Yamanashi Medical University, 1110 Tamaho, Yamanashi 409-3898, Japan. E-mail address:tetsurou{at}res.yamanashi-med.ac.jp.
Received for publication 16 May 2002 and accepted in revised form 1 September 2002.
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