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Association of HLA-DQ Genotype in Autoantibody-Negative and Rapid-Onset Type 1 Diabetes

¹ Third Department of Internal Medicine, Yamanashi Medical University, Yamanashi, Japan
² Department of Molecular Life Science, Tokai University School of Medicine, Isehara, Japan
³ Department of Endocrinology and Metabolism, Toranomon Hospital, Tokyo, Japan
⁴ Okinaka Memorial Institute for Medical Research, Tokyo, Japan

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 HbA_1c levels with complete destruction of ß-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 ß-cell damage in a subtype of autoantibody-negative type 1 diabetes with fulminant clinical features.

Abbreviations: GADAb, GAD autoantibody • HNF-1, hepatocyte nuclear factor-1 • IA-2Ab, insulinoma-associated protein 2/islet cell antigen 512 autoantibody • IAA, insulin autoantibody • ICA, islet cell antibody • OGTT, oral glucose tolerance test

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