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

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.

Different contribution of class II HLA in fulminant and typical autoimmune type 1 diabetes mellitus

“…Analysis of the allelic combination of HLA-DR-DQ has shown that homozygotes with DR4-DQ4 exhibit a greater effect than heterozygotes with DR4-DQ4 regarding predisposition to fulminant diabetes. These findings coincide with small pilot studies, which were performed independently of this study [21,22]. These findings also suggest that HLA-DR4 and/or DQ4 could play an important role in the development of fulminant type 1 diabetes.…”

Autoimmune Pancreatitis: The Emerging Role of Serologic Biomarkers

“…Interestingly, in this issue of Diabetes, Endo et al (10) report that 5 out of 15 patients with AIP were heterozygous for the HLA DRB1* 0405-DQB1*0401 haplotype, which confirms previously published results in a Japanese population (11,12). It is noteworthy that a recent study provided convincing evidence that CD4…”

Relationship of Type 1 Diabetes with Human Leukocyte Antigen (HLA) Class II Antigens Except for DR3 and DR4

“…On the other hand, the frequency and OR of the DRB1*04:05-DQA1*03:03-DQB1*04:01 haplotype in fulminant T1D are higher than those of the DRB1*04:05-DQA1*03:03-DQB1*04:01 haplotype in rapid-onset T1D. The DR9 haplotype is less frequent in fulminant T1D than in rapid-onset T1D and does not confer susceptibility to fulminant T1D Tanaka et al, 2002).…”

“…are the most frequently observed susceptibility haplotypes in the Japanese (Awata et al, 1992;Kawabata et al, 2002;Kobayashi et al, 1993;Maruyama et al, 1994;Murao et al, 2004;Tanaka et al, 2002;Yasunaga et al, 1996). However, studies conducted before the discovery of fulminant T1D may have included patients with fulminant T1D.…”

“…Table 4 shows the phenotype frequencies of DRB1*04:05-DQA1*03:03-DQB1*04:01 and DR9 haplotypes in rapid-onset T1D with fulminant T1D (A0 + A1 + B0 + B1 areas) (Awata et al, 1992;Kawabata et al, 2002;Kobayashi et al, 1993;Maruyama et al, 1994;Yasunaga et al, 1996), rapid-onset T1D (which includes A1 area and excludes B0 area) Murao et al, 2004;, and fulminant T1D (B0 area) Tanaka et al, 2002 Before the existence of fulminant T1D was clarified (Imagawa et al, 2000a), the frequency and odds ratio (OR) of the DRB1*04:05-DQA1*03:03-DQB1*04:01 haplotype were higher than those of the DR9 haplotype in rapid-onset T1D with fulminant T1D (Awata et al, 1992;Kawabata et al, 2002;Kobayashi et al, 1993;Maruyama et al, 1994;Yasunaga et al, 1996). However, the frequency and OR of the DRB1*04:05-DQA1*03:03-DQB1*04:01 haplotype in rapid-onset T1D are lower than those of the DRB1*04:05-DQA1*03:03-DQB1*04:01 haplotype in rapid-onset T1D with fulminant T1D and those of the DR9 haplotype in rapid-onset T1D Murao et al, 2004;Tanaka et al, 2002). On the other hand, the frequency and OR of the DRB1*04:05-DQA1*03:03-DQB1*04:01 haplotype in fulminant T1D are higher than those of the DRB1*04:05-DQA1*03:03-DQB1*04:01 haplotype in rapid-onset T1D.…”