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

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. Diabetes 53: 2684 -2690, 2004 T ype 1 diabetes is the result of a destruction of pancreatic ␤-cells and leads to complete insulin deficiency (1,2). Although type 1 diabetes is frequently considered to be a childhood disease and is characterized by a rapid progression to insulin dependency, the clinical onset of type 1 diabetes is not confined to children. Epidemiological data suggest that 30 -50% of type 1 diabetic patients may develop clinical signs of diabetes after age 20 years (3,4). Moreover, there is increasing evidence to indicate that type 1 diabetes, especially when developed in adulthood, is clinically and immunologically heterogeneous. Insulin secretion abruptly ceases in fulminant type 1 diabetes (5), whereas pancreatic ␤-cell function can be preserved for over a decade in some patients, a condition that is referred to as slowly progressive insulin-dependent diabetes (6) or latent autoimmune diabetes in adults (LADA) (7). Compared with our extensive knowledge of the epidemiological, clinical, and genetic characteristics of childhood-onset type 1 diabetes, our understanding of adult-onset type 1 diabetes is incomplete.Susceptibility to type 1 diabetes is determined by both environmental and genetic factors. Although multiple genes have been implicated, HLA class II genes, especially the HLA-DR and -DQ genes, are most important and are estimated to account for ϳ50% of the susceptibility to the disease (8). These HLA associations vary depending on geographic and ethnic origin (9). It has been shown that Japanese type 1 diabetic patients have different HLA associations than Caucasian patients. In Caucasian populations, the DRB1*...

A novel mutation of WFS1 gene in a Japanese man of Wolfram syndrome with positive diabetes-related antibodies

“…In our case, HLA typing of DR was DR-4 and DR-8 which is an increased risk for Japanese juvenile-onset type 1 diabetes [10]. In addition, serological examination showed positive GAD and IA-2 antibodies.…”

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

“…Conversely, the DR8 haplotype confers susceptibility to Japanese T1D (Awata et al, 1992;Kawabata et al, 2002;Kobayashi et al, 1993;Murao et al, 2004;Ohtsu et al, 2005;Yasunaga et al, 1996) and is present only in Japanese and Korean T1D (Thomson et al, 2007). However, some studies have found no evidence that the DR8 haplotype confers susceptibility to Japanese T1D (Maruyama et al, 1994;Murao et al, 2004;Tanaka et al, 2002). Table 5 shows the phenotype frequency of the DR8 haplotype and the mean onset age of T1D in previous studies.…”

“…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.…”

“…Therefore, it is possible that the A2 type of diabetes is associated with HLA. Previous studies investigating the relationship between HLA class II genes and slow-onset T1D in Japan have focused on the relationship between these genes and the A2 type of diabetes (Kobayashi et al, 1993;Maruyama et al, 1994;Murao et al, 2004;Ohtsu et al, 2005) .…”

“…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.…”