Reevaluation of Human Leukocyte Antigen DR-DQ Haplotype and Genotype in Type 1 Diabetes in the Japanese Population

Abstract

Aim: This study aims at clarifying the human leukocyte antigen haplotypes and genotypes conferring susceptibility or resistance to type 1 diabetes in the Japanese population. Methods: The frequencies of human leukocyte antigen DR-DQ haplotypes and genotypes were compared between 83 type 1 diabetic patients, except for fulminant type 1 diabetes, and control subjects in the Japanese population. The patients were divided by onset age into four groups (ages 5–14, 15–29, 30–49, and 50–71 years); the haplotype frequency was compared between each group. Results: The frequencies of DRB1*0405-DQB1*0401 (DR4), DRB1*0802-DQB1*0302 (DR8), DRB1*0901-DQB1*0303 (DR9), and DRB1*1302-DQB1* 0604 (DR13) haplotypes were significantly higher in the patients than in the control subjects. The frequencies of DRB1* 1501-DQB1*0602 and DRB1*1502-DQB1*0601 haplotypes were significantly lower in the patients than in the controls. The frequencies of DR4/8, DR4/13, DR9/9, and DR9/13 genotypes were significantly higher in the patients than in the control subjects. The DR13 haplotype was the most frequent haplotype in the age group 30–49 years, whereas the other haplotypes but DR13 were the most frequent in the other age groups. Conclusion: DR4, DR8, DR9, and DR13 haplotypes confer susceptibility to type 1 diabetes in Japanese patients.

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

“…The average age at onset of diabetes was relatively low in previous studies (Awata et al, 1992;Kawabata et al, 2002;Kobayashi et al, 1993;Maruyama et al, 1994;Tanaka et al, 2002) which did not find a significant susceptibility to DR13 (16-34 years). In contrast, the average age at onset of diabetes was relatively high in previous studies (Katahira et al, 2008;Murao et al, 2004) which did find susceptibility to DR13 (≥35 years). Exploratory analyses revealed that the DR13 haplotype might also confer risk for T1D in subjects in Norway, Sweden (Graham et al, 1999;Undlien et al, 1999), and Venezuela (Balducci-Silano et al, 1994) who do not carry the DR3 or the DR4 haplotype.…”

“…On the other hand, DRB1*1502-DQA1*0103-DQB1*0601 and DRB1*0803-DQA1*0103-DQB1*0601 haplotypes are present in East Asians, but rare in Caucasians and Blacks (Thomson et al, 2007). These haplotypes confer weak protection against T1D in the Japanese (Katahira et al, 2008;Yasunaga et al, 1996) and Koreans (Park et al, 2000). As with the DQA1*0102-DQB1*0602 haplotype, the DQA1*0103-DQB1*0601 haplotype encodes "non-Arg," an amino acid other than arginine, at position 52 in DQ and aspartic acid at position 57 in DQ .…”

“…Even if the mean onset age is older than 30 years old, this haplotype appears to confer susceptibility to rapid-onset T1D with slow-onset T1D (which includes both A1 and A2 areas) (Katahira et al, 2008;Takeda et al, 2002). However, there are no studies reporting that this haplotype confers susceptibility to slow-onset T1D (which includes A2 area and excludes A1 area) even if the mean onset age is young (Kobayashi et al, 1993;Maruyama et al, 1994;Murao et al, 2004;Ohtsu et al, 2005).…”

“…4.4 DRB1*13:02-DQA1*01:02-DQB1*06:04 (DR13) haplotype Although the DR13 haplotype is observed in almost all ethnic groups (Thomson et al, 2007), a few investigators have demonstrated that this haplotype confers susceptibility to T1D in the Japanese (Katahira et al, 2008;Matsuda et al, 1988;Murao et al, 2004), Caucasians (Graham et al, 1999;Undlien et al, 1999), and Latin Americans (Cruz et al, 2004;BalducciSilano et al, 1994). The average age at onset of diabetes was relatively low in previous studies (Awata et al, 1992;Kawabata et al, 2002;Kobayashi et al, 1993;Maruyama et al, 1994;Tanaka et al, 2002) which did not find a significant susceptibility to DR13 (16-34 years).…”

“…These are thought to be strongly negatively associated with the development of T1D (Khalil et al, 1990;Todd et al, 1987). Although the DRB1*11-DQA1*05-DQB1*0301 haplotype is observed in almost all ethnic groups (Thomson et al, 2007) and confers protection against T1D in Caucasians (Hermann et al, 2003;Undlien et al, 1999;Yasunaga et al, 1996) and Latin Americans (Volpini et al, 2001), this haplotype confers very weak (Huang et al, 1995;Awata et al, 1992;Katahira et al, 2008) or no protection (Bugawan et al, 2002;Park et al, 2000) against T1D in East Asians, including the Japanese.…”