DRB1*0403 Protects Against IDDM in Caucasians With the High-Risk Heterozygous DQA1*0301-DQB1*0302/DQA1*0501-DQB1*0201 Genotype

Abstract

The human leukocyte antigen (HLA) class II genotype DQA1*0301-DQB1*0302/DQA1*0501-DQB1*0201 has been identified as a marker strongly predisposing to insulin-dependent diabetes mellitus (IDDM) in Caucasian populations. Its frequency in control populations (1-3%) is still, however, 1 order of magnitude higher than the prevalence of IDDM, suggesting that its penetrance can be modified by protective factors. In this study we searched for such a factor in the DRB1 locus by studying DRB1*04 polymorphism in 174 European Caucasian IDDM patients and 73 nondiabetic control subjects, all sharing the HLA-DR3/DR4 phenotype. Significant protection was encoded by the DRB1*0403 allele, which was observed in 5 of 49 control subjects (10%) and none of 171 IDDM patients (0%) with the DQA1*0301-DQB1*0302/DQA1*0501-DQB1*0201 genotype (RR = 0.02 [0.01-0.18], P < 0.0005). These data support the concept that protective HLA class II genes can overrule the risk caused by HLA-DQ susceptibility dimers. They also contribute to a possible strategy to screen for nondiabetic individuals with increased genetic risk of developing IDDM.

Specific HLA-DRB and -DQB Alleles and Haplotypes Confer Disease Susceptibility or Resistance in Bahraini Type 1 Diabetes Patients

“…Whereas "protective" haplotypes were previously described for Caucasians (11,26) and non-Caucasians (14), this is the first indication of a protective aspect of this haplotype. The DRB1*100101 allele also afforded some protection not only when it was combined with protective DQB1 alleles, including DQB1*050101 (P Ͻ 0.001; RR ϭ 0.11), but also when it was combined with the susceptible allele DQB1*0302.…”

Retrovirus-Like Long-Terminal Repeat DQ-LTR13 and Genetic Susceptibility to Type 1 Diabetes and Autoimmune Addison’s Disease

“…DRB1*0403 was absent in type 1 diabetic and AAD patients but was the most frequent DRB1*04 allele in healthy control subjects (27% of DRB1*04-positive individuals) (P Ͻ 0.0001). This high frequency of *0403 in healthy control subjects was somewhat unexpected, as much lower frequencies have been observed in other European countries (7)(8)(9). The high prevalence of *0403 among DRB1*04-positive healthy control subjects, along with the low prevalence of high-risk class II haplotypes, can in part explain the lower incidence of type 1 diabetes in continental Italy compared with North European countries (20).…”

“…In each family, genomic DNA samples from the diabetic proband (median age at diagnosis 9 years [range [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19], M:F ratio 1.29) and both parents were analyzed.…”

“…Genetic risk conferred by HLA class II haplotypes is modulated by the DRB1*04 subtype (7). DRB1*0403 confers dominant protection from type 1 diabetes even when part of the high-risk DRB1*03-DQA1*0501-DQB1*0201/DRB1*04-DQA1*0301-DQB1*0302 genotype (7)(8)(9).…”

Prognozirovanie SD 1 tipa v gruppakh vysokogo riska

“…2). У 2 больных в генотипе присутствует аллель DQB 1*0201, ассоциированный с СД 1 типа; только у 1 больной этой группы обнаружен генотип DRB 1*01/01, кото- рый при популяционных исследованиях не был ассо циирован с СД 1 типа, мы не выделяли подтипы DRB1*04 , хотя полиморфизм этого локуса может влиять на риск развития СД 1 типа [9,34]. При генотипировании прямых потомков пациен тов с СД 1 типа выявлено, что из 37 человек 30 (81%) унаследовали ассоциированные с СД 1 типа генотипы DRB1*03, DRB 1*04 и их сочетание, у 3 лиц в генотипе присутствуют ассоциированные с СД 1 типа аллели: у 1 -DQA 1*0501, у 2 пациентов -DQB 1*0201.…”