HLA-DRB1*0403 is associated with dominant protection against IDDM in the general Dutch population and subjects with high-risk DQA1*0301-DQB1*0302/DQA1*0501-DQB1*0201 genotype

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Abstract
Insulin‐dependent (Type 1) diabetes mellitus (IDDM) is a genetically controlled T‐cell mediated autoimmune disease. Recently, subtyping of HLA‐DRB1*04 identified the HLA‐DRB1*0403 allele to be associated with protection in Caucasoids with the highest risk heterzygous genotype DQA1*0301‐DQB1*0302/DQA1*0501‐DQB1*0201. Some studies confirmed this finding, but other reports were not consistent with a dominantly protective trait. We here report the frequency of HLA‐DRB1*0403 in a large cohort (n=200) of Dutch patients with IDDM, their first‐degree family members (n=370), and random controls (n=420) of the general population in The Netherlands. We found that HLA‐DRB1*0403 is strongly associated with dominant protection against development of IDDM in unrelated subject, even in the context of the highest risk HLA‐DQ phenotypes and HLA‐DR4‐DQB1*0302 (P<0.0001).