HLA-DQB1 position 57 defines susceptibility to isolated and polyglandular autoimmunity in adults: Interaction with gender

Abstract

Context: Autoimmune endocrinopathies result from environmental triggers on the genetic background of risk alleles, especially HLA-DR and HLA-DQ with alanine (Ala) in HLA-DQB1 position 57 (Ala57), whereas amino acid Asp57 is protective. Objectives: Differentiate the effects of HLA-DQB1 amino acid variants at position 57 in adult patients with isolated endocrinopathies and autoimmune polyglandular syndrome type 2 (APS-2) compared with healthy controls in relation to gender. Setting: University Hospital Frankfurt, Frankfurt, Germany. Participants: Two hundred seventy-eight patients with APS-2 and 1373 patients with isolated endocrinopathies: [type 1 diabetes (T1D), n = 867], Addison disease (AD, n = 185), autoimmune thyroiditis (AIT, n = 321) and 526 healthy controls. Results: Homozygous HLA-DQB1 Ala57 was more frequent in polyglandular T1D/AIT (OR 11.7, Pc = 3 3 1027) and AD/AIT (OR 4.0, Pc = 3 3 1027), as well as in isolated T1D (OR 9.7, Pc = 3 3 1027) and AD (OR 3.1, Pc = 3 3 1027). Heterozygous HLA-DQB1 57 Ala/non-Ala was increased in women with isolated AD and polyglandular AD/AIT (both OR 1.7, Pc= 0.02) whereas the same amino acid variant was overrepresented in men with T1D compared with women (OR 1.6, Pc = 0.004). The amino acid Ala57 was more frequent (OR 2.0, Pc = 0.02) and the amino acid Asp57 was much more rare (OR 0.4, Pc = 0.007) in the APS-2 cohort T1D/AIT than in AD/AIT. Conclusion: HLA-DQB1 confers strong susceptibility by Ala57 homozygosity and protection by non-Ala57, both in adult isolated and polyglandular diseases. Frequencies of HLA-DQB1 amino acids differentiate between APS-2 T1D/AIT and AD/AIT. HLA-DQB1 Ala57 heterozygous women are at increased risk for AD or AIT, whereas men were found to have an increased susceptibility for T1D.