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 × 10-7) and AD/AIT (OR 4.0, Pc = 3 × 10-7), as well as in isolated T1D (OR 9.7, Pc = 3 × 10-7) and AD (OR 3.1, Pc = 3 × 10-7). 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.
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