Sex Alters the MHC Class I HLA-A Association With Polyglandular Autoimmunity

Context:The major histocompatibility complex (MHC) strongly contributes to the development of polyglandular autoimmunity (PGA). Objective:To evaluate the impact of sex on human leukocyte antigen (HLA) association with PGA for the first time. Design:Cross-sectional immunogenetic study. Setting:Academic tertiary referral Orphan Disease Center for PGA (ORPHA 282196) and immunogenetics laboratory. Subjects:Patients (158) with coexistent type 1 diabetes and autoimmune thyroid disease (adult type 3 PGA, ORPHA 227982) and 479 unrelated healthy controls. Interventions:All 637 white subjects were typed for HLA-A, -B, -DRB1, -DQA1, and -DQB1 alleles at a two-field level. Main Outcome Measures:Modification of the gene-disease association by sex. Results:MHC class I HLA-A association was sex related to both the total white adult type 3 PGA collective (n=158, P=0.0065), as well as in PGA patients with autoimmune Hashimoto thyroiditis (n=91, P=0.010). Compared with HLA-A(star)02:01, A(star)11:01 was over-represented in male patients, yet under-represented in women (OR 1.49, 95% CI 0.55 to 3.88 vs 0.42, 0.12 to 1.17). A(star)24:02 was under-represented in male but not in female patients (OR 0.37, 95% CI 0.11 to 1.04 vs 1.19, 0.65 to 2.15). With the exclusion of the five most frequent alleles (A(star)01:01, A(star)02:01, A(star)03:01, A(star)11:01, and A(star)24:02), the sum of all other identified alleles was under-represented in male patients (OR 0.37, 0.18 to 0.72, P=0.0046). The strong MHC HLA-B association with PGA (P<0.0001) was not sex related (P=0.55). Furthermore, no interaction with sex was observed for the MHC class II HLA-DRB1, -DQA1, and -DQB1 alleles. Conclusion:MHC class I HLA-A association with type 3 PGA is significantly affected by sex.