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

The major histocompatibility complex (MHC) strongly contributes to the development of polyglandular autoimmunity (PGA).

To evaluate the impact of sex on human leukocyte antigen (HLA) association with PGA for the first time.

Cross-sectional immunogenetic study.

Academic tertiary referral Orphan Disease Center for PGA (ORPHA 282196) and immunogenetics laboratory.

Patients (158) with coexistent type 1 diabetes and autoimmune thyroid disease (adult type 3 PGA, ORPHA 227982) and 479 unrelated healthy controls.

All 637 white subjects were typed for HLA-A, -B, -DRB1, -DQA1, and -DQB1 alleles at a two-field level.

Modification of the gene-disease association by sex.

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*02:01, A*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*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*01:01, A*02:01, A*03:01, A*11:01, and A*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.

MHC class I HLA-A association with type 3 PGA is significantly affected by sex.