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