Polymorphism in BACH2 gene is a marker of polyglandular autoimmunity

Purpose Genetically predisposed individuals may develop several autoimmune diseases—autoimmune polyendocrine syndromes (APS). APS types 2–4, are complex disorders, which combine various organ-specific autoimmune conditions. Recent reports support the considerable role of the BACH2 gene in immune cell differentiation and shifting the T-cell balance towards regulatory T-cells. BACH2 polymorphisms are associated with autoimmune disorders, including Addison’s disease (AD), Graves’ disease (GD), and probably type 1 diabetes (T1D). Our study was aimed to investigate the BACH2 variant, rs3757247, in endocrine autoimmunity in the Polish population. Methods The analysis comprised 346 individuals with APS, 387 with T1D only, and 568 controls. Genotyping was performed using TaqMan chemistry. Results APS type 2 was found in 219 individuals, type 3 in 102, and type 4 in 25 subjects. Overall, AD was diagnosed in 244 subjects, Hashimoto’s thyroiditis—in 238, T1D—in 127, GD—in 58, vitiligo and chronic gastritis each in 40 patients, celiac disease—in 28, premature menopause in 18, and alopecia in 4 patients. Minor T allele at rs3757247 was found in 56.4% APS vs. 44.1% control alleles (OR 1.59; 95%CI: 1.30–1.95, p < 0.0001). The distribution of genotypes revealed excess TT homozygotes in the APS cohort (33.2 vs. 20.1% in controls, p < 0.0001). The frequencies of rs3757247 alleles and genotypes in T1D patients did not present significant differences vs. controls (p-values > 0.05). Conclusions These results provide evidence of the association between BACH2 polymorphism and polyglandular autoimmunity. Since carriers of rs3757247 display increased risk for additional autoimmune conditions, this variant could identify individuals prone to develop APS.

Amino Acid Polymorphisms in Hla Class II Differentiate Between Thyroid and Polyglandular Autoimmunity

Context The structure of the human leucocyte antigen (HLA) peptide-binding clefts strongly contributes to monoglandular and polyglandular autoimmunity (AP). Objective To investigate the impact of amino acid polymorphisms on the peptide-binding interactions within HLA class II and its association with AP. Design Immunogenetic study. Setting Tertiary referral center for autoimmune endocrine diseases. Subjects 587 subjects with AP, autoimmune thyroid disease (AITD), type 1 diabetes (T1D), and healthy unrelated controls were typed for HLA class II. Methods Amino acids within the peptide binding cleft that are encoded by HLA class II exon 2 were listed for all codon positions in all subjects. Overall comparisons between disease and control groups with respect to allele distribution at a given locus were performed by assembling rare alleles applying an exact Freeman Halton contingency table test with Monte-Carlo P values based on 150 000 samples. Results The Monte Carlo exact Fisher test demonstrated marked differences in all 3 loci, DQA1, DQB1, and DRB1 (P &lt; .0001) between AP and both AITD and controls, as well as between AP type II (Addison’s disease as a major endocrine component) and AP type III (T1D + AITD). Differences were also noted between AP and T1D pertaining to the DRB1 allele (P &lt; .041). Seven amino acid positions, DRB1-13, DRB1-26, DRB1-71, DRB1-74, DQA1-47, DQA1-56, and DQB1-57, significantly contributed to AP. Five positions in DQA1 (11, 47, 50, 56, and 69) completely correlated (P &lt; .0001). Conclusion Amino acid polymorphisms within HLA class II exon 2 mediate the AP risk and differentiate between thyroid and polyglandular autoimmunity.

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*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 &lt; 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.