Endocrine Abstracts

Background: HLA-DRB1*04 is one of the MHC alleles which is associated with several autoimmune endocrinopathies, including autoimmune Addison’s disease (AAD). The two versions of the gene which encodes the main target of the autoimmune attack in AAD, steroid 21-hydroxylase, are encoded in a gene cluster, called RCCX module, which is a copy number variation located in the MHC class III locus. Previous data from our group showed that AAD patients are more likely to have no copies of the defective version of the steroid 21-hydroxylase gene, CYP21A1P, compared to healthy individuals.

Aim: We examined whether patients in our UK AAD cohort carry the DRB1*04:01 and DRB1*04:04 alleles, and if there is association with the CYP21A1P deletion status.

Methods: Genomic DNA was isolated from the whole blood of AAD patients. We typed 264 AAD individuals for the DRB1*04:01 and DRB1*04:04 alleles by genotyping two SNPs (rs3817964A and rs2736157G, respectively) that tag them in Northern Europeans (CEU). Pearson chi-square test was performed for the testing of the association between the allele frequencies and the CYP21A1P deletion.

Results: Significant results for allele and genotype frequencies were observed for the rs2736157, but not for the rs3817964. The strongest association was seen in case of the rs2736157G, with a significantly higher frequency of G allele in individuals who carry no copies of the CYP21A1P relative to patients who carry copies of the gene (87.5% vs 30%, P=5.8801x10-38) and a calculated allelic odds ratio (OR) of 16.6923 (P<0.0001). No association was observed in case of the rs3817964A, with calculated OR of 0.3259 (P=0.0656).

Conclusion: The results of this study indicate an association between CYP21A1P absence and HLA-DRB1*04:04 allele in a UK AAD cohort. Lack of CYP21A1P could contribute to the breakdown of immune tolerance to steroid 21-hydroxylase in AAD.