Analysis of extended human leukocyte antigen haplotype association with Addison's disease in three populations

Abstract

Objective: Addison's disease is an organ-specific autoimmune disorder with a polygenic background. The aim of the study was to identify non-class II human leukocyte antigen (HLA) susceptibility genes for Addison's disease. Design and methods: Addison's disease patients from three European populations were analysed for selected HLA-DR-DQ alleles and for 11 microsatellite markers covering w4 Mb over the HLA region. Subjects were 69 patients with Addison's disease from Estonia (24), Finland (14) and Russia (31). Consecutively recruited healthy newborns from the same geographical regions were used as controls (269 Estonian, 1000 Finnish and 413 Russian). Association measures for HLA-DRB1, DQB1, DQA1 and 11 microsatellites between D6S273 and D6S2223 were taken. A low-resolution full-house typing was used for HLA class II genes, while microsatellite markers were studied using fluorescence-based DNA fragment sizing technology. Results: We confirmed that the HLA-DR3-DQ2 and the DQB1*0302-DRB1*0404 haplotypes confer disease susceptibility. In Russian patients, we also found an increase of DRB1*0403 allele, combined with DQB1*0305 allele in three out of six cases (P!0.0001). Analysis of 11 microsatellite markers including STR MICA confirmed the strong linkage in DR3-DQ2 haplotypes but DRB1*0404-DQB1*0302 haplotypes were diverse. MICA5.1 allele was found in 22 out of 24 Estonian patients, but results from Finnish and Russian patients did not support its independent role in disease susceptibility. Conclusion: HLA-DRB1*0403 was identified as a novel susceptibility allele for Addison's disease. Additionally, we found no evidence of a non-class II HLA disease susceptibility locus; however, the HLA-DR3-DQ2 haplotype appeared more conserved in patient groups with high DR-DQ2 frequencies.

Extended exome sequencing identifies BACH2 as a novel major risk locus for Addison's disease

“…Using in silico typing from sequencing reads, we could confirm the risk conferred by certain HLA haplotype pairs [8,[67][68][69]. The strongest risk factor is by far the combination of HLA alleles DRB1*03:01 and DRB1*04:04, as previously shown in other populations [8,[67][68][69].…”

“…The strongest risk factor is by far the combination of HLA alleles DRB1*03:01 and DRB1*04:04, as previously shown in other populations [8,[67][68][69]. Despite the fact that we selected only patients with AAD reacting against the same autoantigen, 21-hydroxylase, we detect a great variability at the HLA locus.…”

Pregnancy after azathioprine therapy for ulcerative colitis in a woman with autoimmune premature ovarian failure and Addison’s disease: HLA haplotype characterization

“…In detail, the DRB1*11/ DQB1*0301 genotype is associated with that frequently found in aPOF (14); the DQA1*0501-DQB1*0301 haplotype and DRB1*04-DQ7-9 alleles are both reported as predisposing for UC (15). Several studies showed that the HLA DR3/4, DQ2/ DQ8 (DQA1*0501-DQB1*0201/ DQA1*0301-DQB1* 0302) is the highest-risk predisposing genotype to AD, and the haplotype DQB1*0302-DRB1*0404 is known to confer susceptibility to AD (9,11).…”

21-Hydroxylase epitopes are targeted by CD8 T cells in autoimmune Addison’s disease

“…Histological studies of the adrenal tissue of deceased AD patients show a predominant mononuclear cell infiltrate [6,7]. IAD and APS2 are associated with certain HLA haplotypes or allelic combinations, in particular DR3-DQ2 and DR4-DQ8 [8,9] which are known to predispose to other T cell-mediated autoimmune diseases such as type 1 diabetes and celiac disease. Although less reported, association with the HLA A1-B8-DR3 ancestral haplotype has also been described in earlier studies [10,11].…”