Abstract
BackgroundGene variants known to contribute to Autoimmune Addison's disease (AAD) susceptibility include those at the MHC, MICA, CIITA, CTLA4, PTPN22, CYP27B1, NLRP-1 and CD274 loci. The majority of the genetic component to disease susceptibility has yet to be accounted for.AimTo investigate the role of 19 candidate genes in AAD susceptibility in six European case-control cohorts.MethodsA sequential association study design was employed with genotyping using Sequenom iPlex technology. In phase one, 85 SNPs in 19 genes were genotyped in UK and Norwegian AAD cohorts (691 AAD, 715 controls). In phase two, 21 SNPs in 11 genes were genotyped in German, Swedish, Italian and Polish cohorts (1264 AAD, 1221 controls). In phase three, to explore association of GATA3 polymorphisms with AAD and to determine if this association extended to other autoimmune conditions, 15 SNPs in GATA3 were studied in UK and Norwegian AAD cohorts, 1195 type 1 diabetes patients from Norway, 650 rheumatoid arthritis patients from New Zealand and in 283 UK Graves' disease patients. Meta-analysis was used to compare genotype frequencies between the participating centres, allowing for heterogeneity.ResultsWe report significant association with alleles of two STAT4 markers in AAD cohorts (rs4274624: P = 0.00016; rs10931481: P = 0.0007). In addition, nominal association of AAD with alleles at GATA3 was found in 3 patient cohorts and supported by meta-analysis. Association of AAD with CYP27B1 alleles was also confirmed, which replicates previous published data. Finally, nominal association was found at SNPs in both the NF-κB1 and IL23A genes in the UK and Italian cohorts respectively.ConclusionsVariants in the STAT4 gene, previously associated with other autoimmune conditions, confer susceptibility to AAD. Additionally, we report association of GATA3 variants with AAD: this adds to the recent report of association of GATA3 variants with rheumatoid arthritis.
Highlights
Autoimmune Addison’s disease (AAD) is a rare autoimmune endocrinopathy with a prevalence of 110–140 cases per million in Caucasian European populations [1,2]
We report association of GATA3 variants with AAD: this adds to the recent report of association of GATA3 variants with rheumatoid arthritis
Alleles at 3 SNPs in moderate linkage disequilibrium (LD) (r2 0.39–0.68), rs10026278, rs230532 and rs4698861, were associated with AAD in the UK cases compared to controls
Summary
Autoimmune Addison’s disease (AAD) is a rare autoimmune endocrinopathy with a prevalence of 110–140 cases per million in Caucasian European populations [1,2]. Like many autoimmune endocrine conditions, AAD has a strong and oligo-genetic basis. Individuals with AAD are predisposed to develop other organspecific autoimmune diseases which suggests shared susceptibility loci for these conditions. Most cases of AAD are not attributable to Mendelian abnormalities, but are a complex genetic trait, whereby currently unknown environmental factors interact with a number of genetic variants to cause disease. Gene variants known to contribute to Autoimmune Addison’s disease (AAD) susceptibility include those at the MHC, MICA, CIITA, CTLA4, PTPN22, CYP27B1, NLRP-1 and CD274 loci. The majority of the genetic component to disease susceptibility has yet to be accounted for
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