Association of autoimmune Addison's disease with alleles of STAT4 and GATA3 in European cohorts

Abstract

Background: 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.

Aim: To investigate the role of 19 candidate genes in AAD susceptibility in six European case-control cohorts.

Methods: A 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.

Results: We 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.

Conclusions: Variants 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.

Figure 1. Forest plots of significant meta-analysis results in AAD.

Meta-analysis of rs4274624 and rs10931481 in the STAT4 gene (panel A, B), rs4646536 SNP in the CYP27B1 gene (panel C) and rs3802604 SNP in the GATA3 gene (panel D) in 6 European AAD cohorts. To be included in the analysis, the genotyping call rate per SNP had to be 95% or more for each cohort, in both cases and controls, and the control data set had to not deviate significantly from Hardy Weinberg Equilibrium (P>0.01). Pooled analysis showed little heterogeneity amongst the cohorts (I²≤20%). Using a random effects model, the meta-analysis confirms association between alleles at these four SNPs and AAD. Maximum association was noted at rs4274624 (panel A), with an odds ratio (OR) of 1.27 [95% CI 1.12–1.42), P<0.0001. (*P value = 0.00016 when data analysed under a random effects model in Stata). In panel B, data for the UK and Norwegian cohorts is not presented as the quality control inclusion criteria were not met in these cohorts.