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

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

Cohort information.

<p>Information for each of the six included AAD cohorts.</p><p>*Additional autoimmune comorbidities include type 1 diabetes, autoimmune thyroid disease (Graves' and autoimmune hypothyroidism), pernicious anaemia, vitiligo, autoimmune hepatitis, rheumatoid arthritis, SLE, Sjogren's disease, Coeliac disease, premature ovarian failure, alopecia.</p

Associations with AAD in the German, Swedish, Italian and Polish cohorts in phase 2 of genotyping.

<p>Nominally significant associations with AAD in the German, Swedish, Italian and Polish cohorts in phase 2 of genotyping. No association was observed with alleles at <i>RORA, IL17A, CYP27B1</i> and <i>REL</i> (data not shown).</p><p>*Low LD = r²<0.40, moderate LD = r² 0.40–0.79, significant LD = r²>0.7.</p

Genetic heterogeneity between the six different European control cohorts.

<p>Genetic heterogeneity between the six different European control cohorts. Allele frequencies were compared between all control populations using a chi squared test. The percentage of comparisons where a statistically significant result was seen (P<0.05) is shown in the table. A low percentage indicates that there were few markers at which allele frequencies differed between 2 populations of interest suggesting that there is little genetic heterogeneity between those two populations. A high percentage indicates that allele frequencies between two populations differed significantly at multiple markers, suggesting significant genetic heterogeneity between those two populations. Between the German and Swedish control cohorts, allele frequencies did not differ significantly at a single marker, suggesting that these populations are relatively genetically similar. By contrast, the UK and Italian control cohorts differed significantly at 73% of markers tested, suggesting significant genetic heterogeneity between these two cohorts.</p