Association of Autoimmune Addison's Disease with Alleles of STAT4 and GATA3 in European Cohorts

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.

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

“…Apart from HLA, other already published loci found to be associated with AAD in candidate gene studies did not exceed our significance threshold [27,28]. This could be due to several factors.…”

“…Apart from the wellcharacterized association with the HLA complex [27], little is known about the genetic variants that contribute to disease development [27]. Until now, candidate gene studies have linked genes implicated in co-occurring autoimmune diseases to AAD [27,28]. The rarity of AAD has however, made extensive unbiased genomewide association studies unfeasible.…”

Autoanticorpi anti-surrene nell’insufficienza corticosurrenalica primitiva

“…Recentemente, un ampio studio multicentrico su 1264 pazienti con MAA ha dimostrato una significativa associazione con due marcatori genici di STAT4 in varie coorti europee (rs4274624 e rs10931481) e associazioni significative con i geni NF-κB1 e IL23A in UK ed Italia, rispettivamente [34].…”

Significance and Distribution of the Mic a/B Alleles Among the Worldwide Populations

“…Hence, various approaches were devised to upregulate the MIC expression in the target cells, which would in turn increase the cytotoxicity in tumors [28]. Recently, the polymorphisms and expression of the MHC class I chain(MICA/B)-related alleles are reported to be associated with various complications such as Psoriasis [29], Ocular toxoplasmosis*30+, Behçet's disease [31] 26 Liver disease [32], Liver fibrosis [33], Ankylosing spondylitis [34], Celiac disease [35], HIV infections [36], Autoimmune diseases [37][38][39], and importantly, with Graft rejection [40,41], and numerous cancers [42][43][44][45][46][47].…”