TY - JOUR
T1 - Association of autoimmune Addison's disease with alleles of STAT4 and GATA3 in European Cohorts
AU - Mitchell, Anna L.
AU - Macarthur, Katie D R
AU - Gan, Earn H.
AU - Baggott, Lucy E.
AU - Wolff, Anette S B
AU - Skinningsrud, Beate
AU - Platt, Hazel
AU - Short, Andrea
AU - Lobell, Anna
AU - Kam̈pe, Olle
AU - Bensing, Sophie
AU - Betterle, Corrado
AU - Kasperlik-Zaluska, Anna
AU - Zurawek, Magdalena
AU - Fichna, Marta
AU - Kockum, Ingrid
AU - Eriksson, Gabriel Nordling
AU - Ekwall, Olov
AU - Wahlberg, Jeanette
AU - Dahlqvist, Per
AU - Hulting, Anna Lena
AU - Penna-Martinez, Marissa
AU - Meyer, Gesine
AU - Kahles, Heinrich
AU - Badenhoop, Klaus
AU - Hahner, Stephanie
AU - Quinkler, Marcus
AU - Falorni, Alberto
AU - Phipps-Green, Amanda
AU - Merriman, Tony R.
AU - Ollier, William
AU - Cordell, Heather J.
AU - Undlien, Dag
AU - Czarnocka, Barbara
AU - Husebye, Eystein
AU - Pearce, Simon H S
PY - 2014/3/10
Y1 - 2014/3/10
N2 - 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. © 2014 Mitchell et al.
AB - 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. © 2014 Mitchell et al.
U2 - 10.1371/journal.pone.0088991
DO - 10.1371/journal.pone.0088991
M3 - Article
VL - 9
JO - PLoS ONE
JF - PLoS ONE
IS - 3
M1 - e88991
ER -