title: 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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Mitchell
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom.
authors.forename: Katie D R
authors.initials: KD
authors.lastname: Macarthur
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom.
authors.forename: Earn H
authors.initials: EH
authors.lastname: Gan
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom.
authors.forename: Lucy E
authors.initials: LE
authors.lastname: Baggott
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: Anette S B
authors.initials: AS
authors.lastname: Wolff
authors.affiliation: Department of Medical Genetics, Oslo University Hospital, Oslo, Norway; University of Oslo, Oslo, Norway.
authors.forename: Beate
authors.initials: B
authors.lastname: Skinningsrud
authors.affiliation: CIGMR, Institute of Population Health, University of Manchester, Manchester, United Kingdom.
authors.forename: Hazel
authors.initials: H
authors.lastname: Platt
authors.affiliation: CIGMR, Institute of Population Health, University of Manchester, Manchester, United Kingdom.
authors.forename: Andrea
authors.initials: A
authors.lastname: Short
authors.affiliation: Uppsala University, Uppsala, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Lobell
authors.affiliation: Uppsala University, Uppsala, Sweden.
authors.forename: Olle
authors.initials: O
authors.lastname: Kämpe
authors.affiliation: Uppsala University, Uppsala, Sweden; Karolinska Institutet, Stockholm, Sweden.
authors.forename: Sophie
authors.initials: S
authors.lastname: Bensing
authors.affiliation: Department of Medicine, University of Padua School of Medicine, Padua, Italy.
authors.forename: Corrado
authors.initials: C
authors.lastname: Betterle
authors.affiliation: Department of Endocrinology, Center for Postgraduate Medical Education, Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Kasperlik-Zaluska
authors.affiliation: Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Zurawek
authors.affiliation: Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Fichna
authors.affiliation: Neuroimmunology Unit, Department of Clinical Neuroscience and Centrum for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Kockum
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Nordling Eriksson
authors.affiliation: The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Olov
authors.initials: O
authors.lastname: Ekwall
authors.affiliation: Department of Medical and Health Sciences, Division of Endocrinology, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Wahlberg
authors.affiliation: Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Dahlqvist
authors.affiliation: Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Hulting
authors.affiliation: Department Medicine (Division Endocrinology), University Hospital Frankfurt, Goethe-University, Frankfurt, Germany.
authors.forename: Marissa
authors.initials: M
authors.lastname: Penna-Martinez
authors.affiliation: Department Medicine (Division Endocrinology), University Hospital Frankfurt, Goethe-University, Frankfurt, Germany.
authors.forename: Gesine
authors.initials: G
authors.lastname: Meyer
authors.affiliation: Department Medicine (Division Endocrinology), University Hospital Frankfurt, Goethe-University, Frankfurt, Germany.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Kahles
authors.affiliation: Department Medicine (Division Endocrinology), University Hospital Frankfurt, Goethe-University, Frankfurt, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Badenhoop
authors.affiliation: University Hospital Wuerzburg (Department of Medicine, Endocrinology and Diabetology), Wuerzburg, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Hahner
authors.affiliation: Clinical Endocrinology, Charité Campus Mitte, Charité University Medicine Berlin, Berlin, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Quinkler
authors.affiliation: Department of Internal Medicine, University of Perugia, Perugia, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Falorni
authors.affiliation: Department of Biochemistry, University of Otago, Otago, New Zealand.
authors.forename: Amanda
authors.initials: A
authors.lastname: Phipps-Green
authors.affiliation: Department of Biochemistry, University of Otago, Otago, New Zealand.
authors.forename: Tony R
authors.initials: TR
authors.lastname: Merriman
authors.affiliation: CIGMR, Institute of Population Health, University of Manchester, Manchester, United Kingdom.
authors.forename: William
authors.initials: W
authors.lastname: Ollier
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom.
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Cordell
authors.affiliation: Department of Medical Genetics, Oslo University Hospital, Oslo, Norway; University of Oslo, Oslo, Norway.
authors.forename: Dag
authors.initials: D
authors.lastname: Undlien
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Postgraduate Medical Education, Warsaw, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Czarnocka
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Medicine, Haukeland University Hospital, Bergen, Norway.
authors.forename: Eystein
authors.initials: E
authors.lastname: Husebye
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom.
authors.forename: Simon H S
authors.initials: SH
authors.lastname: Pearce
mesh_terms: D000224:Addison Disease / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001327:Autoimmune Diseases / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D050990:GATA3 Transcription Factor / Q000235:genetics*; D056726:Genetic Association Studies; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease; D060005:Genotyping Techniques; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D009664:Norway; D050797:STAT4 Transcription Factor / Q000235:genetics*; D006113:United Kingdom; D044465:White People; D055815:Young Adult
chemical_list: D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human