Endocrine Abstracts (2012) 28 OC3.6

GATA3 polymorphisms are associated with autoimmune Addison's disease

Anna Mitchell1, Katie MacArthur1, Earn Gan1, Lucy Baggott1, Anette Wolff2, Beate Skinningsrud3,4, Andrea Short5, Olle Kampe6, Sophie Bensing6,7, Corrado Betterle8, Anna Kasperlik-Zaluska13, Barbara Czarnocka9, Marta Fichna10, Anna-Lena Hulting7, Klaus Badenhoop11, Alberto Falorni12, William Ollier5, Dag Undlien3,4, Eystein Husebye2 & Simon Pearce1


1Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom; 2Institute of Medicine, Haukeland University Hospital, Bergen, Norway; 3Department of Medical Genetics, Oslo University Hospital, Oslo, Norway; 4University of Oslo, Oslo, Norway; 5Centre for Integrated Genomic Medical Research, Manchester University, Manchester, United Kingdom; 6Department of Medical Sciences, Uppsala University, Uppsala, Sweden; 7Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; 8Department of Medical and Surgical Sciences, School of Medicine, University of Padua, Padua, Italy; 9Department of Biochemistry and Molecular Biology, Center for Postgraduate Medical Education, Warsaw, Poland; 10Department of Endocrinology, Metabolism, and Internal Diseases, Poznan University of medical sciences, Poznan, Poland; 11Department Medicine 1, Division Endocrinology, University Hospital Frankfurt, Frankfurt, Germany; 12Department of Internal Medicine, University of Perugia, Perugia, Italy; 13Department of Endocrinology, Center for Postgraduate Medical Education, Warsaw, Poland.


Autoimmune Addison’s disease (AAD) is a rare, highly heritable endocrinopathy with an estimated λsibling (ratio of risk to a sibling vs the unrelated background population) of 160–210. The majority of the genetic risk to AAD has yet to be accounted for. We have used a tag-SNP approach to seek association between single nucleotide polymorphisms (SNPs) in the GATA3 gene and autoimmune Addison’s disease (AAD). 2001 AAD cases and 1898 controls were included in this study. In round 1, four GATA3 SNPs (rs3802604, rs570613, rs569421, rs444929) were genotyped by Sequenom iPlex in 309 UK and 382 Norwegian AAD cases and 335 UK and 380 Norwegian controls. In round 2, 3 SNPs (rs3802604, rs569421, rs444929) were genotyped in cohorts from Germany (341 cases, 235 controls), Italy (326 cases, 284 controls), Poland (275 cases, 296 controls) and Sweden (368 cases, 368 controls). In round 1, an association with genotypes and alleles at rs569421 (Pallele 0.0039) and rs444929 (Pallele 0.007) was seen in the UK cohort. In the Norwegian cohort, association was found with genotypes and alleles at rs3802604 (Pallele 0.032). In round 2, association was found only with genotypes at rs444929 in the Polish cohort (Pgenotype 0.03). In a meta-analysis of the results from all 6 cohorts to test for overall effect (RevMan5, random effects model), a significant result was generated at rs3802604 (P 0.01, odds ratio 1.13 [95% CI 1.03 – 1.24]). The GATA3 transcription factor is an important regulator of T-cell development, in particular cells of the Th2 lineage, and is expressed in T cells as well as in a number of other tissues, including the adrenal gland. These data, from the largest collection of AAD patients to date, suggests for the first time, a contribution of GATA3 variants to autoimmune disease susceptibility. This is a novel finding and we are currently fine-mapping the association within GATA3.

Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding: No specific grant from any funding agency in the public, commercial or not-for-profit sector.

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