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CTLA-4 as a genetic determinant in autoimmune Addison's disease

Lookup NU author(s): Dr Anna Mitchell, Professor Heather Cordell, Professor Simon Pearce

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Abstract

In common with several other autoimmune diseases, autoimmune Addison's disease (AAD) is thought to be caused by a combination of deleterious susceptibility polymorphisms in several genes, together with undefined environmental factors and stochastic events. To date, the strongest genomic association with AAD has been with alleles at the HLA locus, DR3-DQ2 and DR4. The contribution of other genetic variants has been inconsistent. We have studied the association of 16 single-nucleotide polymorphisms (SNPs) within the CD28-CTLA-4-ICOS genomic locus, in a cohort comprising 691 AAD patients of Norwegian and UK origin with matched controls. We have also performed a meta-analysis including 1002 patients from European countries. The G-allele of SNP rs231775 in CTLA-4 is associated with AAD in Norwegian patients (odds ratio (OR) = 1.35 (confidence interval (CI) 1.10-1.66), P = 0.004), but not in UK patients. The same allele is associated with AAD in the total European population (OR = 1.37 (CI 1.13-1.66), P = 0.002). A three-marker haplotype, comprising PROMOTER_1661, rs231726 and rs1896286 was found to be associated with AAD in the Norwegian cohort only (OR 2.43 (CI 1.68-3.51), P = 0.00013). This study points to the CTLA-4 gene as a susceptibility locus for the development of AAD, and refines its mapping within the wider genomic locus.


Publication metadata

Author(s): Wolff ASB, Mitchell AL, Cordell HJ, Short A, Skinningsrud B, Ollier W, Badenhoop K, Meyer G, Falorni A, Kampe O, Undlien D, Pearce SHS, Husebye ES

Publication type: Article

Publication status: Published

Journal: Genes & Immunity

Year: 2015

Volume: 16

Issue: 6

Pages: 430-436

Print publication date: 01/09/2015

Online publication date: 23/07/2015

Acceptance date: 16/06/2015

Date deposited: 09/10/2015

ISSN (print): 1466-4879

ISSN (electronic): 1476-5470

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/gene.2015.27

DOI: 10.1038/gene.2015.27


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