title: CTLA-4 as a genetic determinant in autoimmune Addison's disease.
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.
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, Norway.
authors.forename: A S B
authors.initials: AS
authors.lastname: Wolff
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: A L
authors.initials: AL
authors.lastname: Mitchell
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: H J
authors.initials: HJ
authors.lastname: Cordell
authors.affiliation: Centre for Integrated Genomic Medical Research, Institute of Population Health, Manchester University, Manchester, UK.
authors.forename: A
authors.initials: A
authors.lastname: Short
authors.affiliation: Institute of Medical Genetics, University of Oslo, Oslo, Norway.|Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
authors.forename: B
authors.initials: B
authors.lastname: Skinningsrud
authors.affiliation: Centre for Integrated Genomic Medical Research, Institute of Population Health, Manchester University, Manchester, UK.
authors.forename: W
authors.initials: W
authors.lastname: Ollier
authors.affiliation: Department of Endocrinology and Diabetes, Internal Medicine 1, Johann-Wolfgang-Goethe-University's Hospital, Frankfurt, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Badenhoop
authors.affiliation: Department of Endocrinology and Diabetes, Internal Medicine 1, Johann-Wolfgang-Goethe-University's Hospital, Frankfurt, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Meyer
authors.affiliation: Department of Medicine, University of Perugia, Perugia, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Falorni
authors.affiliation: Department of Medicine, Solna, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
authors.forename: O
authors.initials: O
authors.lastname: Kampe
authors.affiliation: Institute of Medical Genetics, University of Oslo, Oslo, Norway.|Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
authors.forename: D
authors.initials: D
authors.lastname: Undlien
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: S H S
authors.initials: SH
authors.lastname: Pearce
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, Norway.|Department of Medicine, Haukeland University Hospital, Bergen, Norway.
authors.forename: E S
authors.initials: ES
authors.lastname: Husebye
mesh_terms: D000224:Addison Disease / Q000235:genetics*; D000328:Adult; D060908:CTLA-4 Antigen / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D033141:Genetic Determinism; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
chemical_list: D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human