title: CIITA gene variants are associated with rheumatoid arthritis in Scandinavian populations.
abstract: Expression of the major autoimmune risk loci DRB1 and DQB1 is regulated by the class II MHC (major histocompatibility complex) transactivator (CIITA), making the CIITA gene a strong autoimmune risk locus candidate. A CIITA promoter single-nucleotide polymorphism (SNP), rs3087456 (-168 A/G), has indeed been associated with several autoimmune diseases, including rheumatoid arthritis (RA). Recently, an intronic SNP rs8048002 has been suggested as a better susceptibility marker in Addison's disease. Therefore, we tested both SNPs in a panel of autoimmune diseases, consisting of Norwegian patients with RA (n=819), juvenile idiopathic arthritis (JIA; n=524), or type 1 diabetes (T1D; n=1211), and 2149 controls. We also included an independent Swedish RA cohort (n=2503) and controls (n=1416). Both rs3087456 and rs8048002 were significantly associated with RA (combined Norwegian and Swedish patients P(corrected)=0.012 and P(corrected)=0.0016, respectively), but not with JIA or T1D. Meta-analysis of 16 RA cohorts confirmed rs3087456 with only marginal significance (P=0.016). However, results were stronger in the Scandinavian subgroup (4 cohorts, P=3.8 × 10(-4)), indicating a population-dependent effect. A similar pattern was observed in a meta-analysis of rs8048002. Our results support involvement of CIITA in RA, but imply that this is population dependent and that the aetiological variant is yet to be discovered.
authors.affiliation: Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway. m.c.eike@medisin.uio.no
authors.forename: M C
authors.initials: MC
authors.lastname: Eike
authors.forename: B
authors.initials: B
authors.lastname: Skinningsrud
authors.forename: M
authors.initials: M
authors.lastname: Ronninger
authors.forename: A
authors.initials: A
authors.lastname: Stormyr
authors.forename: T K
authors.initials: TK
authors.lastname: Kvien
authors.forename: G
authors.initials: G
authors.lastname: Joner
authors.forename: P R
authors.initials: PR
authors.lastname: Njølstad
authors.forename: O
authors.initials: O
authors.lastname: Førre
authors.forename: B
authors.initials: B
authors.lastname: Flatø
authors.forename: L
authors.initials: L
authors.lastname: Alfredsson
authors.forename: L
authors.initials: L
authors.lastname: Padyukov
authors.forename: D E
authors.initials: DE
authors.lastname: Undlien
authors.forename: B A
authors.initials: BA
authors.lastname: Lie
mesh_terms: D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D001323:Autoantibodies / Q000276:immunology; D000939:Epitopes / Q000276:immunology; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D015201:Meta-Analysis as Topic; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012537:Scandinavian and Nordic Countries; D015534:Trans-Activators / Q000235:genetics*; D044465:White People / Q000235:genetics*
chemical_list: D001323:Autoantibodies; D000939:Epitopes; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D015534:Trans-Activators