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 Pcorrected=0.012 and Pcorrected=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.
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Acknowledgements
This research was supported by grants from the South-Eastern Regional Health Authorities and the Research Council of Norway. The EIRA study was supported by grants from: the Swedish Medical Research Council, the Swedish Council for Working Life and Social Research, King Gustaf V:s 80-year foundation, the Swedish Rheumatism Foundation, Stockholm County Council, the insurance company AFA, the EU-supported AutoCure project, NIH (P60 AR047782), and the COMBINE (Controlling chronic inflammatory diseases with combined efforts) project. We thank the Norwegian Bone Marrow Donor Registry for access to control materials, and would like to acknowledge Eva Jemsby, Gull-Britt Almgren and Julia Boström for sample management of the EIRA material.
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Eike, M., Skinningsrud, B., Ronninger, M. et al. CIITA gene variants are associated with rheumatoid arthritis in Scandinavian populations. Genes Immun 13, 431–436 (2012). https://doi.org/10.1038/gene.2012.11
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DOI: https://doi.org/10.1038/gene.2012.11
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