The Genetic Association of Variants in CD6, TNFRSF1A and IRF8 to Multiple Sclerosis: A Multicenter Case-Control Study

Background: In the recently published meta-analysis of multiple sclerosis genome-wide association studies De Jager et al. identified three single nucleotide polymorphisms associated to MS: rs17824933 (CD6), rs1800693 (TNFRSF1A) and rs17445836 (61.5 kb from IRF8). To refine our understanding of these associations we sought to replicate these findings in a large more extensive independent sample set of 11 populations of European origin. Principal Findings: We calculated individual and combined associations using a meta-analysis method by Kazeem and Farral (2005). We confirmed the association of rs1800693 in TNFRSF1A (p 4.1961027, OR 1.12, 7,665 cases, 8,051 controls) and rs17445836 near IRF8 (p 5.35610210, OR 0.84, 6,895 cases, 7,580 controls and 596 case-parent trios) The SNP rs17824933 in CD6 also showed nominally significant evidence for association (p 2.1961025, OR 1.11, 8,047 cases, 9,174 controls, 604 case-parent trios). Conclusions: Variants in TNFRSF1A and in the vicinity of IRF8 were confirmed to be associated in these independent cohorts, which supports the role of these loci in etiology of multiple sclerosis. The variant in CD6 reached genome-wide significance after combining the data with the original meta-analysis. Fine mapping is required to identify the predisposing variants in the loci and future functional studies will refine their molecular role in MS pathogenesis. Citation: The International Multiple Sclerosis Genetics Consortium (2011) The Genetic Association of Variants in CD6, TNFRSF1A and IRF8 to Multiple Sclerosis: A Multicenter Case-Control Study. PLoS ONE 6(4): e18813. doi:10.1371/journal.pone. 0018813 Editor: Lucienne Chatenoud, Universite Paris Descartes, France Received October 7, 2010; Accepted March 16, 2011; Published April 28, 2011 Copyright: 2011 Leppa et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by National Institutes of Health (grants RO1 NS 43559 and RO1 NS049477), Center of Excellence for Complex Disease Genetics of the Academy of Finland (grants 213506, 129680), the Sigrid Juselius Foundation, the Biocentrum Helsinki Foundation, Helsinki University Central Hospital Research Foundation, the Neuropromise EU project (grant LSHM-CT-2005-018637), The Wellcome Trust grant (089061/Z/09/Z), the Cambridge NIHR Biomedical Research Centre, The Danish Council for Strategic Research grant 2142-08-0039, Italian Foundation for Multiple Sclerosis (FISM grants 2008/R/11), Regione Piemonte Ricerca Sanitaria Finalizzata (2007, 2008), Fondazione Cariplo grant nu 20100728, Progetto Strategico 2007 Italian Ministry of Health, CRT Foundation, Torino, National Multiple Sclerosis Foundation (USA) and Swiss MS society. South and Eastern Norway Regional Health Authority is acknowledged for support to genotyping of Norwegian samples. The French network REFGENSEP is financially supported by INSERM (Institut National de la Sante et de la Recherche Medicale), ARSEP (Association pour la Recherche sur la Sclerose En Plaques) and AFM (Association Francaise contre les Myopathies). The German group was supported by a grant from the Bundesministerium fur Bildung und Forschung (Krankheitsbezogenes Kompetenznetzwerk Multiple Sklerose, Control-MS). The Swedish group was supported by the Swedish Medical Research Council, The Soderberg Foundation, Swedish Council for Working Life and Social and the Bibbi och Nils Jensens Stiftelse (Foundation). Benedicte Dubois is a Clinical Investigator of the Research Foundation Flanders (FWO-Vlaanderen) Bayer Chair on fundamental genetic research regarding the neuroimmunological aspects of multiple sclerosis and the Biogen Idec Chair Translational Research in Multiple Sclerosis at the KULeuven, Leuven, Belgium. PLD is a Harry Weaver Neuroscience Scholar of the National MS Society, and this work is supported by R01 NS067305. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: virpi.leppa@thl.fi " Members of the International Multiple Sclerosis Genetics Consortium is provided in the Acknowledgments.