ORIGINAL ARTICLE A cytokine gene screen uncovers SOCS1 as genetic risk factor for multiple sclerosis K Vandenbroeck 1,2 , J Alvarez 3 , B Swaminathan 1 , I Alloza 1 , F Matesanz 4 , E Urcelay 5 , M Comabella 6 , A Alcina 4 , M Fedetz 4 , MA Ortiz 5 , G Izquierdo 7 , O Fernandez 8 , N Rodriguez-Ezpeleta 3 , C Matute 9 , S Caillier 10 , R Arroyo 5 , X Montalban 6 , JR Oksenberg 10 , A Antigu ¨ edad 11 and A Aransay 3 1 Neurogenomiks Laboratory, Department of Neuroscience, University of the Basque Country UPV/EHU, Leioa, Spain; 2 IKERBASQUE, Basque Foundation for Science, Bilbao, Spain; 3 CIC bioGUNE, Parque Tecnolo ´gico de Bizkaia, Derio, Spain; 4 Instituto de Parasitologı ´a y Biomedicina ‘Lo ´pez Neyra’, Consejo Superior de Investigaciones Cientı ´ficas, Granada, Spain; 5 Immunology and Neurology Department, Hospital Clı ´nico S Carlos, Instituto de Investigacio ´n Sanitaria del Hospital Clı ´nico San Carlos (IdISSC), Madrid, Spain; 6 Centre d’Esclerosi Mu ´ ltiple de Catalunya, CEM-Cat, Unitat de Neuroimmunologia Clı ´nica, Hospital Universitari Vall d’Hebron, Barcelona, Spain; 7 Unidad de Esclerosis Mu ´ltiple, Hospital Virgen Macarena, Sevilla, Spain; 8 Servicio de Neurologı ´a, Instituto de Neurociencias Clı ´nicas del Hospital Regional Universitario Carlos Haya de Ma ´laga, Ma ´laga, Spain; 9 Neurotek Laboratory, Department of Neuroscience, University of the Basque Country UPV/EHU, Leioa, Spain; 10 Department of Neurology, University of California, San Francisco, CA, USA and 11 Servicio de Neurologı ´a, Hospital de Basurto, Bilbao, Spain Cytokine and cytokine receptor genes, including IL2RA, IL7R and IL12A, are known risk factors for multiple sclerosis (MS). Excitotoxic oligodendroglial death mediated by glutamate receptors contributes to demyelinating reactions. In the present study, we screened 368 single-nucleotide polymorphisms (SNPs) in 55 genes or gene clusters coding for cytokines, cytokine receptors, suppressors of cytokine signaling (SOCS), complement factors and glutamate receptors for association with MS in a Spanish–Basque resident population. Top-scoring SNPs were found within or nearby the genes coding for SOCS-1 (P ¼ 0.0005), interleukin-28 receptor, alpha chain (P ¼ 0.0008), oncostatin M receptor (P ¼ 0.002) and interleukin-22 receptor, alpha 2 (IL22RA2; P ¼ 0.003). The SOCS1 rs243324 variant was validated as risk factor for MS in a separate cohort of 3919 MS patients and 4003 controls (combined Cochran–Mantel–Haenszel P ¼ 0.00006; odds ratio (OR) ¼ 1.13; 95% confidence interval (CI) ¼ 1.07–1.20). In addition, the T allele of rs243324 was consistently increased in relapsing-remitting/secondary progressive versus primary-progressive MS patients, in each of the six data sets used in this study (P CMH ¼ 0.0096; OR ¼ 1.24; 95% CI 1.05–1.46). The association with SOCS1 appears independent from the chr16MS risk locus CLEC16A. Genes and Immunity (2012) 13, 21–28; doi:10.1038/gene.2011.44; published online 30 June 2011 Keywords: multiple sclerosis; SOCS1; cytokine; genetics; single-nucleotide polymorphism Introduction Multiple sclerosis (MS) is a chronic (CH) inflammatory demyelinating disorder of the central nervous system of unknown etiology, and represents the most common cause of non-traumatic neurological disability in young adults. The observed rates of familial aggregation of MS reflected in the increased risk of siblings, second- and third-degree relatives to develop the disease, as well as twin studies, collectively reject a Mendelian trait as the driving force for susceptibility, but are reconcilable with a polygenic, multifactorial mechanism. 1 Although the human leukocyte antigen (HLA) gene cluster on chromosome 6p21.3 has been known as susceptibility locus since the early 1970s, it was not until 2007, when the first non-HLA genetic risk factors were unequivocally identified via a genome-wide association study (GWAS). 2 Subsequently, seven more GWAS have led to the identification of around 15 validated non-HLA risk loci for MS, including among others IL2RA, IL7R, CD58, EVI5 and CD40. 1 In addition, a meta-analysis of GWAS 3 identified the additional loci CD6, TNFRSF1A and IRF8, and three further loci with sugges- tive evidence arising from this study were subsequently validated as genuine MS risk factors, that is, IL12A, MPHOSPH9 and RSG1. 4 All non-HLA MS-susceptibility alleles known so far are relatively common in the population and contribute only modestly to overall risk (odds ratios (OR) of 1.1–1.3). In the present study, we report the results of a haptag screen primarily focusing on cytokine, cytokine receptor genes and associated signal transduction factors that also covered a small selection of ionotropic glutamate receptors and transporters. The latter category of genes was included based on the observation that glutamate- Received 17 March 2011; revised 5 May 2011; accepted 11 May 2011; published online 30 June 2011 Correspondence: Dr K Vandenbroeck, Neurogenomiks Laboratory, Department of Neuroscience, Universidad del Paı ´s Vasco (UPV/ EHU), Edificio 205, Planta–1, Parque Tecnolo ´ gico de Bizkaia, 48170 Zamudio (Bizkaia), Spain. E-mail: k.vandenbroeck@ikerbasque.org Genes and Immunity (2012) 13, 21–28 & 2012 Macmillan Publishers Limited All rights reserved 1466-4879/12 www.nature.com/gene