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A Cytokine Gene Screen Uncovers SOCS1 As Genetic Risk Factor for Multiple Sclerosis

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A Cytokine Gene Screen Uncovers SOCS1 As Genetic Risk Factor for Multiple Sclerosis Genes and Immunity (2012) 13, 21–28 & 2012 Macmillan Publishers Limited All rights reserved 1466-4879/12 www.nature.com/gene ORIGINAL ARTICLE A cytokine gene screen uncovers SOCS1 as genetic risk factor for multiple sclerosis K Vandenbroeck1,2, J Alvarez3, B Swaminathan1, I Alloza1, F Matesanz4, E Urcelay5, M Comabella6, A Alcina4, M Fedetz4, MA Ortiz5, G Izquierdo7, O Fernandez8, N Rodriguez-Ezpeleta3, C Matute9, S Caillier10, R Arroyo5, X Montalban6, JR Oksenberg10, A Antigu¨ edad11 and A Aransay3 1Neurogenomiks Laboratory, Department of Neuroscience, University of the Basque Country UPV/EHU, Leioa, Spain; 2IKERBASQUE, Basque Foundation for Science, Bilbao, Spain; 3CIC bioGUNE, Parque Tecnolo´gico de Bizkaia, Derio, Spain; 4Instituto de Parasitologı´ay Biomedicina ‘Lo´pez Neyra’, Consejo Superior de Investigaciones Cientı´ficas, Granada, Spain; 5Immunology and Neurology Department, Hospital Clı´nico S Carlos, Instituto de Investigacio´n Sanitaria del Hospital Clı´nico San Carlos (IdISSC), Madrid, Spain; 6Centre d’Esclerosi Mu´ltiple de Catalunya, CEM-Cat, Unitat de Neuroimmunologia Clı´nica, Hospital Universitari Vall d’Hebron, Barcelona, Spain; 7Unidad de Esclerosis Mu´ltiple, Hospital Virgen Macarena, Sevilla, Spain; 8Servicio de Neurologı´a, Instituto de Neurociencias Clı´nicas del Hospital Regional Universitario Carlos Haya de Ma´laga, Ma´laga, Spain; 9Neurotek Laboratory, Department of Neuroscience, University of the Basque Country UPV/EHU, Leioa, Spain; 10Department of Neurology, University of California, San Francisco, CA, USA and 11Servicio 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 (PCMH 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 been known as susceptibility locus since the early 1970s, it was not until 2007, when the first non-HLA genetic risk Multiple sclerosis (MS) is a chronic (CH) inflammatory factors were unequivocally identified via a genome-wide demyelinating disorder of the central nervous system of association study (GWAS).2 Subsequently, seven more unknown etiology, and represents the most common cause GWAS have led to the identification of around 15 of non-traumatic neurological disability in young adults. validated non-HLA risk loci for MS, including among The observed rates of familial aggregation of MS reflected others IL2RA, IL7R, CD58, EVI5 and CD40.1 In addition, a in the increased risk of siblings, second- and third-degree meta-analysis of GWAS3 identified the additional loci CD6, relatives to develop the disease, as well as twin studies, TNFRSF1A and IRF8, and three further loci with sugges- collectively reject a Mendelian trait as the driving force for tive evidence arising from this study were subsequently susceptibility, but are reconcilable with a polygenic, validated as genuine MS risk factors, that is, IL12A, multifactorial mechanism.1 Although the human leukocyte MPHOSPH9 and RSG1.4 All non-HLA MS-susceptibility antigen (HLA) gene cluster on chromosome 6p21.3 has 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). Correspondence: Dr K Vandenbroeck, Neurogenomiks Laboratory, In the present study, we report the results of a haptag Department of Neuroscience, Universidad del Paı´s Vasco (UPV/ screen primarily focusing on cytokine, cytokine receptor EHU), Edificio 205, Planta–1, Parque Tecnolo´gico de Bizkaia, 48170 genes and associated signal transduction factors that also Zamudio (Bizkaia), Spain. E-mail: [email protected] covered a small selection of ionotropic glutamate receptors Received 17 March 2011; revised 5 May 2011; accepted 11 May 2011; and transporters. The latter category of genes was published online 30 June 2011 included based on the observation that glutamate- SOCS1 is associated with MS K Vandenbroeck et al 22 mediated glial injury contributes to white matter pathol- success rate of 97.23%). Risk alleles and their frequencies, ogy as seen in MS.5 The study was performed in two P-values for disease association and ORs of the 20 most phases, with a primary screen of 368 single-nucleotide strongly associated SNPs (Pp0.021), arising from the polymorphism (SNPs) in a Spanish Basque resident case– primary screen, are represented in Table 2. The most control collection of 462 MS patients and 470 controls. Four strongly associated SNPs were found in or nearby the top-scoring SNPs were subsequently analyzed in a genes coding for SOCS1, interleukin-28 receptor, alpha validation cohort composed of five independent sample chain (IL28RA), oncostatin M receptor (OSMR), inter- collections from European and Northern-American origin, leukin-7 receptor (IL-7R) and interleukin-22 receptor, which together included 3919 MS patients and 4003 alpha 2 (IL22RA2) with ORs of around 1.37 and controls. One SNP, rs243324, located in the 50-regulatory uncorrected P-values of 0.003–0.0005. Experimentwise, region of suppressor of cytokine signaling-1 (SOCS1)was none of these associations withstood Bonferroni correc- identified and validated as novel risk factor of MS. tion. Combined single-marker and haplotype analyses highlighted SOCS1 and IL28RA as most strongly asso- ciated gene loci (corrected P-values o0.05; Table 3). Of Results seven IL7R tagSNPs typed, rs6897932 emerged as the single most strongly associated one, in confirmation with Details of sample collections used in the present study earlier reports.2,6,7 Detection of this established risk SNP are provided in Table 1. The primary screen of 384 SNPs may attest to the suitability of this case–control collection was performed in the Bilbao collection. A total of 368 to uncover new risk loci with similar or higher OR. SNPs (mean call frequency, 97.25%) was successfully The four new top-scoring SNPs that have not been genotyped for 462 cases and 470 controls (genotyping reported before (IL7R rs6897932 was excluded) were Table 1 Clinical and demographic features of controls and patients used in the study Population Controls Cases Number Male/Female/ Number Male/Female/ RR and SP/PP/ Age-at-onset EDSS nd (%) nd (%) other/nd (%) (average±s.d.) (mean±s.d.) Bilbao 470 27.9/70.9/1.2 462 28.6/71.4/0.0 81/9.5/2/7.5 30.9±10.3 3.1±2.0 Barcelona 825 46.1/52.8/1.1 708 36.7/63.3/0.0 78/21.2/0.8 30.8±10.2 4.3±2.7 Andalucı´a 1237 30.2/67.5/2.3 1131 29.9/60.7/9.5 80/1/0.9/18.1 29.4±9.9 3.2±1.8 Madrid 832 44.9/53.1/2.0 680 34.5/63.5/2.0 83.2/9.9/0.6/6.3 28.9±8.9 2.9±2.3 UCSF African Americans 658 29.0/69.6/1.4 895 21.0/77.4/1.6 81.7/7/7/4.3 32.8±9.7 4.3±1.6 UCSF Whites 451 33.0/67.0/0.0 505 32.1/67.9/0.0 79.8/3.2/17/0 33.3±9.3 2.04±1.96 Abbreviations: EDSS, expanded disability status scale; nd, not determined, PP, primary progressive; RR, relapsing–remitting; SP, secondary progressive; UCSF, University of California, San Francisco. Table 2 Twenty most strongly associated SNPs in the primary screen of the Bilbao cohort (Pp0.02) Gene SNP Chromosome; chromosome Major/minor Risk Cases, risk Controls, risk P-value OR (95% CI) position (location in gene) allelea allele allele % allele % SOCS1 rs243324 Chr16; 11262471 (50-UTR) C/T T 0.55 0.47 0.0005 1.38 (1.18–1.62) IL28RA rs1416834 Chr1; 24359246 (fourth intron) A/G G 0.41 0.33 0.0008 1.38 (1.17–1.63) OSMR rs3805558 Chr5; 38886646 (first intron) G/A G 0.75 0.69 0.0017 1.38 (1.16–1.65) IL7R rs6897932 Chr5; 35910332 (sixth exon) C/T C 0.76 0.70 0.0022 1.38 (1.15–1.66) IL22RA2 rs202573 Chr6; 137515365 (fifth intron) G/A A 0.33 0.27 0.0026 1.36 (1.14–1.62) IL28RA rs7520329 Chr1; 24371498 (second intron) C/A A 0.30 0.24 0.0026 1.37 (1.14–1.64) GRIK3 rs12067006 Chr1; 37097522 (sixth intron) T/C C 0.29 0.22 0.0034 1.375 (1.14–1.66) IL7R rs6890853 Chr5; 35888068 (50-UTR) G/A G 0.75 0.69 0.0047 1.34 (1.12–1.61) IL31 rs7310689 Chr12; 121217577 (30-UTR) G/A G 0.945 0.91 0.0067 1.66 (1.21–2.28) OSMR rs12657342 Chr5; 38936906 (seventh intron) C/G C 0.79 0.74 0.013 1.31 (1.09–1.59) IL32 rs2015620 Chr16; 3063562 (30-UTR) T/A A 0.34 0.29 0.015 1.27 (1.07–1.51) OSMR rs2278324 Chr5; 38917360 (third intron) C/A A 0.145 0.11 0.015 1.40 (1.10–1.79) IL1RL2 rs17637748 Chr2; 102208147(eighth intron)
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