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A cytokine gene screen uncovers SOCS1 as genetic risk factor for multiple sclerosis

Genes & Immunity volume 13, pages 21–28 (2012)Cite this article

Abstract

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=0.0005), interleukin-28 receptor, alpha chain (P=0.0008), oncostatin M receptor (P=0.002) and interleukin-22 receptor, alpha 2 (IL22RA2; P=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=0.00006; odds ratio (OR)=1.13; 95% confidence interval (CI)=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=0.0096; OR=1.24; 95% CI 1.05–1.46). The association with SOCS1 appears independent from the chr16MS risk locus CLEC16A.

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Acknowledgements

We express our gratitude to all patients and control subjects participating in this study. We thank the Basque Biobank of the Basque Foundation for Health Innovation and Research for supplying DNA samples. This study was supported by grants to K Vandenbroeck from the European Community's Seventh Framework Program (FP7/2007-2013) under grant agreement no 212877 (UEPHA*MS; www.reem.es/uepha-ms/), and from the Gobierno Vasco (Ref. IT512-10; Convocatoria ‘Grupos de Investigación 2010–2015’); by grants to A Aransay from the Gobierno Vasco (Ref. MV-2005-1-13; ‘Convocatoria de Programas de Perfeccionamiento y Movilidad del Personal Investigador 2005’), the Department of Industry, Tourism and Trade of the Government of the Autonomous Community of the Basque Country (Etortek Research Programs 2005–2006) and from the Innovation Technology Department of the Bizkaia County; by project grant FIS PI10/1985 to E Urcelay; by grants to A Alcina from the Fondos Europeos de Desarrollo Regional (FEDER), Ministerio de Ciencia e Innovación (SAF2009-11491) and Junta de Andalucía (P07-CVI-02551); and by grant FIS PI/081636 to F Matesanz.

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Authors and Affiliations

  1. Department of Neuroscience, Neurogenomiks Laboratory, University of the Basque Country UPV/EHU, Leioa, Spain

    K Vandenbroeck, B Swaminathan & I Alloza

  2. IKERBASQUE, Basque Foundation for Science, Bilbao, Spain

    K Vandenbroeck

  3. CIC bioGUNE, Parque Tecnológico de Bizkaia, Derio, Spain

    J Alvarez, N Rodriguez-Ezpeleta & A Aransay

  4. Instituto de Parasitología y Biomedicina ‘López Neyra’, Consejo Superior de Investigaciones Científicas, Granada, Spain

    F Matesanz, A Alcina & M Fedetz

  5. Immunology and Neurology Department, Hospital Clínico S Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain

    E Urcelay, M A Ortiz & R Arroyo

  6. Centre d’Esclerosi Múltiple de Catalunya, CEM-Cat, Unitat de Neuroimmunologia Clínica, Hospital Universitari Vall d'Hebron, Barcelona, Spain

    M Comabella & X Montalban

  7. Unidad de Esclerosis Múltiple, Hospital Virgen Macarena, Sevilla, Spain

    G Izquierdo

  8. Servicio de Neurología, Instituto de Neurociencias Clínicas del Hospital Regional Universitario Carlos Haya de Málaga, Málaga, Spain

    O Fernandez

  9. Department of Neuroscience, Neurotek Laboratory, University of the Basque Country UPV/EHU, Leioa, Spain

    C Matute

  10. Department of Neurology, University of California, San Francisco, CA, USA

    S Caillier & J R Oksenberg

  11. Servicio de Neurología, Hospital de Basurto, Bilbao, Spain

    A Antigüedad

Authors
  1. K Vandenbroeck
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  2. J Alvarez
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  3. B Swaminathan
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  7. M Comabella
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  8. A Alcina
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  9. M Fedetz
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  10. M A Ortiz
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  11. G Izquierdo
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  12. O Fernandez
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  13. N Rodriguez-Ezpeleta
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  14. C Matute
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  15. S Caillier
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  16. R Arroyo
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  18. J R Oksenberg
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  19. A Antigüedad
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  20. A Aransay
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Correspondence to K Vandenbroeck.

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Vandenbroeck, K., Alvarez, J., Swaminathan, B. et al. A cytokine gene screen uncovers SOCS1 as genetic risk factor for multiple sclerosis. Genes Immun 13, 21–28 (2012). https://doi.org/10.1038/gene.2011.44

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  • DOI: https://doi.org/10.1038/gene.2011.44

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