Abstract
A recent genome-wide association study (GWAS) performed by the The Wellcome Trust Case–Control Consortium based on 12 374 nonsynonymous single-nucleotide polymorphisms (SNPs) provided evidence for several genes involved in multiple sclerosis (MS) susceptibility. In this study, we aimed at verifying the association of 19 SNPs with MS, with P-values ≤0.005, in an independent cohort of 732 patients and 974 controls, all Caucasian from the South of Spain. We observed an association of the rs17368528 polymorphism with MS (P=0.04, odds ratio (OR)=0.801, 95% confidence interval (CI)=0.648–0.990). The association of this polymorphism with MS was further validated in an independent set of 1318 patients from the Canadian Collaborative Project (P=0.04, OR=0.838, 95% CI=0.716–0.964). This marker is located on chromosome 1p36.22, which is 1 Mb away from the MS-associated kinesin motor protein KIF1B, although linkage disequilibrium was not observed between these two markers. The rs17368528 SNP results in an amino-acid substitution (proline to leucine) in the fifth exon of the hexose-6-phosphate dehydrogenase (H6PD) gene, in which some variants have been reported to attenuate or abolish H6PD activity, in individuals with cortisone reductase deficiency. This study corroborates the association of one locus determined by GWAS and points to H6PD as a new candidate gene for MS.
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Acknowledgements
We thank the patients with multiple sclerosis and persons who acted as controls for making this study possible. Financial support for the study was provided by the Ministerio de Ciencia e Innovación and Fondos Europeos de Desarrollo Regional (FEDER) (grants PN-SAF2006-02023 and PN-SAF2009-11491) and Junta de Andalucía (P07-CVI-02551) to A Alcina, and Fondo de Investigación Sanitaria (FIS, grant number PI081636) and Servicio Andaluz de Salud (PI0168-2007) to F Matesanz. The Multiple Sclerosis Society of the United Kingdom and the Multiple Sclerosis Society of Canada Scientific Research Foundation support the Canadian Collaborative Study Group. SNP genotyping services were provided by the Spanish ‘Centro Nacional de Genotipado CEGEN-USC, www.cegen.org. María Fedetz is a holder of a fellowship from Fundación IMABIS. Dorothy Ndagire is a holder of Agencia Española Cooperación Internacional (AECI)-Ministerio de Asuntos Exteriores fellowship.
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Alcina, A., Ramagopalan, S., Fernández, Ó. et al. Hexose-6-phosphate dehydrogenase: a new risk gene for multiple sclerosis. Eur J Hum Genet 18, 618–620 (2010). https://doi.org/10.1038/ejhg.2009.213
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DOI: https://doi.org/10.1038/ejhg.2009.213
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