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Blanco-Kelly F.,Hospital Universitario Clinico San Carlos | Alvarez-Lafuente R.,Hospital Clinico San Carlos | Alcina A.,Institute Parasitologia y Biomedicina Lopez Neyra | Abad-Grau M.M.,University of Granada | And 7 more authors.
Genes and Immunity | Year: 2011

TNFRSF6B and TNFRSF14 genes were recently associated with Crohn's disease and rheumatoid arthritis. TNFRSF14 is known as herpes virus entry mediator (HVEM), and herpes viruses have been involved in the aetiology of multiple sclerosis (MS). MS patients present human herpes virus 6 (HHV6) in active plaques and increased antibody responses to HHV6. We aimed to ascertain the role of these genes in MS susceptibility and to investigate the relationship of the gene encoding the widely expressed HVEM receptor with the active replication of HHV6 found in some MS patients. Genotyping of 1370 Spanish MS patients and 1715 ethnically matched controls was performed. HHV6A DNA levels (surrogate of active viral replication) were analysed in serum of MS patients during a 2-year follow-up. Both polymorphisms were associated with MS predisposition, with stronger effect in patients with HHV6 active replicationTNFRSF6B-rs4809330 A: P=0.028, OR1.13; TNFRSF14-rs6684865 A: overall P=0.0008, OR=1.2; and HHV6-positive patients vs controls: P=0.017, OR=1.69. © 2011 Macmillan Publishers Limited All rights reserved. Source


Alcina A.,Institute Parasitologia y Biomedicina Lopez Neyra | Fernandez O.,Institute Neurociencias Clinicas | Gonzalez J.R.,CIBER ISCIII | Catala-Rabasa A.,Institute Parasitologia y Biomedicina Lopez Neyra | And 7 more authors.
European Journal of Human Genetics | Year: 2010

A recent genome-wide association study conducted by the International Multiple Sclerosis Genetic Consortium (IMSGC) identified, among others, a number of putative multiple sclerosis (MS) susceptibility variants at position 1p22. Twenty-one SNPs positively associated with MS were located at the GFI-EVI5-RPL5-FAM69A locus. In this study, we performed an analysis and fine mapping of this locus, genotyping eight Tag-SNPs in 732 MS patients and 974 controls from Spain. We observed an association with MS in three of eight Tag-SNPs: rs11804321 (P=0.008, OR=1.29; 95% CI1.08-1.54), rs11808092 (P=0.048, OR=1.19; 95% CI1.03-1.39) and rs6680578 (P=0.0082, OR=1.23; 95% CI1.07-1.41). After correcting for multiple comparisons and using logistic regression analysis to test the addition of each SNP to the most associated SNPs, we observed that rs11804321 alone was sufficient to model the association. This Tag-SNP captures two SNPs in complete linkage disequilibrium (r2= 1), both located within the 17th intron of the EVI5 gene. Our findings agree with the corresponding data of the recent IMSGC study and present new genetic evidence that points to EVI5 as a factor of susceptibility to MS. © 2010 Macmillan Publishers Limited All rights reserved. Source


Alcina A.,Institute Parasitologia y Biomedicina Lopez Neyra | Vandenbroeck K.,University of the Basque Country | Vandenbroeck K.,Ikerbasque | Otaegui D.,Institute Investigacion Sanitaria BIODONOSTIA | And 19 more authors.
Genes and Immunity | Year: 2010

Genome-wide association studies (GWAS) have revealed that different diseases share susceptibility variants. Twelve single-nucleotide polymorphisms (SNPs) previously associated with different immune-mediated diseases in GWAS were genotyped in a Caucasian Spanish population of 2864 multiple sclerosis (MS) patients and 2930 controls. Three SNPs were found to be associated with MS: rs1678542 in KIF5A (P0.001, odds ratio (OR)1.13, 95% confidence interval (CI)1.05-1.23); rs3184504 in SH2B3 (P0.00001, OR1.19, 95% CI1.10-1.27) and rs763361 in CD226 (P0.00007, OR1.16, 95%CI1.08-1.25). These variants have previously been associated with rheumatoid arthritis and type 1 diabetes. The SH2B3 polymorphism has additionally been associated with systemic lupus erythematosus. Our results, in addition to validating some of these loci as risk factors for MS, are consistent with shared genetic mechanisms underlying different immune-mediated diseases. These data may help to shape the contribution of each pathway to different disorders. © 2010 Macmillan Publishers Limited All rights reserved. Source


Alcina A.,Institute Parasitologia y Biomedicina Lopez Neyra | Ramagopalan S.V.,University of Oxford | Fernandez O.,Institute Neurociencias Clinicas | Catala-Rabasa A.,Institute Parasitologia y Biomedicina Lopez Neyra | And 8 more authors.
European Journal of Human Genetics | Year: 2010

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. © 2010 Macmillan Publishers Limited All rights reserved. Source


Varade J.,Institute Investigacion Sanitaria del Hospital Clinico San Carlos IdISSC | Comabella M.,Hospital Universitari Vall dHebron | Ortiz M.A.,Institute Investigacion Sanitaria del Hospital Clinico San Carlos IdISSC | Arroyo R.,Institute Investigacion Sanitaria del Hospital Clinico San Carlos IdISSC | And 19 more authors.
Multiple Sclerosis Journal | Year: 2012

Background and objectives: Ten genes previously showing different evidence of association with multiple sclerosis have been selected to validate. Methods: Eleven polymorphisms were genotyped with the iPLEX™ Sequenom in a well-powered collection of Spanish origin including 2863 multiple sclerosis cases and 2930 controls. Results: Replication extended to the following polymorphisms: PKN2 (rs305217), GTF2B (rs7538427), EPHA4 (rs1517440), YTHDF3 (rs12115114), ANKFN1 (rs17758761) and PTPRM (rs4798571), which did not reach the threshold of significance in a follow-up of the first genome-wide association study (GWAS) conducted in multiple sclerosis; TMEM39A (rs1132200), which appeared as a newly identified susceptibility gene in the same study; a gene previously reaching GWAS significance in Italy, CBLB (rs9657904); IL12B (rs6887695, rs10045431), a susceptibility gene shared by diverse autoimmune diseases and, finally, another gene showing inconclusive association with multiple sclerosis, CNR1 (rs1049353). Conclusions: Pooled analysis corroborated the effect on MS predisposition of three genes: TMEM39A [rs1132200: p M-H=0.001; ORM-H (95% CI)= 0.84 (0.75-0.93)], IL12B [rs6887695: pM-H=0.03; ORM-H (95% CI)= 1.09 (1.01-1.17)] and CBLB [rs9657904: pM-H=0.01; ORM-H (95% CI)= 0.89 (0.81-0.97)]. © The Author(s) 2012. Source

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