Elena Urcelay, María Fedetz, Guillermo Izquierdo, Fuencisla Matesanz, Belén de la Hera, Angel Garcia-Martinez, Iris Camacho, Jezabel Varadé, Ana de la Encarnación, Ana Maria Arias-Leal, Maria Inmaculada Dominguez-Mozo, Roberto Alvarez-Lafuente, Rafael Arroyo, Marta Garcia-Montojo, Ignacio Casanova, Miguel Lucas, Antonio Alcina, Instituto de Salud Carlos III, Fundación Genzyme, Fundación Alicia Koplowitz, Fundación Mutua Madrileña, Fundación LAIR, [García-Montojo,M, Domínguez-Mozo,M, Árias-Leal,A, Casanova,I, Arroyo,R] Multiple Sclerosis Unit, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Madrid. [Hera,B de la, Varadé,J, Encarnación,A de la, Camacho,I, García-Martínez,A, Urcelay,E, Alvarez-Lafuente,R] Immunology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Madrid, Spain. [Izquierdo,G] Multiple Sclerosis Unit, Hospital Virgen Macarena, Sevilla, Spain. [Lucas,M] Molecular Biology Department, Hospital Virgen Macarena, Sevilla, Spain. [Fedetz,M, Alcina,A, Matesanz,F] Instituto de Parasitologia y Biomedicina ’Lopez-Neyra’-CSIC, Parque Tecnológico de Ciencias de la Salud, Armilla (Granada), Spain., and Instituto de Salud Carlos III-Fondo Investigaciones Sanitarias FIS (10/01985 and 09/02074), Fundación Genzyme, Fundación Alicia Koplowitz, Fundación Mutua Madrileña, and Fundación LAIR.
[Background] Multiple Sclerosis (MS) is an autoimmune demyelinating disease that occurs more frequently in women than in men. Multiple Sclerosis Associated Retrovirus (MSRV) is a member of HERV-W, a multicopy human endogenous retroviral family repeatedly implicated in MS pathogenesis. MSRV envelope protein is elevated in the serum of MS patients and induces inflammation and demyelination but, in spite of this pathogenic potential, its exact genomic origin and mechanism of generation are unknown. A possible link between the HERV-W copy on chromosome Xq22.3, that contains an almost complete open reading frame, and the gender differential prevalence in MS has been suggested., [Results] MSRV transcription levels were higher in MS patients than in controls (U-Mann–Whitney; p = 0.004). Also, they were associated with the clinical forms (Spearman; p = 0.0003) and with the Multiple Sclerosis Severity Score (MSSS) (Spearman; p = 0.016). By mapping a 3 kb region in Xq22.3, including the HERV-W locus, we identified three polymorphisms: rs6622139 (T/C), rs6622140 (G/A) and rs1290413 (G/A). After genotyping 3127 individuals (1669 patients and 1458 controls) from two different Spanish cohorts, we found that in women rs6622139 T/C was associated with MS susceptibility: [χ2; p = 0.004; OR (95% CI) = 0.50 (0.31-0.81)] and severity, since CC women presented lower MSSS scores than CT (U-Mann–Whitney; p = 0.039) or TT patients (U-Mann–Whitney; p = 0.031). Concordantly with the susceptibility conferred in women, rs6622139*T was associated with higher MSRV expression (U-Mann–Whitney; p = 0.003)., [Conclusions] Our present work supports the hypothesis of a direct involvement of HERV-W/MSRV in MS pathogenesis, identifying a genetic marker on chromosome X that could be one of the causes underlying the gender differences in MS., This work was supported by grants from: Instituto de Salud Carlos III-Fondo Investigaciones Sanitarias FIS (10/01985 and 09/02074), Fundación Genzyme, Fundación Alicia Koplowitz, Fundación Mutua Madrileña, and Fundación LAIR.