title: HERV-W polymorphism in chromosome X is associated with multiple sclerosis risk and with differential expression of MSRV.
abstract: 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.
authors.affiliation: Multiple Sclerosis Unit, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Profesor Martin Lagos s/n,, 28240, Madrid, Spain. mgmontojo@salud.madrid.org.
authors.forename: Marta
authors.initials: M
authors.lastname: García-Montojo
authors.forename: Belén
authors.initials: B
authors.lastname: de la Hera
authors.forename: Jezabel
authors.initials: J
authors.lastname: Varadé
authors.forename: Ana
authors.initials: A
authors.lastname: de la Encarnación
authors.forename: Iris
authors.initials: I
authors.lastname: Camacho
authors.forename: María
authors.initials: M
authors.lastname: Domínguez-Mozo
authors.forename: Ana
authors.initials: A
authors.lastname: Árias-Leal
authors.forename: Angel
authors.initials: A
authors.lastname: García-Martínez
authors.forename: Ignacio
authors.initials: I
authors.lastname: Casanova
authors.forename: Guillermo
authors.initials: G
authors.lastname: Izquierdo
authors.forename: Miguel
authors.initials: M
authors.lastname: Lucas
authors.forename: Maria
authors.initials: M
authors.lastname: Fedetz
authors.forename: Antonio
authors.initials: A
authors.lastname: Alcina
authors.forename: Rafael
authors.initials: R
authors.lastname: Arroyo
authors.forename: Fuencisla
authors.initials: F
authors.lastname: Matesanz
authors.forename: Elena
authors.initials: E
authors.lastname: Urcelay
authors.forename: Roberto
authors.initials: R
authors.lastname: Alvarez-Lafuente
mesh_terms: D000328:Adult; D041321:Chromosomes, Human, X / Q000235:genetics*; D020077:Endogenous Retroviruses / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics*; D011110:Polymorphism, Genetic; D018570:Risk Assessment