HERV-W polymorphism in chromosome X is associated with multiple sclerosis risk and with differential expression of MSRV

Retrovirology

Roberto Alvarez-Lafuente²  Elena Urcelay²  Fuencisla Matesanz¹  Rafael Arroyo⁵  Antonio Alcina¹  Maria Fedetz¹  Miguel Lucas³  Guillermo Izquierdo⁴  Ignacio Casanova⁵  Ángel García-Martínez²  Ana Arias-Leal⁵  María Domínguez-Mozo⁵  Iris Camacho²  Ana de la Encarnación²  Jezabel Varadé²  Belén de la Hera²  Marta García-Montojo⁵ 

[1] Instituto de Parasitologia y Biomedicina ’Lopez-Neyra’-CSIC, Parque Tecnológico de Ciencias de la Salud, Av. del Conocimiento s/n., 18016, Armilla (Granada), Spain;Immunology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Profesor Martin Lagos s/n., 28240, Madrid, Spain;Molecular Biology Department, Hospital Virgen Macarena, Av. Dr. Fedriani, 3., 41071, Sevilla, Spain;Multiple Sclerosis Unit, Hospital Virgen Macarena, Av. Dr. Fedriani, 3., 41071, Sevilla, Spain;Multiple Sclerosis Unit, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Profesor Martin Lagos s/n., 28240, Madrid, Spain

关键词: Autoimmunity;    Gender differences;    Sex;    Chromosome x;    Multiple sclerosis associated retrovirus;    HERV-W;    Human endogenous retrovirus;    Multiple sclerosis;   

Others  :  804252
DOI  :  10.1186/1742-4690-11-2

 received in 2013-07-10, accepted in 2013-12-16,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 García-Montojo et al.; licensee BioMed Central Ltd.

【 图 表 】

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