Human Endogenous Retrovirus HERV-Fc1 Association with Multiple Sclerosis Susceptibility: A Meta-Analysis

Belén De La Hera,Alfredo Antigüedad,Ianire Astobiza,Antonio Alcina,Oscar Fernández,Fuencisla Matesanz,María Fedetz,Iraide Alloza,Jezabel Varadé,Marta García-Montojo,Elena Urcelay,Koen Vandenbroeck,Rafael Arroyo,Guillermo Izquierdo,Laura Leyva,Roberto Álvarez-Lafuente

doi:10.1371/journal.pone.0090182

Abstract

BackgroundHuman endogenous retroviruses (HERVs) are repetitive sequences derived from ancestral germ-line infections by exogenous retroviruses and different HERV families have been integrated in the genome. HERV-Fc1 in chromosome X has been previously associated with multiple sclerosis (MS) in Northern European populations. Additionally, HERV-Fc1 RNA levels of expression have been found increased in plasma of MS patients with active disease. Considering the North-South latitude gradient in MS prevalence, we aimed to evaluate the role of HERV-Fc1on MS risk in three independent Spanish cohorts.MethodsA single nucleotide polymorphism near HERV-Fc1, rs391745, was genotyped by Taqman chemistry in a total of 2473 MS patients and 3031 ethnically matched controls, consecutively recruited from: Northern (569 patients and 980 controls), Central (883 patients and 692 controls) and Southern (1021 patients and 1359 controls) Spain. Our results were pooled in a meta-analysis with previously published data.ResultsSignificant associations of the HERV-Fc1 polymorphism with MS were observed in two Spanish cohorts and the combined meta-analysis with previous data yielded a significant association [rs391745 C-allele carriers: pM-H = 0.0005; ORM-H (95% CI) = 1.27 (1.11–1.45)]. Concordantly to previous findings, when the analysis was restricted to relapsing remitting and secondary progressive MS samples, a slight enhancement in the strength of the association was observed [pM-H = 0.0003, ORM-H (95% CI) = 1.32 (1.14–1.53)].ConclusionAssociation of the HERV-Fc1 polymorphism rs391745 with bout-onset MS susceptibility was confirmed in Southern European cohorts.

Highlights

Multiple sclerosis (MS) is a complex autoimmune disorder characterized by multifocal demyelination, axonal loss and neurodegeneration within the central nervous system of genetically susceptible individuals [1]
In terms of environmental factors, higher latitude has been reported to correlate with increased prevalence of multiple sclerosis (MS) [3] probably driven by differences in sunlight exposure and vitamin D levels [4,5], repeatedly mentioned as environmental factors related with the risk of developing MS [6]
Considering the mentioned effect of latitude on MS prevalence, we aimed to replicate the association of the HERVFc1 polymorphism rs391745 with relapsing remitting and secondary progressive MS in three independent Spanish cohorts, to ascertain whether the reported association is exclusive of higher latitudes in Europe or else is a general MS risk factor

Summary

Introduction

Multiple sclerosis (MS) is a complex autoimmune disorder characterized by multifocal demyelination, axonal loss and neurodegeneration within the central nervous system of genetically susceptible individuals [1]. Clinical symptoms vary according to the location of the neurological lesions and patients often suffer an initial clinical isolated syndrome followed by a series of recurringremitting events with neurological impairment (RRMS). Patients recover their near normal neurological function after each episode, but with the course of the disease an irreversible progression of clinical disability termed secondary progression (SPMS) may appear and early therapeutic intervention is claimed to delay this process. HERV-Fc1 RNA levels of expression have been found increased in plasma of MS patients with active disease. Considering the North-South latitude gradient in MS prevalence, we aimed to evaluate the role of HERV-Fc1on MS risk in three independent Spanish cohorts

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