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

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.背景 人类内源性逆转录病毒（Human endogenous retroviruses, HERVs）是一类源自外源性逆转录病毒感染祖先生殖细胞的重复序列，不同的HERV家族已整合至宿主基因组中。此前有研究发现，X染色体上的HERV-Fc1与北欧人群中的多发性硬化（multiple sclerosis, MS）存在关联。此外，活动性多发性硬化患者的血浆中HERV-Fc1的RNA表达水平显著升高。鉴于多发性硬化患病率存在南北纬度梯度差异，本研究旨在评估HERV-Fc1在西班牙三个独立队列中对多发性硬化发病风险的影响。 方法 本研究通过Taqman化学法对位于HERV-Fc1附近的单核苷酸多态性位点rs391745进行基因分型，共纳入2473名多发性硬化患者与3031名种族匹配的健康对照，所有受试者均为连续入组，分别来自西班牙北部（569名患者、980名对照）、中部（883名患者、692名对照）及南部（1021名患者、1359名对照）。本研究将所得结果与已发表的数据进行荟萃分析合并。 结果 在两个西班牙队列中均观察到HERV-Fc1多态性与多发性硬化存在显著关联；结合既往数据开展的荟萃分析同样显示出显著关联[rs391745的C等位基因携带者：荟萃分析P值pM-H=0.0005；合并比值比ORM-H（95%置信区间CI）=1.27（1.11~1.45）]。与既往研究结果一致，当分析限定于复发缓解型与继发进展型多发性硬化样本时，关联强度略有增强[pM-H=0.0003，ORM-H（95%CI）=1.32（1.14~1.53）]。 结论 本研究在南欧队列中证实，HERV-Fc1多态性位点rs391745与发作性多发性硬化的易感性存在关联。