HERV linked to MS susceptibility in another study

de la Hera B, Varadé J, García-Montojo M, Alcina A, Fedetz M, Alloza I, Astobiza I, Leyva L, Fernández O, Izquierdo G, Antigüedad A, Arroyo R, Alvarez-Lafuente R, Vandenbroeck K, Matesanz F, Urcelay E. Human Endogenous Retrovirus HERV-Fc1 Association with Multiple Sclerosis Susceptibility: A Meta-Analysis. PLoS One. 2014 Mar;9(3):e90182.

BACKGROUND: Human 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 withmultiple 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-Fc1 on MS risk in three independent Spanish cohorts.
METHODS: A 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.
RESULTS: Significant 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)].
CONCLUSION: Association of the HERV-Fc1 polymorphism rs391745 with bout-onset MS susceptibility was confirmed in Southern European cohorts.

So genetic variants of Human endogenous retro virus has some slight associated with MS and will please the ProfGs in their aim for the Charcot Project.

The previously reported association was confirmed in cohorts from Northern and Central Spain, but a significant effect of the opposite allele was detected in the cohort from Southern Spain. This finding, already described in the literature as “flip-flop phenomenon” where significant associations for the same disease occur at opposite alleles of the same polymorphism, has been observed.  This study adds interest of HERV-Fc1 to  HERV-W, HERV-H and HERV-K18 but these have not been picked up be genome association studies does this mean something missed or something else? 

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  • The findings in the paper by de la Hera et al. could be explained by gender bias. Since the SNP rs391745 is located on the X-chromosome, odds ratios should have been estimated for each sex and combined by a relevant method, e.g. Mantel-Haenszel which was used for the meta-analysis. Otherwise at least a comparable ratio of females to males should have been ensured among cases and controls. Neither of these measures were taken in the study. In the cohort showing the strongest association from Northern Spain, OR 1.39 (95% CI: 1.05-1.84), there were 73% female cases and only 46% female controls. With an overall C-allele frequency of 10.8% and Hardy-Weinberg equilibrium among cases and controls, one should expect to observe an odds ratio of 1.23 because of gender bias rather than the normally assumed odds ratio of 1.00 for no difference in a case-control study. Using this approach the expected odds ratios due to gender bias for the three geographic regions are: Northern Spain (OR: 1.23), Central Spain (OR: 1.09), and Southern Spain (OR: 0.99). The study by de la Hera et al. therefore hardly supports a role for the endogenous retrovirus HERV-Fc1 in multiple sclerosis. All necessary data to repeat the analysis are available in the published tables.

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