Contribute to disease or does disease activate the virus? In spite
Contribute to disease or does disease activate the virus? In spite of the importance of these findings, this is a problem that cannot be solved within the frame of BKT140 site expression studies of ubiquitous genomic elements. To get around this obstacle, we initially chose to study the genetics of endogenous retroviral loci, followed by physiological experiments only when the identity of a genetically associated locus was established. As far as is known, the disease cannot alter specific polymorphisms in polyclonal DNA, which is used in these studies. The direction of causality is thus relatively certain to be from DNA to disease; not the reverse. By means of an approach based on genetic epidemiology, single nucleotide polymorphisms (SNPs) in close proximity of fifty endogenous retroviral loci were tested for statistical association with MS. The fifty loci were chosen because their sequences indicate that between PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/28549975 zero and two mutations would enable encoding at least one full length viral protein. Markers near a specific endogenous retroviral locus, HERV-Fc1, located on thehuman X-chromosome, were found to be associated with disease in a Danish cohort of 350 MS cases and 500 controls [22]. HERV-Fc1 had not previously been related to MS. The association was repeated in one Danish, and in one Norwegian cohort [22,23]. A fourth (Danish) cohort was negative for disease association [22]. Subtypes of MS have also been studied for association with HERV-Fc1. Bout Onset MS, the common forms of MS encompassing Relapsing/Remitting MS and Secondary Progressive MS, was associated with the locus, while another form of MS, Primary Progressive MS, seemed not to be [23]. Interestingly, an independent study has indicated that Primary Progressive MS may be associated with another endogenous retroviral locus at chromosome 7, HERV-16 (SNP rs996343) [24]. In a series of expression studies [25], it was shown that the level of HERV-H/F GAG protein (determined by antibodies targeting but not specific to HERV-Fc1) is increased in PBMCs from MS patients relative to healthy controls. It was also found that the PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/27872238 level of protein was elevated in the circulating T-cell compartment in MS patients with a recent history of attacks, relative to patients in a stable state and to healthy controls. Finally, in agreement with this it was found that expression of HERV-Fc1 RNA in plasma was increased 4-fold in patients with a recent history of attacks, relative to patients in a stable state and to healthy controls. Combined with the genetic studies this suggests an active role of HERV-Fc1 in the pathogenesis of MS. A search for extra germ line copies of HERV-Fc1 in MS was unfruitful [26]. Treatment with 5-aza-dC (5-azadeoxycytidine) resulted in demethylation of HERV-Fc1 5LTR and significantly increased levels (up to 50 000 fold) of HERV-Fc1 mRNA expression in cells previously not expressing HERV-Fc1, or with a very low basic expression level [27,28]. This confirms that retroelements are generally epigenetically silenced in somatic cells [29]. Although we have no data as of yet, one could imagine that other physiological mechanisms might also activate expression of HERV products and could contribute to disease. Another line of inquiry supports the involvement of retrovirus in MS. Genes known to restrict the replication of viruses, namely TRIM5, TRIM22 and BST2, have been shown to influence the risk of MS [22, and Nex?et. al manuscript submitted]. The so-called APOBEC3 genes showed a simila.