Unfixed HERV-K insertional polymorphisms as risk factors for multiple sclerosis in a Slavic cohort: the role of PTPRN2

Multiple sclerosis (MS) is a chronic inflammatory, immune-mediated demyelinating disease of the central nervous system. While its etiology involves complex interactions between genetic and environmental factors, a significant portion of its genetic risk remains unexplained. Human endogenous retroviruses (HERVs) have emerged as potential contributors to this susceptibility; specifically, the HERV-K (HML-2) family contains unfixed elements—insertional polymorphisms—that represent a novel and under-explored source of genomic variability.

In this study, we employed a targeted next-generation sequencing-based screening method followed by a confirmatory stage using long-range PCR in an extended cohort of Caucasian Slavic descent (n = 253) to identify HERV-K insertions associated with MS. We identified a polymorphic HERV-K insertion within the introns of the PTPRN2 gene that was significantly overrepresented in MS cases compared to controls (OR = 2.04; Padj= 0.023). Notably, PTPRN2 has been previously implicated in MS pathology through altered DNA methylation and diminished protein levels in cerebrospinal fluid.

Additionally, an insertion in RASGRF2 reached nominal significance within the familial MS cohort (P = 0.0078). Our results provide novel evidence that HERV-K insertional polymorphisms constitute a distinct component of the genetic architecture of MS. We propose a model of “neuro-exaptation” wherein these mobile elements, potentially through EBV-mediated transactivation, contribute to the complex etiology of the disease by disrupting host gene regulation.

These findings open new avenues for understanding the interplay between the genome, the epigenome, and environmental risk factors in neuroinflammation. This research was funded by the Slovenian Research and Innovation Agency, research programs P3-0326 and P4-0220. Clinical Institute of Genomic Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia Lovro Vidmar, Aleksander Turk, Aleš Maver & Borut Peterlin Institute for Genomic Literacy, 1241, Kamnik, Slovenia Biotechnical Faculty, University of Ljubljana, Ljubljana, Slovenia Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia Clinic of Neurology, UCCS, Belgrade, Serbia Faculty of Medicine, University of Belgrade, Belgrade, Serbia Department of Biology and Medical Genetics, School of Medicine, University of Rijeka, Rijeka, Croatia The authors declare no competing interests.

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