Genetic Determinants of Antibody Levels in Cerebrospinal Fluid in Multiple Sclerosis: Possible Links to Endogenous Retroviruses

Abstract

The pathogenesis of multiple sclerosis (MS) has not been clarified. In addition to environmental factors; genetic determinants have been implicated in the pathogenesis of MS. Furthermore, endogenous retroviruses (ERV) might play a role in MS. The presence of oligoclonal immunoglobulin in cerebrospinal fluid (CSF) is a typical feature of MS. Recently, genetic polymorphisms in loci on human chromosomes 6, 14 and 18 have been identified as major determinants of CSF antibody levels in MS. The functional relevance of these single nucleotide polymorphisms (SNPs) remains unclear and none of them is located in an open reading frame. In previous studies, we identified ERV sequences in the vicinity of MS associated SNPs. Here, we describe the identification of ERV sequences in the neighborhood of SNPs associated with CSF antibody levels. All of the identified SNPs are located in the vicinity of ERV sequences. One of these sequences has very high homology to a sequence derived from the so-called MS-associated retrovirus (MSRV). Another cluster of three ERV sequences from the immunoglobulin heavy chain locus has retained the typical organization of retroviral genomes. These observations might shed new light on a possible association between ERVs and MS pathogenesis.

Human Endogenous Retroviruses Are Ancient Acquired Elements Still Shaping Innate Immune Responses

“…These analyses are by now an established method to identify risk loci linked to autoimmune conditions, but rarely take into account HERV sequences and their networking with cellular genes. As an example, MS-associated SNPs showed a significant enrichment of HERV insertion and potential HERV ORFs in their genetic neighborhood as compared to control SNPs ( 135 , 136 ). Accordingly, SNPs in the antiviral gene TRIM5 were shown to be negatively correlated to MS, while SNPs around a HERV-Fc1 locus on chromosome X had a significant association with the disease, with a risk that was strongly influenced by the two genes in an additive fashion ( 137 ).…”

Leisure Activities, Genetic Risk, and Frailty: Evidence from the Chinese Adults Aged 80 Years or Older

“…IRF1-AS1-rs11745587, ATF6B-rs8283, ABCC4-rs4148497, and SLC22A5-rs2073643 were associated with asthma [67][68][69][70][71] and ATF6B-rs8283 and MUCL3-rs9501035 with risk of systemic lupus erythematosus [72,73]. Rs9271640 (close to HLA-DRB1 | LOC124901301), LOC643339-rs7302522, and RPL37-rs6876367 were associated with multiple sclerosis [74][75][76][77]; SLAMF8-rs2501341, CDC25B-rs3761218, and rs17207986 (close to ATF6B | TNXB) with inflammatory bowel disease [78][79][80]; and IRF1-AS1-rs11745587 and ADORA2A-rs2236624 with rheumatoid arthritis [81,82]. These SNPs could potentially play roles in immune dysfunction and inflammation, mediating the incidence of frailty.…”