Identification of the genetic mechanism that associates L3MBTL3 to multiple sclerosis

Abstract

Multiple sclerosis (MS) is a complex and demyelinating disease of the central nervous system. One of the challenges of the post-GWAS era is to understand the molecular basis of statistical associations to reveal gene networks and potential therapeutic targets. The L3MBTL3 locus has been associated with MS risk by GWAS. To identify the causal variant of the locus, we performed fine mapping in a cohort of 3440 MS patients and 1688 healthy controls. The variant that best explained the association was rs6569648 (P = 4.13E-10, OR = 0.71, 95% CI = 0.64–0.79), which tagged rs7740107, located in intron 7 of L3MBTL3. The rs7740107 (A/T) variant has been reported to be the best expression and splice quantitative trait locus (eQTL and sQTL) of the region in up to 35 human GTEx tissues. By sequencing RNA from blood of 17 MS patients and quantification by digital qPCR, we determined that this eQTL/sQTL originated from the expression of a novel short transcript starting in intron 7 near rs7740107. The short transcript was translated into three proteins starting at different translation initiation codons. These N-terminal truncated proteins lacked the region where L3MBTL3 interacts with the transcriptional regulator RBPJ (Recombination Signal Binding Protein for Immunoglobulin Kappa J Region) which, in turn, regulates the Notch signaling pathway. Our data and other functional studies suggest that the genetic mechanism underlying the MS association of rs7740107 affects not only the expression of L3MBTL3 isoforms, but might also involve the Notch signaling pathway.

Association of the L3MBTL3 rs1125970 and rs4897367 Gene Polymorphisms With Coronary Heart Disease Susceptibility in the Chinese Population: A Case–Control Study

“…31 In addition, it has been concluded that the genetic mechanism of rs740107 associated with MS may involve its effect on L3MBTL3 expression. 29 Taken together, we proposed that L3MBTL3 polymorphisms may play a potential role in CHD development. However, no data have been reported on the relationship between L3MBTL3 polymorphisms and CHD susceptibility.…”

“…[34][35][36] In addition, it has been concluded that the causal effect associated with MS protection would be the up-regulation of L3MBTL3 expression. 29 Based on these findings, we hypothesized that the protective effect may be attributed to its influence on gene expression. The potential functions of SNPs demonstrated that rs1125970 was associated with the regulation of enhancer histone marks, alterations in motifs, and selected eQTL hits.…”

“…26 A study in Italy showed CD14 polymorphisms that influence the reactivity of inflammatory cells may play a role in determining the first clinical presentation of CHD. 27 Emerging evidences have indicated that L3MBTL3 polymorphisms are markedly associated with human diseases, such as alcoholinduced osteonecrosis femoral head necrosis, 28 MS, 29,30 and diabetes. 31 In addition, it has been concluded that the genetic mechanism of rs740107 associated with MS may involve its effect on L3MBTL3 expression.…”

CNS Border-Associated Macrophages: Ontogeny and Potential Implication in Disease

“…MS features encompass neuroinflammation, demyelination, and axonal loss within the CNS [99,100]. Several mechanisms have been proposed to be implicated in the pathophysiology of MS [101][102][103]. Nevertheless, the potential role of BAMs in MS has been only recently investigated [47,104].…”