Genomic and functional evaluation of TNFSF14 in multiple sclerosis susceptibility

Among multiple sclerosis (MS) susceptibility genes, the strongest non-human leukocyte antigen (HLA) signal in the Italian population maps to the TNFSF14 gene encoding LIGHT, a glycoprotein involved in dendritic cell (DC) maturation. Through fine-mapping in a large Italian dataset (4,198 patients with MS and 3,903 controls), we show that the TNFSF14 intronic SNP rs1077667 is the primarily MS-associated variant in the region. Expression quantitative trait locus (eQTL) analysis indicates that the MS risk allele is significantly associated with reduced TNFSF14 messenger RNA levels in blood cells, which is consistent with the allelic imbalance in RNA-Seq reads (P < 0.0001). The MS risk allele is associated with reduced levels of TNFSF14 gene expression (P < 0.01) in blood cells from 84 Italian patients with MS and 80 healthy controls (HCs). Interestingly, patients with MS are lower expressors of TNFSF14 compared to HC (P < 0.007). Individuals homozygous for the MS risk allele display an increased percentage of LIGHT-positive peripheral blood myeloid DCs (CD11c(+), P = 0.035) in 37 HCs, as well as in in vitro monocyte-derived DCs from 22 HCs (P = 0.04). Our findings suggest that the intronic variant rs1077667 alters the expression of TNFSF14 in immune cells, which may play a role in MS pathogenesis. Copyright (C) 2021, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Limited and Science Press. All rights reserved.

Automated summary

In a study conducted with a large Italian dataset, the intronic variant rs1077667 of the TNFSF14 gene was identified as the primarily MS-associated variant, with the MS risk allele being significantly associated with reduced TNFSF14 mRNA levels in blood cells. Furthermore, patients with MS were found to have lower expression of TNFSF14 compared to healthy controls, and individuals homozygous for the MS risk allele displayed increased percentage of LIGHT-positive peripheral blood myeloid DCs. These findings suggest that the intronic variant rs1077667 alters the expression of TNFSF14 in immune cells, potentially playing a role in MS pathogenesis.