The researchers went on to examine how rs1800693 affects the function of TNFR1. They found that in individuals who carried this SNP, exon 6 was frequently spliced out of the TNFRSF1A mRNA, leading to production of a soluble form of TNFR1, termed Δ6-TNFR1, that was secreted from the cell instead of being sequestered in the Golgi apparatus. Fugger and colleagues showed that the Δ6-TNFR1 protein isoform was capable of binding to and thereby neutralizing

TNF.“This risk effect mirrors the clinical experience with TNF blockers, whereby these drugs, whose properties are analogous to—although greater in magnitude than—those of Δ6-TNFR1, have been found to promote or exacerbate the disease,” explains Fugger. According to the researchers, these new findings reinforce the clinical utility of GWAS findings in conditions such as MS.“Such studies can enable the delineation of disease pathways, and as drugs targeting genetically dependent pathways are likely to have larger effects than any associated genetic variants, there is the potential to therapeutically skew these pathways towards disease resistance,” concludes Fugger.