A pharmacogenetic study implicates NINJ2 in the response to Interferon-β in multiple sclerosis

Background: Multiple sclerosis (MS) is a disease in which biomarker identification is fundamental to predict response to treatments and to deliver the optimal drug to patients. We previously found an association between rs7298096, a polymorphism upstream to theNINJ2gene, and the 4-year response to interferon-beta (IFN beta) treatment in MS patients. Objectives: To analyse the association between rs7298096 and time to first relapse (TTFR) during IFN beta therapy in MS patients and to better investigate its functional role. Methods: Survival analysis was applied in three MS cohorts from different countries (n = 1004). We also studied the role of the polymorphism on gene expression using GTEx portal and a luciferase assay. We interrogated GEO datasets to explore the relationship betweenNINJ2expression, IFN beta and TTFR. Results: Rs7298096(AA)patients show a shorter TTFR than rs7298096(G)-carriers (Pmeta-analysis = 3 x 10(-4), hazard ratio = 1.41). Moreover, rs7298096(AA)is associated with a higherNINJ2expression in blood (p = 7.0 x 10(-6)), which was confirmed in vitro (p = 0.009). Finally,NINJ2expression is downregulated by IFN beta treatment and related to TTFR. Conclusions: Rs7298096 could influence MS disease activity during IFN beta treatment by modulatingNINJ2expression in blood. The gene encodes for an adhesion molecule involved in inflammation and endothelial cells activation, supporting its role in MS.