Uncovering the anti-EBV response of brain-homing CD8+T cells in MS through disease-related HLA and natalizumab treatment

Abstract

Introduction: Multiple sclerosis (MS) is a complex disorder characterized by high heterogeneity in term of disease course, inflammatory activity and treatment response. Objectives/Aims: To explore the genetic contribution to medium-term disease activity at gene, pathway and tissue-specific network levels, applying a genome-wide association study followed by a network-based approach. Methods: Relapsing-remitting MS patients, who started a first-line treatment at San Raffaele Hospital (OSR) and with at least 4-year follow-up were included in the study. Two independent cohorts were evaluated (OSR1 and OSR2). Genome-wide genotype data of both cohorts were obtained and high-quality imputed SNPs were retained in the analysis. After standard quality controls , the association with NEDA status at 4-year follow-up was calculated fitting a logistic regression model. A fixed-effect inverse-variance weighted meta-analysis was then carried out on the shared markers across the two cohorts. The gene-based association was assessed using VEGAS v2.0 tool. Genes were then prioritized using "dmfind" tool considering two tissue-specific interactomes brain and lymphocytes from "HumanBase" database , and pathway analysis was performed. Results: OSR1 cohort included 1086 patients, while OSR2 cohort included 208 patients. More than 6 millions SNPs were screened and after meta-analysis, 23 SNPs showed suggestive evidence of association with NEDA status (p<10-5). The top-associated variant (rs11689046, OR= 0.42, p=3.73×10-7) is located near the 5' of SERPINE2, a gene involved in processes like coagulation and inflammation. The gene-wise analysis led to the identification of 223 genes (p⩽ 0.01); among them the more interesting gene was ILRUN, that plays an important role in the inhibition of cytokine production and in the immune homeostasis maintenance. The network analysis was conducted in two tissue specific modules: brain (BM) and lymphocytes (LM). BM was composed of