Contributions
Abstract: EP1462
Type: Poster Sessions
Abstract Category: Pathology and pathogenesis of MS - Genetics/Epigenetics
Introduction: Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) characterized by demyelination and axonal degeneration. Several risk factors are involved in the disease; immune cells, that are known to migrate from peripheral blood to CNS, play a key role in MS pathogenesis. In a recent genome-wide association study we identified rs7298096, located 3.5Kb upstream to NINJ2 gene, which encodes for an adhesion molecule, as associated with response to Interferon β (IFNβ) treatment in MS patients.
Aims: To study the functional role of rs7298096 and NINJ2 in MS inflammatory activity.
Methods: We performed survival analyses on 3 cohorts of IFNβ-treated MS patients (n=928) from Italy, Spain and Australia to study the association between rs7298096 and time to first relapse (TTFR) after drug start (4-year follow-up). eQTL analysis was performed using GTEx Portal and an in vitro luciferase assay was also conducted. To better characterize the role of NINJ2 in inflammation, co-expression analysis was performed using COXPRESSdb, followed by pathway analysis. Expression of NINJ2 in immune cell types from 24 untreated MS patients was measured through RNAseq. NINJ2 mRNA and protein expression will be evaluated in monocytes of MS patients under several conditions through qPCR and immunocytochemistry assays.
Results: Rs7298096G patients showed a longer TTFR after IFN-β therapy start compared to rs7298096AA patients (HR=1.51,P=2x10-4). The SNP had a strong eQTL association with NINJ2 gene expression in whole blood (P=7.0x10-6;β=0.13); the effect of rs7298096 on gene expression was confirmed in vitro (P=0.01). Co-expression analysis suggests an involvement of NINJ2 in pathways related to immune system and, among them, in the leukocyte transendothelial migration pathway (P=5.0x10-4). Monocytes showed a higher NINJ2 expression compared to the other immune cell types (P< 0.0001, fold increase: monocytes-B cells=1.8; monocytes-T cells=1.7). qPCR and immunocytochemistry experiments are ongoing.
Conclusions: Starting from genetic data, we focused our attention to a specific membrane adhesion molecule, the ninjurin2, encoded by the NINJ2 gene, that is already known to play a role in the adhesion between monocytes and endothelial cells and that could be involved in the migration of immune cells inside the CNS and in the onset of relapses. Additional analyses and experiments are required to better assess the role of the protein in inflammation.
Disclosure: F Martinelli Boneschi received honoraria for consulting, research grant and travel expenses from TEVA neuroscience, Biogen IDEC, Merck Serono, Roche and Sanofi-Genzyme. J Río has received speaking honoraria and personal compensation for participating on Advisory Boards from Almirall, Bayer-Schering Healthcare, Biogen-Idec, Genzyme, Merck-Serono, Novartis, Teva, and Sanofi-Aventis. LM Villar received research grants, or payment for lecturing, or participated in advisory boards from Merck-Serono, Sanofi-Genzyme, Biogen, Roche and Novartis. X Montalban has received speaking honoraria and travelexpenses for participation in scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Actelion, Almirall, Bayer, Biogen, Celgene, Hoffmann-La Roche, Merck, Novartis, Oryzon Genomics, Sanofi-Genzyme and Teva Pharmaceutical. V. Martinelli has received honoraria from Biogen-Idec, Merck, Bayer, TEVA, Novartis and Genzyme. G. Comi has received compensation for consulting services and/or speaking activities with Novartis, Teva, Sanofi, Genzyme, Merck, Biogen, Excemed, Roche, Almirall, Chugai, Receptos, Forward Pharma. F Esposito received honoraria from Almirall and Genzyme. S Peroni: nothing to disclose. M Sorosina: nothing to disclose. AM Osiceanu: nothing to disclose. F Clarelli: nothing to disclose. C Guaschino: nothing to disclose. S Malhotra: nothing to disclose. L Midaglia: nothing to disclose. JC Álvarez-Cermeño: nothing to disclose. J Lechner-Scott: nothing to disclose. N Spataro: nothing to disclose. A Navarro: nothing to disclose. M Comabella: nothing to disclose.
Abstract: EP1462
Type: Poster Sessions
Abstract Category: Pathology and pathogenesis of MS - Genetics/Epigenetics
Introduction: Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) characterized by demyelination and axonal degeneration. Several risk factors are involved in the disease; immune cells, that are known to migrate from peripheral blood to CNS, play a key role in MS pathogenesis. In a recent genome-wide association study we identified rs7298096, located 3.5Kb upstream to NINJ2 gene, which encodes for an adhesion molecule, as associated with response to Interferon β (IFNβ) treatment in MS patients.
Aims: To study the functional role of rs7298096 and NINJ2 in MS inflammatory activity.
Methods: We performed survival analyses on 3 cohorts of IFNβ-treated MS patients (n=928) from Italy, Spain and Australia to study the association between rs7298096 and time to first relapse (TTFR) after drug start (4-year follow-up). eQTL analysis was performed using GTEx Portal and an in vitro luciferase assay was also conducted. To better characterize the role of NINJ2 in inflammation, co-expression analysis was performed using COXPRESSdb, followed by pathway analysis. Expression of NINJ2 in immune cell types from 24 untreated MS patients was measured through RNAseq. NINJ2 mRNA and protein expression will be evaluated in monocytes of MS patients under several conditions through qPCR and immunocytochemistry assays.
Results: Rs7298096G patients showed a longer TTFR after IFN-β therapy start compared to rs7298096AA patients (HR=1.51,P=2x10-4). The SNP had a strong eQTL association with NINJ2 gene expression in whole blood (P=7.0x10-6;β=0.13); the effect of rs7298096 on gene expression was confirmed in vitro (P=0.01). Co-expression analysis suggests an involvement of NINJ2 in pathways related to immune system and, among them, in the leukocyte transendothelial migration pathway (P=5.0x10-4). Monocytes showed a higher NINJ2 expression compared to the other immune cell types (P< 0.0001, fold increase: monocytes-B cells=1.8; monocytes-T cells=1.7). qPCR and immunocytochemistry experiments are ongoing.
Conclusions: Starting from genetic data, we focused our attention to a specific membrane adhesion molecule, the ninjurin2, encoded by the NINJ2 gene, that is already known to play a role in the adhesion between monocytes and endothelial cells and that could be involved in the migration of immune cells inside the CNS and in the onset of relapses. Additional analyses and experiments are required to better assess the role of the protein in inflammation.
Disclosure: F Martinelli Boneschi received honoraria for consulting, research grant and travel expenses from TEVA neuroscience, Biogen IDEC, Merck Serono, Roche and Sanofi-Genzyme. J Río has received speaking honoraria and personal compensation for participating on Advisory Boards from Almirall, Bayer-Schering Healthcare, Biogen-Idec, Genzyme, Merck-Serono, Novartis, Teva, and Sanofi-Aventis. LM Villar received research grants, or payment for lecturing, or participated in advisory boards from Merck-Serono, Sanofi-Genzyme, Biogen, Roche and Novartis. X Montalban has received speaking honoraria and travelexpenses for participation in scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Actelion, Almirall, Bayer, Biogen, Celgene, Hoffmann-La Roche, Merck, Novartis, Oryzon Genomics, Sanofi-Genzyme and Teva Pharmaceutical. V. Martinelli has received honoraria from Biogen-Idec, Merck, Bayer, TEVA, Novartis and Genzyme. G. Comi has received compensation for consulting services and/or speaking activities with Novartis, Teva, Sanofi, Genzyme, Merck, Biogen, Excemed, Roche, Almirall, Chugai, Receptos, Forward Pharma. F Esposito received honoraria from Almirall and Genzyme. S Peroni: nothing to disclose. M Sorosina: nothing to disclose. AM Osiceanu: nothing to disclose. F Clarelli: nothing to disclose. C Guaschino: nothing to disclose. S Malhotra: nothing to disclose. L Midaglia: nothing to disclose. JC Álvarez-Cermeño: nothing to disclose. J Lechner-Scott: nothing to disclose. N Spataro: nothing to disclose. A Navarro: nothing to disclose. M Comabella: nothing to disclose.