Abstract Details

Title A Genome-Wide Association Study Highlights a Possible Involvement of Mast Cells and Neutrophils in Disease Activity in Multiple Sclerosis

Topic Multiple Sclerosis

Presentation(s) S11 - MS Immunology and Basic Science (4:08 PM-4:16 PM)

Poster/Presentation
Number 002

Objective To perform a Genome-Wide Association Study (GWAS) to unravel possible genetic variants associated with disease activity (DA) in relapsing-remitting (RR) multiple sclerosis (MS) patients.

Background Recently, important data coming from genetic studies showed new biological pathways involved in the susceptibility to MS [International Multiple Sclerosis Genetics Consortium, Science 2019]. However, to date, no GWAS has been published targeting DA in MS and the basis of the broad heterogeneity in the clinical spectrum of MS is still largely unknown.

Design/Methods We studied a cohort of 790 Italian patients with diagnosis of RR-MS at the beginning of a first-line disease-modifying treatment with available whole-genome genetic data. For each patient, we assessed DA during a 2-year follow-up according to the Non-Evidence/Evidence of Disease Activity-3 (NEDA/EDA) status. After per-marker and per-individual quality controls and principal component analysis, 778 patients and 607.864 Single-Nucleotide Polymorphisms (SNPs) underwent the GWAS.

Results We identified two SNPs in chromosome 14 (rs1956932 and rs17104242) which passed the threshold for genome-wide significance and exert a protective role toward EDA status at 2-years (rs1956932: OR=0.35 [95% CI: 0.24-0.50] and p=8.45E-09; rs17104242: OR=0.36 [95% CI: 0.25-0.52] and p=2.26E-08). For other SNPs in the same region of chromosome 14, we found a suggestive association for a protective effect toward DA. Functional annotation pointed out a possible involvement of the pathways of chymase-1 and cathepsin-G, which are known to modulate the activity and the degranulation of mast cells and neutrophils. Such cells are involved in mechanisms like the regulation of the permeability of the blood-brain barrier and the triggering of an immune reaction towards the central nervous systems at peripheral sites.

Conclusions In this preliminary GWAS, interesting signals have emerged regarding the function of mast cells and neutrophils which, if confirmed in further studies, may provide important knowledge on mechanisms underlying DA in RR-MS patients.

Authors/Disclosures
Antonino Giordano (San Raffaele Scientific Institute) PRESENTER	Mr. Giordano has nothing to disclose.
Melissa Sorosina	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Elisabetta Mascia	No disclosure on file
	No disclosure on file
Massimo Filippi, MD, FAAN (Ospedale San Raffaele, Neuroimaging Research Unit)	Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Alexion, Almirall, Biogen, Merck, Novartis, Roche, Sanofi. Dr. Filippi has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion, Biogen, Bristol-Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi-Aventis, Sanofi-Genzyme, Takeda. Dr. Filippi has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck-Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, and TEVA. Dr. Filippi has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer Nature. The institution of Dr. Filippi has received research support from Biogen Idec, Merck-Serono, Novartis, Roche, the Italian Ministry of Health, the Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla.
Federica Esposito	Federica Esposito has received personal compensation in the range of $0-$499 for serving as a Consultant for Merck. Federica Esposito has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Federica Esposito has received personal compensation in the range of $0-$499 for serving as a Consultant for Novartis. Federica Esposito has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Federica Esposito has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck. The institution of Federica Esposito has received research support from Italian MS Society. The institution of Federica Esposito has received research support from Italian Ministry of Health. The institution of Federica Esposito has received research support from ERA Net. The institution of Federica Esposito has received research support from European Commission. Federica Esposito has received intellectual property interests from a discovery or technology relating to health care.

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