Nadia Barizzone
Elena Boggio
Luca Gigliotti
Melissa Sorosina
Chiara Basagni
Roberta Bordoni
Ferdinando Clarelli
Santosh Anand
Eleonora Mangano
Domizia Vecchio
Elena Corsetti
Serena Martire
Simona Perga
Daniela Ferrante
Alberto Gajofatto
Andrei Ivashynka
Claudio Solaro
Roberto Cantello
Vittorio Martinelli
Giancarlo Comi
Massimo Filippi
Federica Esposito
Maurizio Leone
Gianluca De Bellis
Umberto Dianzani
Filippo Martinelli-Boneschi
Sandra D'Alfonso
a Department of Health Sciences, Center on Autoimmune and Allergic Diseases (CAAD), UPO, University of Eastern Piedmont, A. Avogadro, Novara 28100, Italy;
b Consorzio Interuniversitario di Biotecnologie (CIB), Trieste 34149, Italy;
c Laboratory of Human Genetics of Neurological Disorders, Institute of Experimental Neurology, Division of Neurosciences, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy;
d National Research Council of Italy, Institute for Biomedical Technologies, Segrate, Milan 20090, Italy;
e Department of Genetic Medicine and Development (GEDEV), Faculty of Medicine, University of Geneva Medical School, Geneva 1211, Switzerland;
f Department of Informatics, Systems and Communications (DISCo), University of Milano-Bicocca, Milan 20126, Italy;
g MS Centre, SCDU Neurology, AOU Maggiore della Carità, Novara 28100, Italy;
h Department of Translational Medicine, Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Eastern Piedmont, Novara, Avogadro University, Novara 28100, Italy;
i Neuroscience Institute Cavalieri Ottolenghi, Orbassano, Turin 10043, Italy;
j Neurobiology Unit, Neurology - CReSM (Regional Referring Center of Multiple Sclerosis), AOU San Luigi Gonzaga, Orbassano, Turin 10043, Italy;
k Department of Neuroscience ‘Rita Levi Montalcini’, University of Turin, Turin 10126, Italy;
l Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona 37134, Italy;
m UO Neurologia Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia 71013, Italy;
n Centro Recupero e Rieducazione Funzionale “Mons L Novarese”, Moncrivello (VC) 13040, Italy;
o Department of Neurology, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy;
p Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan 20132, Italy;
q Vita-Salute San Raffaele University, Milan 20138, Italy;
r Neurophysiology Unit, IRCCS San Raffaele Scientific Institute, Milan 20138, Italy;
s Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Milan 20122, Italy;
t Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neurology Unit and MS Center, Milan 20122, Italy
Funds: We thank the International Multiple Sclerosis Genetic Consortium. This work was supported by the Italian Foundation of Multiple Sclerosis (FISM, 2011/R/14 2015/R/10, 2019/R-Multi/033) by the Italian Ministry of Health (RF-2016-02361294) and the AGING Project for Department of Excellence at the Department of Translational Medicine (DIMET), Universita del Piemonte Orientale, Novara, Italy. M.Z. supported by Consorzio Interuniversitario di Biotecnologie (CIB). N.B. and A.I. were partially supported by MultipleMS project (Horizon 2020 European Grant 733161), Stockholm.
Received Date: 2020-07-27
Accepted Date:2021-03-05
Rev Recd Date:2021-02-24
Publish Date:2021-06-20
Abstract
Abstract
Among multiple sclerosis (MS) susceptibility genes, the strongest non-human leukocyte antigen (HLA) signal in the Italian population maps to the TNFSF14 gene encoding LIGHT, a glycoprotein involved in dendritic cell (DC) maturation. Through fine-mapping in a large Italian dataset (4,198 patients with MS and 3,903 controls), we show that the TNFSF14 intronic SNP rs1077667 is the primarily MS-associated variant in the region. Expression quantitative trait locus (eQTL) analysis indicates that the MS risk allele is significantly associated with reduced TNFSF14 messenger RNA levels in blood cells, which is consistent with the allelic imbalance in RNA-Seq reads (P<0.0001). The MS risk allele is associated with reduced levels of TNFSF14 gene expression (P<0.01) in blood cells from 84 Italian patients with MS and 80 healthy controls (HCs). Interestingly, patients with MS are lower expressors of TNFSF14 compared to HC (P<0.007). Individuals homozygous for the MS risk allele display an increased percentage of LIGHT-positive peripheral blood myeloid DCs (CD11c+, P = 0.035) in 37 HCs, as well as in in vitro monocyte-derived DCs from 22 HCs (P = 0.04). Our findings suggest that the intronic variant rs1077667 alters the expression of TNFSF14 in immune cells, which may play a role in MS pathogenesis.Keywords: Multiple sclerosis,
TNFSF14,
LIGHT,
Fine-mapping analysis,
SNV
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