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Genomic and functional evaluation of TNFSF14 in multiple sclerosis susceptibility

Journal of Genetics and Genomics 2021年第6期48卷 497-507页

作者： Miriam Zuccala 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 Beilis Umberto Dianzani Filippo Martinelli-Boneschi Sandra D’Alfonso Department of Health Sciences Center on Autoimmune and Allergic Diseases(CAAD)UPOUniversity of Eastern PiedmontA.AvogadroNovara 28100Italy Consorzio Interuniversitario di Biotecnologie(CIB) Trieste 34149Italy Laboratory of Human Genetics of Neurological Disorders Institute of Experimental NeurologyDivision of NeurosciencesIRCCS San Raffaele Scientific InstituteMilan 20132Italy National Research Council of Italy Institute for Biomedical TechnologiesSegrateMilan 20090Italy Department of Genetic Medicine and Development(GEDEV) Faculty of MedicineUniversity of Geneva Medical SchoolGeneva 1211Switzerland Department of Informatics Systems and Communications(DISCo)University of Milano-BicoccaMilan 20126Italy MS Centre SCDU NeurologyAOU Maggiore della CaritàNovara 28100Italy Department of Translational Medicine Interdisciplinary Research Center of Autoimmune Diseases(IRCAD)University of Eastern PiedmontNovaraAvogadro UniversityNovara 28100Italy Neuroscience Institute Cavalieri Ottolenghi OrbassanoTurin 10043Italy Neurobiology Unit Neurology-CReSM(Regional Referring Center of Multiple Sclerosis)AOU San Luigi GonzagaOrbassanoTurin 10043Italy Department of Neuroscience‘Rita Levi Montalcini’ University of TurinTurin 10126Italy Department of Neuroscience Biomedicine and Movement SciencesUniversity of VeronaVerona 37134Italy UO Neurologia Fondazione IRCCS Casa Sollievo della Sofferenza San Giovanni RotondoFoggia 71013Italy Centro Recupero e Rieducazione Funzionale“Mons L Novarese” Moncrivello(VC)13040Italy Department of Neurology IRCCS San Raffaele Scientific InstituteMilan 20132Italy Neuroimaging Research Unit Institute of Experimental NeurologyDivision of NeuroscienceIRCCS San Raffaele Scientific InstituteMilan 20132Italy Vita-Salute San Raffaele University Milan 20138Italy Neurophysiology Unit IRCCS San Raffaele Scientific InstituteMilan 20138Italy Dino Ferrari Centre Neuroscience SectionDepartment of Pathophysiology and Transplantation(DEPT)University of MilanMilan 20122

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)*** fine-mapping in a large Italian dataset(4,198 patients with MS and3,903 controls),we show that the TNFSF14 intronic SNP rs1077667 is the primarily MS-associated variant in the *** quantitative trait locus(e QTL)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(Pperipheral blood myeloid DCs(CD11 c+,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.

关键词： Multiple sclerosis TNFSF14 LIGHT Fine-mapping analysis SNV

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