title: Response to interferon-beta treatment in multiple sclerosis patients: a genome-wide association study.
abstract: Up to 50% of multiple sclerosis (MS) patients do not respond to interferon-beta (IFN-β) treatment and determination of response requires lengthy clinical follow-up of up to 2 years. Response predictive genetic markers would significantly improve disease management. We aimed to identify IFN-β treatment response genetic marker(s) by performing a two-stage genome-wide association study (GWAS). The GWAS was carried out using data from 151 Australian MS patients from the ANZgene/WTCCC2 MS susceptibility GWAS (responder (R)=51, intermediate responders=24 and non-responders (NR)=76). Of the single-nucleotide polymorphisms (SNP) that were validated in an independent group of 479 IFN-β-treated MS patients from Australia, Spain and Italy (R=273 and NR=206), eight showed evidence of association with treatment response. Among the replicated associations, the strongest was observed for FHIT (Fragile Histidine Triad; combined P-value 6.74 × 10-6) and followed by variants in GAPVD1 (GTPase activating protein and VPS9 domains 1; combined P-value 5.83 × 10-5) and near ZNF697 (combined P-value 8.15 × 10-5).
authors.affiliation: School of Pharmacy and Medical Sciences and Sansom Institute for Health Research, University of South Australia, Frome Road, Adelaide, South Australia, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Mahurkar
authors.affiliation: South Australian Health &Medical Research Institute and Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia.|Australian Institute of Health Innovation, University of New South Wales, Sydney, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Moldovan
authors.affiliation: School of Pharmacy and Medical Sciences and Sansom Institute for Health Research, University of South Australia, Frome Road, Adelaide, South Australia, Australia.
authors.forename: V
authors.initials: V
authors.lastname: Suppiah
authors.affiliation: Laboratory of Genetics of Complex Neurological Disorders, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Sorosina
authors.affiliation: Laboratory of Genetics of Complex Neurological Disorders, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Clarelli
authors.affiliation: Laboratory of Genetics of Complex Neurological Disorders, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.|Department of Neurology and Neurorehabilitation, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Liberatore
authors.affiliation: Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Receca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Malhotra
authors.affiliation: Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Receca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: X
authors.initials: X
authors.lastname: Montalban
authors.affiliation: Servicio de Neurología, Basurto Hospital, Bilbao, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Antigüedad
authors.affiliation: Flinders University and Medical Centre, Adelaide, South Australia, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Krupa
authors.affiliation: Department of Medicine (Royal Melbourne Hospital), The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: V G
authors.initials: VG
authors.lastname: Jokubaitis
authors.affiliation: Centre for Immunology and Allergy Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: F C
authors.initials: FC
authors.lastname: McKay
authors.affiliation: Centre for Immunology and Allergy Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: P N
authors.initials: PN
authors.lastname: Gatt
authors.affiliation: Western Australian Neuroscience Research Institute, Centre for Neuromuscular and Neurological Disorders, University of WA, Nedlands, Western Australia, Australia.
authors.forename: M J
authors.initials: MJ
authors.lastname: Fabis-Pedrini
authors.affiliation: Laboratory of Genetics of Complex Neurological Disorders, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Martinelli
authors.affiliation: Laboratory of Genetics of Complex Neurological Disorders, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.|Department of Neurology and Neurorehabilitation, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Comi
authors.affiliation: Hunter Medical Research Institute, The University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Lechner-Scott
authors.affiliation: Western Australian Neuroscience Research Institute, Centre for Neuromuscular and Neurological Disorders, University of WA, Nedlands, Western Australia, Australia.|Institute of Immunology and Infectious Diseases, Murdoch University, Western Australia, Australia.
authors.forename: A G
authors.initials: AG
authors.lastname: Kermode
authors.affiliation: Flinders University and Medical Centre, Adelaide, South Australia, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Slee
authors.affiliation: Menzies Institute for Medical Research, University of Tasmania, Tasmania, Australia.
authors.forename: B V
authors.initials: BV
authors.lastname: Taylor
authors.affiliation: Neurogenomiks Group, Universidad del País Vasco (UPV/EHU), Leioa, Spain.|Achucarro Basque Center for Neuroscience, Zamudio, Spain.|Ikerbasque, Basque Foundation of Science, Bilbao, Spain.
authors.forename: K
authors.initials: K
authors.lastname: Vandenbroeck
authors.affiliation: Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Receca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Comabella
authors.affiliation: Laboratory of Genetics of Complex Neurological Disorders, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.|Department of Neurology and Neurorehabilitation, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: F M
authors.initials: FM
authors.lastname: Boneschi
authors.affiliation: School of Pharmacy and Medical Sciences and Sansom Institute for Health Research, University of South Australia, Frome Road, Adelaide, South Australia, Australia.
authors.forename: C
authors.initials: C
authors.lastname: King
mesh_terms: D000328:Adult; D001315:Australia; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006801:Humans; D016899:Interferon-beta / Q000627:therapeutic use*; D007558:Italy; D008297:Male; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D013030:Spain
chemical_list: D005819:Genetic Markers; D016899:Interferon-beta