Response to interferon-beta treatment in multiple sclerosis patients: a genome-wide association study

S Mahurkar¹, M Moldovan^{2

3}, V Suppiah¹, M Sorosina⁴, F Clarelli⁴, G Liberatore^{4

5}, S Malhotra⁶, X Montalban⁶, A Antigüedad⁷, M Krupa⁸, V G Jokubaitis⁹, F C McKay¹⁰, P N Gatt¹⁰, M J Fabis-Pedrini¹¹, V Martinelli⁴, G Comi^{4

5}, J Lechner-Scott¹², A G Kermode^{11

13}, M Slee⁸, B V Taylor¹⁴, K Vandenbroeck^{15

16

17}, M Comabella⁶, F M Boneschi^{4

5}; Australian and New Zealand Multiple Sclerosis Genetics Consortium (ANZgene); C King¹

Affiliations

¹ School of Pharmacy and Medical Sciences and Sansom Institute for Health Research, University of South Australia, Frome Road, Adelaide, South Australia, Australia.
² South Australian Health &Medical Research Institute and Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia.
³ Australian Institute of Health Innovation, University of New South Wales, Sydney, Australia.
⁴ Laboratory of Genetics of Complex Neurological Disorders, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
⁵ Department of Neurology and Neurorehabilitation, San Raffaele Scientific Institute, Milan, Italy.
⁶ 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.
⁷ Servicio de Neurología, Basurto Hospital, Bilbao, Spain.
⁸ Flinders University and Medical Centre, Adelaide, South Australia, Australia.
⁹ Department of Medicine (Royal Melbourne Hospital), The University of Melbourne, Parkville, Victoria, Australia.
¹⁰ Centre for Immunology and Allergy Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.
¹¹ Western Australian Neuroscience Research Institute, Centre for Neuromuscular and Neurological Disorders, University of WA, Nedlands, Western Australia, Australia.
¹² Hunter Medical Research Institute, The University of Newcastle, Newcastle, New South Wales, Australia.
¹³ Institute of Immunology and Infectious Diseases, Murdoch University, Western Australia, Australia.
¹⁴ Menzies Institute for Medical Research, University of Tasmania, Tasmania, Australia.
¹⁵ Neurogenomiks Group, Universidad del País Vasco (UPV/EHU), Leioa, Spain.
¹⁶ Achucarro Basque Center for Neuroscience, Zamudio, Spain.
¹⁷ Ikerbasque, Basque Foundation of Science, Bilbao, Spain.

PMID: 27001119
DOI: 10.1038/tpj.2016.20

Response to interferon-beta treatment in multiple sclerosis patients: a genome-wide association study

S Mahurkar et al. Pharmacogenomics J. 2017 Jul.

. 2017 Jul;17(4):312-318.

doi: 10.1038/tpj.2016.20. Epub 2016 Mar 22.

Authors

Affiliations

¹ School of Pharmacy and Medical Sciences and Sansom Institute for Health Research, University of South Australia, Frome Road, Adelaide, South Australia, Australia.
² South Australian Health &Medical Research Institute and Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia.
³ Australian Institute of Health Innovation, University of New South Wales, Sydney, Australia.
⁴ Laboratory of Genetics of Complex Neurological Disorders, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
⁵ Department of Neurology and Neurorehabilitation, San Raffaele Scientific Institute, Milan, Italy.
⁶ 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.
⁷ Servicio de Neurología, Basurto Hospital, Bilbao, Spain.
⁸ Flinders University and Medical Centre, Adelaide, South Australia, Australia.
⁹ Department of Medicine (Royal Melbourne Hospital), The University of Melbourne, Parkville, Victoria, Australia.
¹⁰ Centre for Immunology and Allergy Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.
¹¹ Western Australian Neuroscience Research Institute, Centre for Neuromuscular and Neurological Disorders, University of WA, Nedlands, Western Australia, Australia.
¹² Hunter Medical Research Institute, The University of Newcastle, Newcastle, New South Wales, Australia.
¹³ Institute of Immunology and Infectious Diseases, Murdoch University, Western Australia, Australia.
¹⁴ Menzies Institute for Medical Research, University of Tasmania, Tasmania, Australia.
¹⁵ Neurogenomiks Group, Universidad del País Vasco (UPV/EHU), Leioa, Spain.
¹⁶ Achucarro Basque Center for Neuroscience, Zamudio, Spain.
¹⁷ Ikerbasque, Basque Foundation of Science, Bilbao, Spain.

PMID: 27001119
DOI: 10.1038/tpj.2016.20

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).

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References

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Response to interferon-beta treatment in multiple sclerosis patients: a genome-wide association study

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Response to interferon-beta treatment in multiple sclerosis patients: a genome-wide association study

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