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  • Application of pharmacogenomics to investigate adverse drug reactions to the disease-modifying treatments for multiple sclerosis: a case–control study protocol for dimethyl fumarate-induced lymphopenia

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Neurology
Protocol
Application of pharmacogenomics to investigate adverse drug reactions to the disease-modifying treatments for multiple sclerosis: a case–control study protocol for dimethyl fumarate-induced lymphopenia
  1. Kaarina Kowalec1,
  2. Elaine Kingwell1,
  3. Robert Carruthers1,
  4. Ruth Ann Marrie2,
  5. Sasha Bernatsky3,
  6. Anthony Traboulsee1,
  7. Colin J D Ross4,5,
  8. Bruce Carleton5,6,
  9. Helen Tremlett1
  1. 1 Faculty of Medicine, Division of Neurology and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancover, British Columbia, Canada
  2. 2 Departments of Internal Medicine and Community Health Sciences, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada
  3. 3 Division of Rheumatology, McGill University, Montreal, Quebec, Canada
  4. 4 Faculty of Pharmaceutical Sciences, University of British Columbia, Vancover, British Columbia, Canada
  5. 5 B.C. Childrens Hospital Research Institute, Vancouver, Canada
  6. 6 Faculty of Medicine, Department of Pediatrics, University of British Columbia, Vancouver, Canada
  1. Correspondence to Prof. Helen Tremlett; helen.tremlett{at}ubc.ca

Abstract

Introduction Adverse drug reactions (ADRs) are a global public health issue. The potential for pharmacogenomic biomarkers has been demonstrated in several therapeutical areas, including HIV infection and oncology. Dimethyl fumarate (DMF) is a licensed disease-modifying therapy for the treatment of multiple sclerosis (MS). The use of DMF in MS has been associated with a severe reduction in lymphocyte counts and reports of progressive multifocal leukoencephalopathy. Here, we outline the protocol for a case–control study designed to discover genomic variants associated with DMF-induced lymphopenia. The ultimate goal is to replicate these findings and create an efficient and adaptable approach towards the identification of genomic markers that could assist in mitigating adverse drug reactions in MS.

Methods and analysis The population sample will comprise DMF-exposed patients with MS, with cases representing those who developed lymphopenia and controls who did not. DNA genotyping will take place using a high-throughput genome-wide array. Fine mapping and imputation will be performed to focus in on the potentially causal variants associated with lymphopenia. Multivariable logistic regression will be used to compare genotype and allele frequencies between the cases and the controls, with consideration of potential confounders. The association threshold will be set at p<1.0×10−5 for the discovery of genomic association analyses to select variants for replication.

Ethics and dissemination Ethics approval has been obtained from the respective research ethics board, which includes written informed consent. Findings will be disseminated widely, including at scientific conferences, via podcasts (targeted at both healthcare professionals as well as patients and the wider community), through patient engagement and other outreach community events, written lay summaries for all participants and formal publication in peer-reviewed scientific journals.

  • Multiple sclerosis
  • Adverse events
  • clinical pharmacology
  • Genetics

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/

https://doi.org/10.1136/bmjopen-2017-016276

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    Footnotes

    • Contributors KK, EK and HT contributed to the concept and design of the study, and drafting of the article. All authors reviewed, commented and approved the final manuscript.

    • Funding This work was supported by the Canadian Institutes of Health Research (CIHR) – Drug Safety and Effectiveness Network (British Columbia site PI: Tremlett).

    • Competing interests AT has received grant support from Hoffman la Roche and Sanofi Genzyme; steering committee membership for Hoffman la Roche; consultancy for Biogen, Chugai, EMD Serono, Hoffman la Roche, Medimmune, Sanofi Genzyme and Teva Neuroscience. RAM has conducted clinical trials for Sanofi-Aventis and receives research funding from CIHR, the National MS Society, the MS Society of Canada, the MS Scientific Research Foundation, Research Manitoba and the Waugh Family Chair in Multiple Sclerosis. CJDR receives funding support from the Canadian Institutes of Health Research, Canadian Foundation for Innovation, Canadian Hearing Foundation, BC Children's Hospital Foundation, BC Children’s Hospital Research Canadian Gene Cure Foundation, Teva Pharmaceutical Industries Inc., Genome BC and the CIHR Drug Safety & Effectiveness Network. BC currently receives research funding from the Canadian Institutes of Health Research, Genome Canada, Genome British Columbia and BC Children’s Hospital Research (Vancouver, Canada) and has previously held matching funds support for Genome Canada funding from Pfizer Canada (unrestricted). HT has received speaker honoraria and/or travel expenses to attend conferences in the last 5 years from the Consortium of MS Centres (2013), National MS Society (2012, 2014, 2016), ECTRIMS (2012–2016), the Chesapeake Health Education Program, US Veterans Affairs (2012), Novartis Canada (2012), Biogen Idec (2014) and AAN (2013–2016). All speaker honoraria are either declined or donated to an MS charity or to an unrestricted grant for use by her research group.

    • Ethics approval The University of British Columbia Clinical Research Ethics Board and the Vancouver Coastal Health Research Institute.

    • Provenance and peer review Not commissioned; externally peer reviewed.