{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T20:11:53Z","timestamp":1787170313561,"version":"build-2736575974"},"reference-count":36,"publisher":"BMJ","issue":"5","funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2017,4,19]]},"published-print":{"date-parts":[[2017,5]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>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\u2013control 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and analysis<\/jats:title>\n                    <jats:p>\n                      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&lt;1.0\u00d710\n                      <jats:sup>\u22125<\/jats:sup>\n                      for the discovery of genomic association analyses to select variants for replication.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2017-016276","type":"journal-article","created":{"date-parts":[[2017,6,2]],"date-time":"2017-06-02T20:10:12Z","timestamp":1496434212000},"page":"e016276","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["Application of pharmacogenomics to investigate adverse drug reactions to the disease-modifying treatments for multiple sclerosis: a case\u2013control study protocol for dimethyl fumarate-induced lymphopenia"],"prefix":"10.1136","volume":"7","author":[{"given":"Kaarina","family":"Kowalec","sequence":"first","affiliation":[{"name":"Faculty of Medicine, Division of Neurology and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancover, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine","family":"Kingwell","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Division of Neurology and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancover, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Carruthers","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Division of Neurology and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancover, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth Ann","family":"Marrie","sequence":"additional","affiliation":[{"name":"Departments of Internal Medicine and Community Health Sciences, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sasha","family":"Bernatsky","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, McGill University, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Traboulsee","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Division of Neurology and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancover, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin J D","family":"Ross","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, University of British Columbia, Vancover, British Columbia, Canada"},{"name":"B.C. 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