Kowalec Kaarina, Kingwell Elaine, Carruthers Robert, Marrie Ruth Ann, Bernatsky Sasha, Traboulsee Anthony, Ross Colin J D, Carleton Bruce, Tremlett Helen
Faculty of Medicine, Division of Neurology and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancover, British Columbia, Canada.
Departments of Internal Medicine and Community Health Sciences, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada.
BMJ Open. 2017 Jun 2;7(5):e016276. doi: 10.1136/bmjopen-2017-016276.
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.
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 for the discovery of genomic association analyses to select variants for replication.
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.
药物不良反应是一个全球性的公共卫生问题。药物基因组生物标志物在包括艾滋病毒感染和肿瘤学在内的多个治疗领域已显示出潜力。富马酸二甲酯（DMF）是一种用于治疗多发性硬化症（MS）的已获许可的疾病改善疗法。在MS中使用DMF与淋巴细胞计数严重减少以及进行性多灶性白质脑病的报告有关。在此，我们概述了一项病例对照研究的方案，该研究旨在发现与DMF诱导的淋巴细胞减少相关的基因组变异。最终目标是重复这些发现，并创建一种高效且适应性强的方法来识别基因组标记，以帮助减轻MS中的药物不良反应。
人群样本将包括暴露于DMF的MS患者，病例组为出现淋巴细胞减少的患者，对照组为未出现淋巴细胞减少的患者。将使用高通量全基因组阵列进行DNA基因分型。将进行精细定位和归因，以聚焦于与淋巴细胞减少相关的潜在因果变异。将使用多变量逻辑回归来比较病例组和对照组之间的基因型和等位基因频率，并考虑潜在的混杂因素。在发现基因组关联分析中，关联阈值将设定为p<1.0×10，以选择用于重复验证的变异。
已获得各自研究伦理委员会的伦理批准，其中包括书面知情同意。研究结果将广泛传播，包括在科学会议上、通过播客（针对医疗保健专业人员以及患者和更广泛的社区）、通过患者参与和其他外展社区活动、为所有参与者撰写通俗易懂的总结以及在同行评审的科学期刊上正式发表。
