Genetic Polymorphisms and the Cardiovascular Risk of Non-Steroidal Anti-Inflammatory Drugs

Abstract

The cardiovascular safety of cyclooxygenase-2 (COX-2) selective non-steroidal anti-inflammatory drugs (NSAIDs) is of concern, although the majority of users remain free of adverse outcomes. A gene-drug interaction may contribute to the variation in individual response to NSAIDs.In a case-only study of 460 patients selected from a cohort admitted for an acute coronary syndrome we genotyped 115 single nucleotide polymorphisms (SNPs). We observed statistically significant gene-drug interactions between NSAID exposure and 16SNPs. Of these, four interactions strengthened and remained significant in a COX-2 subgroup including a SNP in the C-Reactive Protein (CRP) gene (OR=3.6; 95%Confidence Interval [CI], 1.6 -7.9; P=0.001), two SNPs in the cyclooxygenase-1 (COX-1) gene (OR=6.9; 95% CI, 1. P=0.02 and OR=6.9; 95% CI, P=0.02) and one SNP in the Klotho gene (OR=2.3; 95% CI, 1.4-3.9; P=0.002).Genetic polymorphisms within the COX-1, CRP and Klotho genes are candidates for gene-drug interactions influencing the cardiovascular outcomes of users of NSAIDs.These findings suggest that genetic susceptibility may contribute to coronary instability in some users of this class of drugs.iv Contribution of AuthorsThis thesis includes the text of a manuscript that will be submitted for publication. I (Christine St.Germaine) wrote the application for funding for the MUHC pilot project competition, the ethics protocol, the thesis, and the manuscript. I used the existing database and the suggested study design to develop the study methods. I also reviewed the literature and suggested a list of possible candidate genes to study. I was primarily responsible for the statistical analysis conducted in SAS Dr. James Brophy was primarily responsible for the supervision of this project. He proposed the research question and suggested the case-only study design. He provided comments, suggestions and revisions on the application for funding to the MUHC pilot project competition, all chapters in the thesis and drafts of the manuscript.Dr. Jamie Engert shared his knowledge and guidance in genetics. He answered questions regarding genetics databases and software used in this thesis. He contributed to the selection of candidate genes and provided advice on the methods of statistical analysis for this genetic study as well as comments, suggestions and revisions for the thesis and the manuscript.Dr. Hanley attended committee meetings and provided statistical advice. He also offered comments and suggestions to improve the quality of the manuscript and the thesis.Dr. Peter Bogaty provided the genetic samples and database of patient information used in this study. Luce Boyer assisted in the retrieval and delivery of genetic samples.All authors contributed to the interpretation of the results of this study.ix

Celecoxib for the Right Person at the Right Dose and Right Time: An Updated Overview

“…This may be attributed to genetic differences between patients. In fact, two PTGS1 SNPs (rs10303135 and rs12353214) were significantly associated with acute coronary syndrome in patients taking celecoxib as found by St Germaine et al [29]. Kraus et al [20] found two variants of the prostaglandin E2 synthase gene (rs2241271 and rs2302821), one in the C-reactive protein gene (rs1800947) and three in the epidermal growth factor receptor signaling gene (rs6017996, rs6018256, and rs6018257), to be associated with celecoxib cardiovascular side effect.…”

The risk of coronary thrombosis with cyclo‐oxygenase‐2 inhibitors does not vary with polymorphisms in two regions of the cyclo‐oxygenase‐2 gene

“…In a large nested case cohort study in Denmark, Vogel and colleagues found no interaction between two polymorphisms of the COX‐2 gene: rs5275 (studied here) and rs689466, and recent consumption of NSAIDs [41]. In a case only study of subjects with ACS, St Germaine and colleagues in Quebec, Canada studied a total of 14 polymorphisms of the COX‐2 gene and found no interaction with use of NSAIDs [42]. Significantly, St Germaine and colleagues also found no interaction between polymorphisms of CYP2C9 and NSAID use.…”

Pharmacogenetics of non-steroidal anti-inflammatory drugs: existing problems for clinical practice

“…Изучалась роль генетического полиморфизма гена PTGS1 в развитии кардиотоксичности НПВП. В когортном исследовании Recurrence and Inflammation in the Acute Coronary Syndromes Study (n = 1210) было отобрано 115 пациентов с острым коронарным синдромом (ОКС), принимавших НПВП (рофекоксиб, целекоксиб и неселективные НПВП), сравнивали с группой из 345 пациентов, не применявших НПВП [21]. Два одиночных нуклеотидных варианта гена PTGS1 (rs10303135 и rs12353214) были статистически значимо связаны с ОКС преимущественно для селективных ингибиторов ЦОГ-2 -ОР составил 6,94 для rs10303135 и 7,11 для rs12353214 [21].…”