Genetic polymorphisms and the cardiovascular risk of non-steroidal anti-inflammatory drugs.
The cardiovascular safety of cyclooxygenase-2-selective (coxibs) and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) is of concern, although most users remain free of adverse outcomes. A gene-drug interaction could modulate this cardiovascular risk through prostaglandin synthesis or inflammatory pathways. From an existing acute coronary syndrome cohort (Recurrence and Inflammation in the Acute Coronary Syndromes Study) (n = 1,210), a case-only study was performed by identifying 115 patients exposed to NSAIDs (rofecoxib [n = 43], celecoxib [n = 49], or nonselective NSAIDs [n = 23]) and 345 unexposed patients matched for age, gender, and hospital center. These patients were genotyped for 115 candidate single-nucleotide polymorphisms (SNPs). Statistically significant associations between NSAID exposure and 9 SNPs in 6 genes were observed. Analyzing patients exposed only to coxibs and their matched unexposed cases, significant associations remained for 5 SNPs at 4 loci (prostaglandin-endoperoxide synthase-1 [PTGS1], chromosome 9p21.3, C-reactive protein [CRP], and klotho [KL]). Two independent SNPs from the PTGS1 gene gave similar results under a recessive model, with odds ratios for the association with NSAID exposure of 6.94 (95% confidence interval 1.35 to 35.65, p = 0.016) and 7.11 (95% confidence interval 1.38 to 36.74, p = 0.033). A significant association was also observed for a SNP in the CRP gene (rs1205) (additive odds ratio 1.64, 95% confidence interval 1.18 to 2.27, p = 0.003). In conclusion, these findings suggest that genetic variability may contribute to the susceptibility for acute coronary syndromes observed in some NSAID users. In particular, genetic polymorphisms in the PTGS1 and CRP genes appear to be candidates for a possible gene-drug interaction influencing the acute coronary risk associated with NSAID use, but these findings will require confirmation in larger cohorts.
Department of Epidemiology and Biostatistics, McGill University, Montreal, Quebec, Canada.
Christine G
CG
St Germaine
Peter
P
Bogaty
Luce
L
Boyer
James
J
Hanley
James C
JC
Engert
James M
JM
Brophy
D054058:Acute Coronary Syndrome / Q000139:chemically induced / Q000453:epidemiology / Q000235:genetics*; D000483:Alleles; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D002097:C-Reactive Protein / Q000235:genetics* / Q000378:metabolism; D016001:Confidence Intervals; D051545:Cyclooxygenase 1 / Q000235:genetics* / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D004247:DNA / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D005787:Gene Frequency / Q000187:drug effects; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015994:Incidence; D007249:Inflammation / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009509:New Brunswick / Q000453:epidemiology; D016017:Odds Ratio; D011110:Polymorphism, Genetic / Q000187:drug effects*; D011379:Prognosis; D011792:Quebec / Q000453:epidemiology; D012189:Retrospective Studies; D012307:Risk Factors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D002097:C-Reactive Protein; D004247:DNA; D051545:Cyclooxygenase 1; C496511:PTGS1 protein, human