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

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The risk of cardiovascular events with non‐steroidal anti‐inflammatory drugs (NSAIDs) varies with individual drugs and with dosage. Little is known about other factors that can modify risk. • Polymorphisms of the COX‐2 gene conceivably could alter the risk of myocardial infarction and also the risk from NSAIDs. WHAT THIS STUDY ADDS • Two common polymorphisms of the COX‐2 gene, rs 20417 (G > C) and rs 5275 (T > C), were not associated with variation in the risk of acute coronary syndrome, and individually did not alter the risk associated with use of NSAIDs. • Haplotype analysis identified a trend to protection against NSAID‐related cardiovascular risk with the ‘low risk’ haplotype, but the effect was weak and if confirmed, the clinical utility would be limited. AIMS To investigate whether polymorphisms of the cyclo‐oxygenase‐2 (COX‐2) gene modify the adverse cardiovascular effects of COX‐2 inhibitors. METHODS A case control study was conducted in the Hunter Region of New South Wales, Australia. Cases (n= 460) were hospitalized with acute coronary syndrome (ACS). Controls (n= 640) were recruited from the electoral rolls. Structured interviews gathered information on variables including recent ingestion of non‐steroidal anti‐inflammatory drugs (NSAIDs). Targeted genotyping of rs 20417(G > C) and rs5275 (T > C) polymorphisms was performed by real‐time polymerase chain reaction using allele‐specific probes RESULTS Ingestion of any NSAID in the week prior to interview was associated with an elevated risk for ACS: adjusted odds ratio 1.8 (1.2, 2.5). The rs 20417 and rs 5275 polymorphisms were not singly associated with risk for ACS: adjusted odds ratios 1.1 (0.80, 1.5) and 1.2 (0.88, 1.5), respectively. Individually, the polymorphisms did not modify the risk of ACS with the drugs. When analyses were conducted by haplotype, the adjusted odds ratio with celecoxib or rofecoxib in individuals who had one or two copies of the ‘low risk’ haplotype (no GT) was 1.2 (0.29, 5.0), compared with 2.1 (1.1, 4.0) with the ‘high risk’ haplotype (one or two copies of GT). CONCLUSIONS We found little evidence of a gene/drug interaction. We found a statistically non‐significant trend toward a lower risk of coronary events with NSAIDs in the presence of the ‘low risk’ haplotype. Even if confirmed, the clinical utility of the finding would be limited as this haplotype is carried by a minority of the population.

Eicosanoids and Their Drugs in Cardiovascular Diseases: Focus on Atherosclerosis and Stroke

“…These observations prompted to investigate whether COX‐2 gene polymorphisms might correlate with this variability and with the CV risk associated with the use of these drugs. However, two polymorphisms at the 5′ and 3′‐untranslated regions of the COX‐2 gene, despite having both significant effects on reducing COX‐2 expression and, thus, should be considered “low risk” haplotype, have not been shown to be correlated with a lower risk of coronary events in patients taking COXIBs . In addition, the −765G>C polymorphism has been variably associated with the risk of MI and stroke …”

“…However, two polymorphisms at the 5 and 3 -untranslated regions of the COX-2 gene, despite having both significant effects on reducing COX-2 expression 338,339 and, thus, should be considered "low risk" haplotype, have not been shown to be correlated with a lower risk of coronary events in patients taking COXIBs. 340 In addition, the −765G>C polymorphism has been variably associated with the risk of MI and stroke. 341,342 Furthermore, some studies have suggested that COX inhibitors may have pharmacological mechanisms in addition to their COX activity inhibition.…”

PTGS2 gene polymorphism -765G>C is associated with coronary artery disease: a meta-analysis

“…Therefore, the identification of genetic determinants associated with CAD risk has tremendous importance from a public health perspective. Recently, a number of case-control studies have suggested that -765G>C polymorphism in the PTGS2 gene is associated with the risk of CAD (Cipollone et al, 2004(Cipollone et al, , 2009Hegener et al, 2006;Lee et al, 2008;Szczeklik et al, 2008;Kohsaka et al, 2008;Huuskonen et al, 2008;Li et al, 2009;Rudock et al, 2009;Sanak et al, 2010;McGettigan et al, 2011;Ol et al, 2011).…”