Interactions between CES2, CYP2C9, UGT1A6 and COX1 genetic variants and acetylsalicylic acid modify the risk of myocardial infarction

Introduction: To investigate whether genetic variants in the enzymes CES2, CYP2C9, UGT1A6, COX1 and COX2 modify the effectiveness of acetylsalicylic (ASA) therapy in the prevention of myocardial infarction (MI). Methods: In a population-based registry of pharmacy records linked to hospital discharge records (PHARMO RLS), a nested case-control study was performed. Cases had a first MI between 1991 and 2005, controls were matched to MI cases by age, gender and region. Patients were genotyped for tagging SNPs in genes coding for CES2, CYP2C9, UGT1A6, COX1 and COX2. Logistic regression was used to assess the interaction between ASA and genetic variants on the risk of MI and to adjust for confounding. Results: The influence of 22 tagging SNPs was assessed in 853 cases and 887 control subjects. ASA-use was associated with a reduced risk of MI (adjusted odds ratio (ORadj) 0.74 (95% CI 0.56-0.97), P = 0.032). The CES2 rs11568311 and CYP2C9 rs1057910 variants were found to interact with ASA treatment (adjusted synergy index (SIadj) 0.43 (0.21- 0.90), P = 0.025 and SIadj 0.44 (0.22-0.91), P = 0.026, respectively). Two variants in the UGT1A6 gene showed a significant interaction with ASA (rs11563251, P = 0.044 and rs3771342, P = 0.023). In addition, two COX1 variants were associated with modified effectiveness of ASA (rs10306135: SIadj 1.5 (1.0-2.7), P = 0.042 and rs5788: SIadj 1.5 (1.0- 2.6), P = 0.023). No significant interactions between other genetic variants and the effect of ASA were observed. Conclusion: Common genetic variants in the CES2, CYP2C9, UGT1A6 and COX1 genes might be associated with modified effectiveness of ASA in the prevention of MI.