Interaction between COX-1 and COX-2 Variants Associated with Aspirin Resistance in Chinese Stroke Patients

Abstract

There have been conflicting results for the association between cyclooxygenase (COX) genetic variants and aspirin resistance (AR). The aim of this study was to investigate the association of the COX genetic variants and interaction among these variants with AR in patients with acute ischemic stroke (IS). We consecutively enrolled 850 acute IS patients. Platelet aggregation activity was measured before and after a 7- to 10-day aspirin treatment. The four variants from COX genes were examined using mass spectrometry. Gene-gene interactions were analyzed using generalized multifactor dimensionality reduction (GMDR) methods. Among the 850 acute IS patients, 175 (20.6%) patients had AR, 45 (5.3%) patients had aspirin semiresistance (ASR), and 630 (74.1%) patients had aspirin sensitivity (AS). The genotype distributions of the 4 variants did not differ significantly between the ASR + AR group and the AS group using the single-locus analytical approach. However, the GMDR analysis showed a significant gene-gene interaction between COX-1 (rs3842787) and COX-2 (rs20417), and scored 10/10 for cross-validation consistency and 9 for the sign test (P = .0127). Individual patients with the combination of rs3842787CT and rs20417CC or rs3842787CT and rs20417GC had a significantly higher risk of ASR + AR than those with rs3842787CC and rs20417GG. The high-risk interactions between rs3842787 and rs20417 were independent predictors of ASR + AR, and were associated with lower reduction of platelet aggregation activity. The interactions of rs3842787 and rs20417 were associated with AR. The combinational analysis used in this study may provide further insight into the complex genetic risk of AR.