The Association of Four Common Polymorphisms from Four Candidate Genes (COX-1, COX-2, ITGA2B, ITGA2) with Aspirin Insensitivity: A Meta-Analysis

Abstract

ObjectiveEvidence is mounting suggesting that a strong genetic component underlies aspirin insensitivity. To generate more information, we aimed to evaluate the association of four common polymorphisms (rs3842787, rs20417, rs201184269, rs1126643) from four candidate genes (COX-1, COX-2, ITGA2B, ITGA2) with aspirin insensitivity via a meta-analysis.Methods and ResultsIn total, there were 4 (353/595), 6 (344/698), 10 (588/878) and 7 (209/676) articles (patients/controls) qualified for rs3842787, rs20417, rs20118426 and rs1126643, respectively. The data were extracted in duplicate and analyzed by STATA software (Version 11.2). The risk estimate was expressed as odds ratio (OR) and 95% confidence interval (95% CI). Analyses of the full data set indicated significant associations of rs20417 (OR; 95% CI; P: 1.86; 1.44–2.41; <0.0005) and rs1126643 (2.37; 1.44–3.89; 0.001) with aspirin insensitivity under allelic model. In subgroup analyses, the risk estimate for rs1126643 was greatly potentiated among patients with aspirin semi-resistance relative to those with aspirin resistance, especially under dominant model (aspirin semi-resistance: 5.44; 1.42–20.83; 0.013 versus aspirin resistance: 1.96; 1.07–3.6; 0.03). Further grouping articles by ethnicity observed a stronger prediction of all, but rs20417, examined polymorphisms for aspirin insensitivity in Chinese than in Caucasians. Finally, meta-regression analyses observed that the differences in percentage of coronary artery disease (P = 0.034) and averaged platelet numbers (P = 0.012) between two groups explained a large part of heterogeneity for rs20417 and rs1126643, respectively.ConclusionOur findings provide strong evidence that COX-2 and ITGA2 genetic defects might increase the risk of having aspirin insensitivity, especially for aspirin semi-resistance and in Chinese populations.

Platelet response to increased aspirin dose in patients with persistent platelet aggregation while treated with aspirin 81 mg

“…A meta‐analysis of 27 studies reports a higher probability of genetic polymorphisms in aspirin‐resistant patients. There were an 8% increase in polymorphisms of the COX‐2 gene and a 20% increase in polymorphisms of the ITGA2 gene in patients exhibiting aspirin resistance . In contrast to patients who have these polymorphisms, the data from the present study suggest that most patients who do not obtain an adequate antiplatelet response to low‐dose aspirin simply require a higher dose of aspirin.…”

“…There were an 8% increase in polymorphisms of the COX-2 gene and a 20% increase in polymorphisms of the ITGA2 gene in patients exhibiting aspirin resistance. 31 In contrast to patients who have these polymorphisms, the data from the Measurements were performed at 37°C at a stirring speed of 1200 RPM. Whole blood (500 mL) was diluted 1:1 with 0.9% NaCl and prewarmed for 5 minutes at 37°C.…”

The Development of an In Vitro Assay for the Prospective Determination of Aspirin Sensitivity

“…In addition, pharmacodynamic resistance may also be from patient genomics or transcriptomics. For example, there have been studies showing polymorphisms that may alter aspirin binding to COX‐1 . It has also been hypothesized that certain patients may have excessive expression of COX‐2 compared with COX‐1 .…”

“…For example, there have been studies showing polymorphisms that may alter aspirin binding to COX-1. [15][16][17] It has also been hypothesized that certain patients may have excessive expression of COX-2 compared with COX-1. 18,19 In the case of patients whose platelets may express more than normal amounts of COX-2, this form of the enzyme is capable of being further induced, whereas COX-1 cannot, which can potentially lead to changes in aspirin sensitivity over the course of therapy.…”

Common Polymorphisms within Genes Encoding Platelet Receptors: Still a Way to Go?

“…The average frequency of the ITGA2 gene 807T allele was 40.77% in Caucasian patients with aspirin insensitivity, and as high as 58.58% in the Chinese patients. This ethnicity-specific effect suggests that different genetic backgrounds may account for this discrepancy or that different populations may have different linkage disequilibrium patterns due to their evolutionary history [8]. …”