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      Associations of MDR1, TBXA2R, PLA2G7, and PEAR1 genetic polymorphisms with the platelet activity in Chinese ischemic stroke patients receiving aspirin therapy

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          Abstract

          Aim:

          Aspirin resistance has an incidence of 5%–65% in patients with ischemic stroke, who receive the standard dose of aspirin, but the platelet function is inadequately inhibited, thereby leading to thrombotic events. Numerous evidence shows that thromboxane A 2 receptor (TXA 2 receptor, encoded by TBXA2R), lipoprotein-associated phospholipase A 2 (Lp-PLA 2, encoded by PLA2G7) and platelet endothelial aggregation receptor-1 ( PEAR1, encoded by PEAR1) are crucial in regulating platelet activation, and P-glycoprotein (P-gp, encoded by MDR1) influences the absorption of aspirin in the intestine. In this study we examined the correlation between MDR1, TBXA2R, PLA2G7, PEAR1 genetic polymorphisms and platelet activity in Chinese ischemic stroke patients receiving aspirin therapy.

          Methods:

          A total of 283 ischemic stroke patients receiving 100 mg aspirin for 7 d were genotyped for polymorphisms in MDR1 C3435T, TBXA2R (rs1131882), PLA2G7 (rs1051931, rs7756935), and PEAR1 (rs12566888, rs12041331). The platelet aggregation response was measured using an automatic platelet aggregation analyzer and a commercially available TXB 2 ELISA kit.

          Results:

          Thirty-three patients (11.66%) were insensitive to aspirin treatment. MDR1 3435TT genotype carriers, whose arachidonic acid (AA) or adenosine diphosphate (ADP)-induced platelet aggregation was lower than that of CC+CT genotype carriers, were less likely to suffer from aspirin resistance (odds ratio=0.421, 95% CI: 0.233–0.759). The TBXA2R rs1131882 CC genotype, which was found more frequently in the aspirin-insensitive group (81.8% vs 62.4%) than in the sensitive group, was identified as a risk factor for aspirin resistance (odds ratio=2.712, 95% CI: 1.080–6.810) with a higher level of AA-induced platelet aggregation. Due to the combined effects of PLA2G7 rs1051931 and rs7756935, carriers of the AA-CC haplotype had a higher level of ADP-induced platelet aggregation, and were at considerably higher risk of aspirin resistance than noncarriers (odds ratio=8.233, 95% CI: 1.590–42.638).

          Conclusion:

          A considerable portion (11.66%) of Chinese ischemic stroke patients are insensitive to aspirin treatment, which may be correlated with the MDR1 C3435T, TBXA2R (rs1131882), and PLA2G7 (rs1051931–rs7756935) polymorphisms.

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          Most cited references28

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          Stroke and stroke care in China: huge burden, significant workload, and a national priority.

          Liping Liu, David Wang, K S Lawrence Wong … (2011)
          At the same time as the world recognizes the rapid economic development in China, Chinese healthcare system has also had significant improvement. However, this nation of 1.4 billion faces tough challenges in treating stroke, the leading cause of death in China. The recently completed Chinese National Stroke Registry has provided new information on the status of stroke epidemiology, diagnosis, management, and prevention strategies in China. In this article, we summarized these new findings, described the effort of providing and improving stroke care, and illustrated the challenges in risk factor modification and secondary stroke prevention. Well-designed epidemiological surveys and clinical trials for stroke prevention and management are still urgently needed in China.
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            Lipoprotein-associated phospholipase A2 and risk of coronary disease, stroke, and mortality: collaborative analysis of 32 prospective studies

            (2010)
            Summary Background Lipoprotein-associated phospholipase A2 (Lp-PLA2), an inflammatory enzyme expressed in atherosclerotic plaques, is a therapeutic target being assessed in trials of vascular disease prevention. We investigated associations of circulating Lp-PLA2 mass and activity with risk of coronary heart disease, stroke, and mortality under different circumstances. Methods With use of individual records from 79 036 participants in 32 prospective studies (yielding 17 722 incident fatal or non-fatal outcomes during 474 976 person-years at risk), we did a meta-analysis of within-study regressions to calculate risk ratios (RRs) per 1 SD higher value of Lp-PLA2 or other risk factor. The primary outcome was coronary heart disease. Findings Lp-PLA2 activity and mass were associated with each other (r=0·51, 95% CI 0·47–0·56) and proatherogenic lipids. We noted roughly log-linear associations of Lp-PLA2 activity and mass with risk of coronary heart disease and vascular death. RRs, adjusted for conventional risk factors, were: 1·10 (95% CI 1·05–1·16) with Lp-PLA2 activity and 1·11 (1·07–1·16) with Lp-PLA2 mass for coronary heart disease; 1·08 (0·97–1·20) and 1·14 (1·02–1·27) for ischaemic stroke; 1·16 (1·09–1·24) and 1·13 (1·05–1·22) for vascular mortality; and 1·10 (1·04–1·17) and 1·10 (1·03–1·18) for non-vascular mortality, respectively. RRs with Lp-PLA2 did not differ significantly in people with and without initial stable vascular disease, apart from for vascular death with Lp-PLA2 mass. Adjusted RRs for coronary heart disease were 1·10 (1·02–1·18) with non-HDL cholesterol and 1·10 (1·00–1·21) with systolic blood pressure. Interpretation Lp-PLA2 activity and mass each show continuous associations with risk of coronary heart disease, similar in magnitude to that with non-HDL cholesterol or systolic blood pressure in this population. Associations of Lp-PLA2 mass and activity are not exclusive to vascular outcomes, and the vascular associations depend at least partly on lipids. Funding UK Medical Research Council, GlaxoSmithKline, and British Heart Foundation.
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              Collaborative overview of randomised trials of antiplatelet therapy--I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists' Collaboration.

              Collaboration Antiplatelet Trialists’, R Altman, R. Diaz-Guerrero … (1994)
              To determine the effects of "prolonged" antiplatelet therapy (that is, given for one month or more) on "vascular events" (non-fatal myocardial infarctions, non-fatal strokes, or vascular deaths) in various categories of patients. Overviews of 145 randomised trials of "prolonged" antiplatelet therapy versus control and 29 randomised comparisons between such antiplatelet regimens. Randomised trials that could have been available by March 1990. Trials of antiplatelet therapy versus control included about 70,000 "high risk" patients (that is, with some vascular disease or other condition implying an increased risk of occlusive vascular disease) and 30,000 "low risk" subjects from the general population. Direct comparisons of different antiplatelet regimens involved about 10,000 high risk patients. In each of four main high risk categories of patients antiplatelet therapy was definitely protective. The percentages of patients suffering a vascular event among those allocated antiplatelet therapy versus appropriately adjusted control percentages (and mean scheduled treatment durations and net absolute benefits) were: (a) among about 20,000 patients with acute myocardial infarction, 10% antiplatelet therapy v 14% control (one month benefit about 40 vascular events avoided per 1000 patients treated (2P < 0.00001)); (b) among about 20,000 patients with a past history of myocardial infarction, 13% antiplatelet therapy v 17% control (two year benefit about 40/1000 (2P < 0.00001)); (c) among about 10,000 patients with a past history of stroke or transient ischaemic attack, 18% antiplatelet therapy v 22% control (three year benefit about 40/1000 (2P < 0.00001)); (d) among about 20,000 patients with some other relevant medical history (unstable angina, stable angina, vascular surgery, angioplasty, atrial fibrillation, valvular disease, peripheral vascular disease, etc), 9% v 14% in 4000 patients with unstable angina (six month benefit about 50/1000 (2P < 0.00001)) and 6% v 8% in 16,000 other high risk patients (one year benefit about 20/1000 (2P < 0.00001)). Reductions in vascular events were about one quarter in each of these four main categories and were separately statistically significant in middle age and old age, in men and women, in hypertensive and normotensive patients, and in diabetic and nondiabetic patients. Taking all high risk patients together showed reductions of about one third in non-fatal myocardial infarction, about one third in non-fatal stroke, and about one third in vascular death (each 2P < 0.00001). There was no evidence that non-vascular deaths were increased, so in each of the four main high risk categories overall mortality was significantly reduced. The most widely tested antiplatelet regimen was "medium dose" (75-325 mg/day) aspirin. Doses throughout this range seemed similarly effective (although in an acute emergency it might be prudent to use an initial dose of 160-325 mg rather than about 75 mg). There was no appreciable evidence that either a higher aspirin dose or any other antiplatelet regimen was more effective than medium dose aspirin in preventing vascular events. The optimal duration of treatment for patients with a past history of myocardial infarction, stroke, or transient ischaemic attack could not be determined directly because most trials lasted only one, two, or three years (average about two years). Nevertheless, there was significant (2P < 0.0001) further benefit between the end of year 1 and the end of year 3, suggesting that longer treatment might well be more effective. Among low risk recipients of "primary prevention" a significant reduction of one third in non-fatal myocardial infarction was, however, accompanied by a non-significant increase in stroke. Furthermore, the absolute reduction in vascular events was much smaller than for high risk patients despite a much longer treatment period (4.4% antiplatelet therapy v 4.8% control; five year
              Article 0 comments Cited 141 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Acta Pharmacol Sin
                Journal ID (iso-abbrev): Acta Pharmacol. Sin
                Title: Acta Pharmacologica Sinica
                Publisher: Nature Publishing Group
                ISSN (Print): 1671-4083
                ISSN (Electronic): 1745-7254
                Publication date (Print): November 2016
                Publication date (Electronic): 19 September 2016
                Volume: 37
                Issue: 11
                Pages: 1442-1448
                Affiliations
                [1 ]Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University , Guangzhou 510006, China
                [2 ]Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine , Guangzhou 510120, China
                [3 ]Department of Pharmacy, General Hospital of Guangzhou Military Command of PLA , Guangzhou 510110, China
                Author notes
                [#]

                These authors contributed equally to this work.

                Article
                Publisher Item ID: aps201690
                DOI: 10.1038/aps.2016.90
                PMC ID: 5099418
                PubMed ID: 27641736
                SO-VID: 30be4ebd-e626-4731-92b7-ae66795ed2b5
                Copyright © Copyright © 2016 CPS and SIMM
                History
                Date received : 26 March 2016
                Date accepted : 22 June 2016
                Categories
                Subject: Original Article

                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: ischemic stroke,aspirin resistance,platelet activity,mdr1,tbxa2r,pla2g7,pear1,genetic polymorphisms
                Data availability:
                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: ischemic stroke, aspirin resistance, platelet activity, mdr1, tbxa2r, pla2g7, pear1, genetic polymorphisms

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