title: Associations of MDR1, TBXA2R, PLA2G7, and PEAR1 genetic polymorphisms with the platelet activity in Chinese ischemic stroke patients receiving aspirin therapy.
abstract: OBJECTIVE
  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 A2receptor (TXA2receptor, encoded by TBXA2R), lipoprotein-associated phospholipase A2(Lp-PLA2, 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 TXB2ELISA 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.|Department of Pharmacy, General Hospital of Guangzhou Military Command of PLA, Guangzhou 510110, China.
authors.forename: Ling-Ling
authors.initials: LL
authors.lastname: Peng
authors.affiliation: Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou 510120, China.
authors.forename: Yuan-Qi
authors.initials: YQ
authors.lastname: Zhao
authors.affiliation: Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou 510120, China.
authors.forename: Zi-Yi
authors.initials: ZY
authors.lastname: Zhou
authors.affiliation: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Jin
authors.affiliation: Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou 510120, China.
authors.forename: Min
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Xin-Meng
authors.initials: XM
authors.lastname: Chen
authors.affiliation: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Ling-Yan
authors.initials: LY
authors.lastname: Chen
authors.affiliation: Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou 510120, China.
authors.forename: Ye-Feng
authors.initials: YF
authors.lastname: Cai
authors.affiliation: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Jia-Li
authors.initials: JL
authors.lastname: Li
authors.affiliation: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Min
authors.initials: M
authors.lastname: Huang
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000235:genetics*; D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000368:Aged; D044466:Asian People; D001241:Aspirin / Q000627:therapeutic use*; D001792:Blood Platelets / Q000187:drug effects*; D002545:Brain Ischemia / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide; D011956:Receptors, Cell Surface / Q000235:genetics*; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000235:genetics*; D020521:Stroke / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D013929:Thromboxane B2 / Q000096:biosynthesis / Q000097:blood; D017211:Treatment Failure
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; C502809:PEAR1 protein, human; D010975:Platelet Aggregation Inhibitors; D011956:Receptors, Cell Surface; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013929:Thromboxane B2; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C526684:PLA2G7 protein, human; D001241:Aspirin