COX-1 Gene-smoking Interaction And Prognosis In Ischemic Stroke Patients

Background and Purpose:Aspirin is the most widely used drug for secondary prevention of stroke.Despite received therapeutic doses of aspirin for secondary prevention of stroke,a part of patients still do not respond appropriately to aspirin and experience adverse clinical outcomes.This phenomenon has been described as aspirin resistance.A number of genetic and environmental factors may lead alone or together to aspirin resistance.Cyclooxygenase-1(COX-1),a key role in aspirin’s therapeutic target,is encoded by COX-1 gene.Genetic variation of COX-1 gene may result in aspirin resistance.As an important environmental factor,smoking is related to various diseases.However,questions about whether there exists an interaction between COX-1 gene and smoking and what degree of the interaction,as well as the impact of the interaction on prognosis in stroke patients treated with aspirin are largely unknown.Our aim was to examine the effects of COX-1 gene polymorphisms,smoking status,and their interaction on functional outcomes in a cohort of Chinese Han patients with stroke during aspirin therapy.Methods:Based on Nanjing Stroke Registry Program,we screened acute ischemic stroke patients treated with aspirin between December 2009 and October 2012.Inclusion criteria were:1)Chinese Han ethnicity;2)aged 18 years or older;3)diagnosed with acute ischemic stroke,which was defined as focal neurological dysfunction persisting>24h and confirmed by imaging evidence;4)treated with enteric-coated aspirin(100mg daily)within 48h after symptom onset;5)with a modified Rankin Scale(mRS)score≤ 1 before the index stroke;6)agreed to take part in this study and had qualified blood samples.Exclusion criteria were:1)treated with anticoagulants,non-steroid anti-inflammatory drugs or other antiplatelet agents besides aspirin;2)stoke subtype was classified as cardio-embolism according to the Trial of Org 10172 in Acute Stroke Treatment(TOAST)criteria;3)discontinued or changed the antiplatelet regime before the 90-day follow-up;4)had a history of bleeding or hematological disorder;5)diagnosed with malignancies;6)diagnosed with severe liver or kidney dysfunction.Three single nucleotide polymorphisms(SNPs)rs1330344,rs3842788,and rs5788 in COX-1 gene were determined for genotyping by Improved Multiple Ligase Detection Reaction(iMLDR).Poor functional outcomes were defined as a modified Rankin Scale(mRS)of 3-6 at 90-day follow-up.We applied Logistic regression,haplotype analysis,and interaction analysis to evaluate the association of COX-1 gene polymorphisms and COX-1 gene-smoking interaction with functional outcomes.Results:A total of 617 patients were enrolled.Poor functional outcomes occurred in 145(23.5%)patients.When adjusting age,sex,hypertension,and NIH Stroke Scale(NIHSS)scores by Logistic regression,CC genotype of rs1330344 was associated with poor functional outcomes(RR = 1.73;95%CI:1.17-2.37).A similar connection was found in the CGC haplotype(RR = 1.40;95%CI:1.08-1.77).We found a significant interaction between rs1330344 and smoking status(P interaction ＝0.018);the interaction effect between the COX-1 haplotype and smoking also showed statistical significance(P interaction = 0.040).Conclusions:In Chinese Han stroke patients treated with aspirin,there might be an interaction between COX-1 gene and smoking,increasing the risk of poor functional outcomes.COX-1 gene-smoking interaction might in part reflect the heterogeneity in the prognosis of patients treated with aspirin.