title: Association of ALOX5AP1 SG13S114T/A variant with ischemic stroke, stroke subtypes and aspirin resistance.
abstract: The important role of genetic variants in the etiology and pathophysiology of stroke is being increasingly recognized. Simultaneously, the influence of genetic factors in the clinical outcome of drug therapy cannot be ignored. 5-lipoxygenase activating (ALOX5AP) gene involved in the synthesis of leukotrienes, has been recognized as an important gene contributing towards susceptibility of stroke risk. Leukotrienes are involved in the physiological mechanism of atherosclerotic events and inflammation. The present study was designed to identify the association of SG13S114T/A polymorphism in ALOX5AP1 gene with risk of stroke, its subtypes and aspirin resistance. We studied six hundred and ten patients with ischemic stroke and six hundred and ten age and sex matched healthy controls. The ischemic stroke was classified according to Trial of Org 10172 in Acute stroke Treatment. ALOX5AP1 SG13S114T/A polymorphism was determined using PCR RFLP methods. Follow-up was done for all the patients for a period of 3 months, 6 months and 12 months. The patients were classified into two groups responders and non-responders. The non-responders were identified to have a poor clinical outcome defined as a score of more than 2 on modified Rankin Scale Score and less than 5 on extended Glassgow Outcome Scale from stroke onset. We found statistically significant difference in the genotypic distribution between patients and controls (for AA vs TT, χ2=9.894; p=0.001, odds ratio=1.68 (95% confidence interval (CI); 1.215, 2.326). Significant difference was observed in the frequency of A and T alleles in patients and controls (A vs T χ(2)=10.23; p=0.001, odds ratio=1.301 (95% CI; 1.107, 1.528). Multiple logistic regression analysis revealed, the most predictive risk factor for stroke was AA genotype [adjusted odds ratio=1.660 (95% CI; 1.167-2.361) and p=0.005], hypertension, smoking and diabetes (p<0.001 in each case). We also found a significant association of AA genotype with intracranial large artery atherosclerosis (p=0.002, odds ratio=2.04, (95%CI; 1.279-3.275) and cardioembolism (p<0.001, odds ratio=4.73 (95% CI; 2.661-8.439). The risk of aspirin resistance was significantly higher among patients with AA genotype in comparison to carriers of homozygous TT genotype (AA vs TT, χ2=22.25, odds ratio=2.983, 95% CI; 1.884- 4.723, p<0.001). The frequency of recurrence and death events was more in non-responders. We didn't find a significant association of the aspirin dose with outcome. Our results indicate that the individuals bearing AA genotype of ALOX5AP1 SG13S114T/A polymorphism are more prone to stroke and bad outcome as well as with aspirin resistance than TA and TT genotypes.
authors.affiliation: Institute of Genetics and Hospital for Genetic Diseases, Osmania University, Begumpet, Hyderabad-500016, India.
authors.forename: Vandana
authors.initials: V
authors.lastname: Sharma
authors.forename: Sneha
authors.initials: S
authors.lastname: Dadheech
authors.forename: Subhash
authors.initials: S
authors.lastname: Kaul
authors.forename: A
authors.initials: A
authors.lastname: Jyothy
authors.forename: Anjana
authors.initials: A
authors.lastname: Munshi
mesh_terms: D058927:5-Lipoxygenase-Activating Proteins; D000328:Adult; D000368:Aged; D001241:Aspirin / Q000009:adverse effects*; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D005343:Fibrinolytic Agents / Q000009:adverse effects*; D005500:Follow-Up Studies; D005787:Gene Frequency; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D020521:Stroke / Q000145:classification / Q000188:drug therapy / Q000235:genetics
chemical_list: D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; D005343:Fibrinolytic Agents; D001241:Aspirin
keywords: 5-Lipoxygenase activating protein (ALOX5AP); Aspirin non-responders; Aspirin responders; Genetic variants; Ischemic stroke; Leukotrienes