Investigation Of Carotid Atherosclerostic Plaque And The Role Of Inflammation And Endothelial Function-related Genetic Polymorphisms In The Pathogenesis Of Carotid Atherosclerostic Plaque In The High Risk Stroke Population

Objective: The aim of this study was to investigate the prevalence of carotid atherosclerostic plaque,and evaluate the association of carotid plaque with variants in genes involved in inflammation and endothelial function in the high risk stroke population.Methods: Three base hospitals for stroke screening survey(The People’s Hospital of Deyang City,The Affiliated Hospital of Southwest Medical University,and The Suining Central Hospital)were randomly selected from the nine base hospitals for stroke screening survey in Sichuan Province have.Then,the eight communities were selected among the districts of the three hospitals using a cluster random sampling method.The residents aged≥40 years and lived in the community for more than six months were initially screened using a structured face-to-face questionnaire of chinese stroke high risk population screening scale by interviewers,and the high risk stroke population were screened out.Carotid plaque and plaque phenotype were assessed by carotid ultrasound in the high risk stroke population.The single nucleotide polymorphisms(SNPs)of 19 variants in 10 genes related to inflammation and endothelial function were examined using matrix-assisted laser desorption/ionization time flight mass spectrometry(MALDI-TOF MS).Gene-gene interaction among the 19 variants was analyzed by generalized multifactor dimensionality reduction(GMDR).Results: 1.Among the 2377 high stroke risk population,852(35.8%)had carotid plaque,454(53.3%)had stable plaque,398(46.7%)had vulnerable plaque.Compared with individuals with no plaque,age was older,male,current smoking,hypertension and taking antihypertensive drugs were significantly more frequent,and levels of total cholesterol,triglyceride,fasting blood glucose,homocysteine were higher in individuals with plaque.2.Univariate analysis shows that there were the statistical significances of genotype distributions for the IL1 A rs1609682,HABP2 rs7923349 and PPARA rs4253655 between high stroke risk population with and without carotid plaque,for PPARA rs4253655 and NOS2A rs2297518 between high stroke risk population with vulnerable plaque and without carotid plaque,for IL1 A rs1609682 and HABP2rs7923349 between high stroke risk population with carotid plaque and healthy controls.However,there were no significant differences of genotype distributions in the19 SNPs between high stroke risk population with stable plaque and vulnerable plaque,or high stroke risk population with stable plaque and without plaque.3.GMDR analysis found that there was an significant interaction among the 19 SNPs,and the best interactive model for carotid vulnerable plaque was interaction among ITGA2 rs1991013、HABP2 rs7923349、NOS2A rs8081248 and IL1A rs1609682,which cross-validation consistency was 10 /10 and sign test was 9(P = 0.017).4.We assessed the association between different genotype combinations of the 4 variants and risk of carotid vulnerable plaque.Compared to the individuals carrying wild-type genotypes rs1609682 GG、rs7923349 GG、rs1991013 GG,and rs8081248 GG,the relative risk of different genotype combinations among the 4 variants for vulnerable plaque was investigated.The results revealed that 4 genotype combinations making larger contributions to carotid vulnerable plaque were those individuals carrying rs1609682 TT,rs7923349 TT,rs1991013 GA and rs8081248 GA(OR=2.02,95% CI 1.12～4.33,P=0.008);rs1991013 AA,rs1609682 TT,rs7923349 TT and rs8081248 AA(OR=2.83,95% CI 1.26～5.38,P=0.005);rs1609682 GT,rs7923349 GT,rs1991013 GA and rs8081248 GA(OR=1.85,95% CI1.03～2.98,P=0.038);rs1609682 GT,rs7923349 GT,rs1991013 AA and rs8081248 AA(OR=1.93,95% CI 1.07～3.84,P=0.028).The aforementioned four genotype combinations were defined as the high-risk interactive genotype.The other genotype combinations of the 4 variants did not reach statistical significance(P > 0.05),and were defined as the low-risk interactive genotype.5.After adjusting the covariates,multivariate Logistic regression showed that the high-risk interactive genotype among rs1609682,rs7923349,rs1991013,and rs8081248 was independently associated with a higher risk for carotid vulnerable plaque(OR=2.81,95% CI 1.32～7.49,P=0.005).Conclusion: 1.In this study,we found that the prevalence of carotid plaque was very high in the high stroke risk population.2.Specific SNPs of 19 variants in 10 genes involved in endothelial function and inflammation were associated with carotid plaque and carotid vulnerable plaque in high stroke risk population.3.There was an significant interaction among the 19 SNPs,and the high-risk interactive genotype among the 4 variants contributed to a higher risk for carotid vulnerable plaque.4.Multivariate Logistic regression showed that the high-risk interactive genotype among the 4 variants was independently associated with a higher risk for carotid vulnerable plaque.