Association Of SAA, Tanis, And CYP2C19Genetic Polymorphisms With Pathogenesis, Prognosis And Personalized Therapy Of Coronary Artery Disease

Objective:1) To explore the associations of genetic polymorphisms of SAA and itsreceptor Tanis which both involved in inflammation and lipid metabolism with coronaryheart disease and its risk factors in different ethnic groups in Xinjiang;2) to investigatethe relationship between cytochrome P4502C19loss-of-function alleles and prognosis ofcoronary artery disease after PCI;3) to explore the personalized antiplatelet therapyaccording to CYP2C19genotype in patients with coronary artery disease and itspromotional value. Methods:1) A case-control study including2004cases with coronaryheart disease confirmed by coronary angiography and1902gender-, age-, andethnic-matched normal healthy controls was desighed for the present study. Usingrestriction fragment length polymorphism and real-time PCR methods, we genotyped8SNPs in the SAA and Tanis genes and analyzed the relationship between these SNPs andcoronary artery disease and its risk factors (including HDL, uric acid and blood glucoselevels);2) A cohort study was designed to observe the relationship between geneticpolymorphisms of SAA, Tanis, and CYP2C19and prognosis of1068patients withcoronary artery disease after percutaneous coronary stent implantation (PCI), thegenotypes were detected by RFLP methods. All these1068patients were fellow-up forone year, we observed the differces in stent thrombosis, nonfatal myocardial infarction,total mortality and bleeding events among three genetypes in SAA, Tanis and CYP2C19gene, respectively;3) A single-center randomized-controlled including301patients withcoronary heart disease after PCI was designed to assess the safety and effective ofindividual theray according to CYP2C29genoty. These301patients were randomlydivided into the personalized treatment group (n=151) and conventional therapy group(n=150). In the personalized group, the CYP2C19genotype was detected by use of rapidtest kit before treatment with antiplatelet angent. The patients with extensive metabolizer(EMs) were given clopidogrel50mg·qd plus aspirin100mg·qd; the patients withintermediate metabolizer (IMs) were given clopidogrel75mg·qd plus aspirin100mg·qd; the patients with poor metabolizer (PMs) treated with clopidogrel75mg·qd and aspirin100mg·qd plus Cilostazol100mg twice daily. The conventional treatment group were notdetected the CYP2C19genotype and were given dual antiplatelet therapy (clopidogrel75mg·qd and aspirin100mg·qd). The differences in stent thrombosis, nonfatal myocardialinfarction, total mortality and bleeding events between these two groups were observed30days and180days after PCI. Results:1) rs12218in the SAA gene and rs1384656inthe Tanis gene was associated with coronary artery disease in both Han ethnic and Uygurethnic in Xinjiang. Rs12218CC genotypes and rs1384656CC genotype significantlyincreased the risk of coronary heart disease, after adjustment for other factors, rs12218and rs1384656gene polymorphism was still independent risk factors for coronary heartdisease; rs12218gene polymorphism significantly affected plasma GLU, HDL-C, andSAA levels, and rs1384656significantly affect plasma GLU and triglyceride levels inhealthy people;2) the frequencie of CYP2C19loss-of-function allele was high up to57.5%in Chinese coronary heart disease population; CYP2C19poor metabolizerssignificantly increased risk of cardiovascular adverse events. By COX multivariateregression analysis showed that after adjusting for other factors CYP2C19poormetabolizer phenotype is an independent risk factor of cardiovascular adverse events incoronary heart disease patients after PCI; no association of SAA and its receptor Tanisgene polymorphism with adverse prognosis of coronary heart disease after PCI;3) After30-day follow-up, the CYP2C19genotype-based personalized group have lower totalmortality (P=0.043) compare to that in the conventional group. There were significantdifference in incidence of stent thrombosis, myocardial infarction, and bleeding eventsbetween these two groups (all P＞0.05); after180-days follow-up, there were notsignificant difference in incidence of stent thrombosis, myocardial infarction betweenthese two groups (all P＞0.05), but the incidence of overall MACE events, bleedingevents and death in the personalized group was lower than those in conventional group (P＜0.05). Conclusion:1) genetic polymorphisms of SAA and Tanis were associated withcoronary heart disease in both Uygur and Han ethnic, which maybe result from alterationof plasma GLU, triglyceride and SAA levels with genetic mutation in SAA and Tanis;2)There were no associations between genetic polymorphisms of SAA and Tanis and adversprognosis of coronary artery disease after PCI;3) The carriers with CYP2C19loss-of-function alleles have higher risk of stent thrombosis, death, and myocardialinfarction;4) CYP2C19genotype-based individualization of antiplatelet therapy cansignificantly improve the clinical outcome after PCI in patients with coronary artery disease.