The Study On The Association Of Lp-PLA2 Gene Polymorphism With Coronary Heart Disease And Related Risk Factors

backgroundCoronary heart disease(CHD)has become one of the most common cardiovascular diseases that seriously threaten human health and affect people's quality of life.In Europe,cardiovascular disease resulted in almost 4.1 million deaths,of which more than one third were caused by CHD.Risk factors for coronary heart disease involves smoking,overweight,hypertension,hyperlipidemia,etc.However,only a fraction of individuals with risk factors finally develop CHD,indicating that genetic susceptibility might play an important role in CHD development.The oxidation and inflammation contribute to the formation and development of atherosclerosis.The phospholipids are oxidized by the oxidized lipids(such as fatty acids)in the LDL and the consequent peroxides result in the formation of LDL with a mild modification and initiate a series of procedures to form the early fatty streaks.And the formation and accumulation of lipid peroxide will eventually accelerate the development of atherosclerosis.The high-density lipoprotein is considered to exhibit capability of anti-atherosclerosis,because of its effect of promoting the reverse cholesterol transport as well as its efforts of anti-oxidation and anti-inflammation.Several enzymes included in HDL participate in this function,one of which is lipoprotein-associated phospholipase A2(Lp-PLA2).lipoprotein-associated phospholipase A2(Lp-PLA2)is also known as platelet activating factor-acetylhydrolase(PAF-AH),wich is a subtype of phospholipase superfamily.On one hand,the Lp-PLA2 can hydrolyze the platelet activating factor(PAF)and the oxidized lipid products induced by the oxidation of LDL or oxidative stress,which therefore is considered to have the capability of anti-atherosclerosis.On the other hand,studies have revealed that the Lp-PLA2 may hydrolyze oxidized phospholipids to generate lysophosphatidyl choline(lyso-PC)and free oxidized fatty acids,both of which play a critical role in atherogenesis.It has been reported that genetic factors accounted for approximately 60%of factors influencing activity of plasma Lp-PLA2.Therefore,this study was to study the association between Lp-PLA2 gene polymorphism and CHD in Chinese Han population and the effects of different phenotypes of Lp-PLA2 gene polymorphism on the progression and outcome of coronary heart disease,and to provide a new target for the diagnosis and treatment of CHD.Objective1.The study is designed to investigate the polymorphism of R92H,V279F,I198T,and A379V of Lp-PLA2 in Chinese CAD patients,compared with healthy control;also to compare and analyze the difference of the distribution of genotype and allele between these two populations.2.To analyze the association of the polymorphism of R92H,V279F,I198T,and A379V of Lp-PLA2 with susceptibility to coronary heart disease.Also to identify the role of Lp-PLA2 in CAD progression.Method1.Inclusion criterion was the presence of typical angina pectoris with a diameter stenosis>50%in at least one major coronary artery,or the presence of MI history.Age-matched healthy control without CAD,DM and hyperlipidemia.Demographic features and traditional risk factors of CAD,including age,sex,smoking,family history,past history(with or without HTN,DM or hyperlipidemia)and lipid profile were collected.The result of CAG and the MI history were also collected to evaluate the severity of CAD.2.The venous blood samples were drawn after an overnight fast.3.Genotyping for R92H,V279F,I198T,and A379V polymorphism of Lp-PLAZ were determined for each subject using Taqman.probe allele discrimination method.The frequencies of genotypes and alleles were analyzed and compared between CAD patients and controls.4.The associations of SNPs with phenotypes were analyzed using relevant statistical methods.ResultsFirst stage1.Stratified by Gensini score and clinical types,no significant associations were observed between subgroups and the controls in I198T and V279F genotypes and allele frequencies.2.As for subgroups stratified by numbers of diseased coronary branches,only subjects with one diseased coronary branches carried higher frequencies of genotype IT+TT,VF+FF and F allele as compared to the controls.No associations were observed between patients with multi-vessel lesions and controls in I198T and V279F.3.In the further analysis of risk factors,blood fat levels and proportions of diabetes and hypertension patients in subjects carrying IT+TT and VF+VV genotypes showed no difference with II and VV genotypes.Second stage1.RH+HH genotype,RH genotype,and H allele of R92H were significantly associated with an increased risk of CHD(P = 0.005,P = 0.009,and P = 0.003,respectively),while no associations were observed between V279F and I198T and CHD(A379V was not analyzed because of deviation from Hardy-Weinberg equilibrium).2.Correlations between R92H and CHD still existed after adjustment for confounding risk factors of CHD(P = 0.001).Furthermore,stratified analyses showed subgroups of the senior,hypertension,non-smoking,non-diabetics,and male subjects brought a higher risk for CHD(P = 0.015,P = 0.001,P = 0.001,P = 0.002,and P = 0.004,respectively).3.We also observed a lower level of protective factor HDL-C in CHD patients carrying genotype RH+HH than patients with RR(P = 0.047).4.Furthermore,we conducted haplotype analysis and detected more harmful effects of haplotypes HVI and RVT as compared with other haplotypes(P = 2.538×10-3 and P =0.031).Conclusion:1.No associations existed between I198T and V279F polymorphisms in Lp-PLA2 and CHD.2.These findings indicated that R92H variant in PLA2G7 gene might contribute to CHD susceptibility in a Chinese Han population.(1)The H allele of R92H was significantly associated with an increased risk of CHD.The frequency of individuals carrying genotype of RH in cases was significantly higher than that in CHD-free group.(2)Male patients and patients more than 65 years old gained much higher risk for CHD,In addition,a stronger harmful effect was observed among nonsmokers.Cases with hypertension showed an increased risk for CHD.As for subgroup stratified by diabetics,significant difference only existed in groups without diabetics.(3)Haplotypes HVI and RVT were significantly associated with an increased risk of CHD than others,whereas haplotypes RFT and RVI were significantly associate with a decreased risk of CHD as compared to other haplotypes.