| ObjectiveCoronary atherosclerosis is a complex disease influenced by various factors.Population with dyslipidemia are at higher risk for atherosclerosis.The major objective of this study was to select susceptible SNPs and investigate the combination effect of gene-environment interaction on coronary atherosclerosis in Chinese Han population with dyslipidemia.Genetic Risk Score was applied to explore the effect of cumulative genetic risk,aimed to help early screening for susceptible population and provide evidences for the precise health management of high-risk groups.MethodsBased on the community population in Ningbo.Zhejiang.China,we conducted a1 to 3 matched nested case-control study to explore the possible comprehensive factors of coronary atherosclerosis.Excluding those with severe liver disease and cancer,a total of 2349 subjects were recruited in our study,of which 1359 were patients with dyslipidemia.After a three-year-follow-up,166 subjects with dyslipidemia were diagnosed as coronary atherosclerosis,which were selected as cases.For each case,three subjects with dyslipidemia were chosen as controls,matched by age and gender.General characteristics such as smoking status,alcohol consumption,physical activity were collected by questionnaires.Height,weight,blood pressure and lipid levels were retrieved from clinical data.103 SNPs from candidate genes were measured by ligase detection reaction.Based on the research before,rs2479409(PCSK9),rs17321515(near TRIB1),rs2954029(near TRIB1),rs4743763(ABCA1),rs671(ALDH2),rs12934922(BCMO1),rs3764261(CETP)and rs16996148(CILP2)were chosen for further exploration.Epidata 3.1 software was used for data input,SPSS 23.0,Plink 1.07,GPlink 2.0and GMDR 0.9 software were performed for data analysis.Chi-square test and independent t test were applied to compare the differences between cases and controls;Logistic regression was utilized to evaluate the association between gene-disease and behavior-disease;the interactions of gene-gene and gene-environment were workedout by General Multifactor Dimensionality Reduction(GMDR)and crossover analysis.Genetic risk score was estimated by simple risk allele counts GRS(cGRS).P<0.05 was regarded as statistical significance for all the results.Results1.Association between genetic factors and coronary atherosclerosis: Logistic regression showed that the PCSK9 loci rs2479409-A was a risk factor for coronary atherosclerosis(OR=1.368,95%CI:1.038~1.803;P=0.026),individuals with AA or AG genotype were found at a higher risk for disease compared with GG(OR=1.529,95% CI: 1.055~2.216;P=0.025).Near TRIB1 gene rs17321515-G was the risk allele(OR=1.378,95%CI:1.064~1.785;P=0.015),the risk of GG carriers was higher than that of AA or AG(OR=1.556,95%CI:1.068~2.268;P=0.021).Near TRIB1 gene rs2954029-T was the risk allele(OR=1.387,95%CI:1.072~1.795;P=0.013),The risk of TT carriers was significantly higher than that of AT or AA carriers(OR=1.572,95%CI:1.080~2.288;P=0.018).ABCA1 rs4743763-T was the risk allele(OR=1.461,95%CI:1.025~2.083;P=0.036),TT carriers were found to be more susceptible for coronary atherosclerosis(OR=1.504,95%CI:1.009~2.241;P=0.045).ALDH2 loci rs671-A was a risk factor for coronary atherosclerosis(OR=1.492,95%CI:1.127~1.975;P=0.005),AA or AG carriers had a higher risk for disease(OR=1.514,95%CI:1.057~2.167;P=0.024),what's more,AA homozygous were thought to be more susceptible than AG or GG carriers(OR=2.143,95%CI:1:1.144~4.018;P=0.017).BCMO1 rs12934922-A was the risk allele(OR=1.592,95%CI:1.046~2.421;P=0.030),AA genotype carriers had 68.3% higher risk than those of AT / TT(OR=1.683,95%CI:1.061~2.670;P=0.027).2.Association between behaviors and coronary atherosclerosis: Logistic regression showed that after adjusted for blood pressure,BMI(Body Mass Index)and education,fried intake(OR=1.637,95%CI: 1.127~2.378;P=0.010)and sweet intake(OR=1.733,95%CI: 1.158~2.595;P=0.008)seemed to be risk factors for coronary atherosclerosis;moderate-to-high intensity physical activity would lead to a reduction of coronary atherosclerosis risk(OR=0.511,95%CI: 0.309~0.846;P=0.009).3.Association of gene-environment interaction with the risk of coronary atherosclerosis: BCMO1 gene loci rs12934922 had interactions with physical activity,fried intake and sweet intake.AA genotype and sedentary or light-intensity physical activity(combined OR=8.822,95%CI: 1.169~66.551;P=0.035),fried intake(combined OR=2.946,95%CI: 1.169~66.551,P=0.007)and sweet intake(Combined OR=3.954,95%CI: 1.525~10.251,P=0.005)had combined effects towards the increasing risk of coronary atherosclerosis;ALDH2 gene loci rs671 with physical activity,fried intake and dessert intake had interaction effect.AA or AG genotype and sedentary or light-physical activity(combined OR=2.237,95%CI: 1.137~4.400;P =0.02),fried intake(combined OR = 2.026,95%CI: 1.206~3.405;P=0.008)and sweet intake(combined OR=2.888,95%CI: 1.557~5.356;P=0.001)had combined effects influencing the risk of coronary atherosclerosis.4.GRS for coronary atherosclerosis: rs2479409(PCSK9),rs17321515(TRIB1),rs2954029(TRIB1),rs4743763(ABCA1),rs671(ALDH2)and rs12934922(BCMO1)six associated SNPs were included in the GRS estimate,the results explained that for those with dyslipidemia,the selected SNPs accounted for 30.08% of the coronary atherosclerosis causes.We performed two kinds of GRS to estimate the relationship between GRS score and coronary atherosclerosis.In the three-stage classified GRS,compared with the reference group(GRS=0~5),the risk of coronary atherosclerosis increased to 2.933 times in the group scored 6~9(95%CI:1.756~4.898;P<0.001)and4.74 times in the group scored 10~12(95%CI:2.253~9.974: P<0.001);in the continuous GRS,the risk of coronary atherosclerosis was increased by 27.9%(OR=1.279,95% CI: 1.154~1.418,P <0.001)for each additional GRS point.It positively implied that there might be a dose-response relationship between GRS score and the risk of coronary atherosclerosis.Conclusion1.In patients with dyslipidemia,SNPs rs2479409(PCSK9)?rs17321515(near TRIB1)?rs2954029(near TRIB1)?rs4743763(ABCA1)?rs671(ALDH2)and rs12934922(BCMO1)are associated with the susceptibility of coronaryatherosclerosis;rs671(ALDH2)and rs12934922(BCMO1)have interaction with physical activity,fried intake and sweet intake,which may have a combined effect on the risk of coronary atherosclerosis.2.There may have a dose-response relationship between GRS and the risk of coronary atherosclerosis,individual with more risk alleles seems to suffer higher susceptibility of coronary atherosclerosis.3.Precision health management should be actively carried out for the purpose of preventing cardiovascular events.With the development of genetic testing and big data analysis technology,assessment for disease susceptibility could be more comprehensive and accurate.For the high risk group,personalized health management guidance should be performed,so as to realize the goal of health on holistic and full range of medical services. |
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