| Background and objectiveNowadays,coronary heart disease has emerged as a major cause of death and disease burden both in China and worldwide.By identifying high-risk groups early through risk assessment and promptly promoting healthy lifestyles or pharmacological interventions are effective means of reducing the morbidity and mortality from coronary heart disease.Both environmental and genetic factors are involved in the development of coronary heart disease.Genome-wide association studies(GWAS)have identified a large number of genetic variants associated with coronary heart disease or its risk factors.Moreover,the integration of these genetic variants into a polygenic risk score(PRS)can facilitate the assessment and classification of coronary heart disease risk among the general population.Currently,there are several coronary heart disease PRS that have been successfully constructed and have demonstrated promising applications for coronary heart disease risk assessment.Nevertheless,the PRS are mainly based on European populations with limited accuracy if applied to non-European populations.Therefore,it is necessary to construct PRS for coronary heart disease in non-European populations.According to American Heart Association(AHA),7 cardiovascular health(CVH)indicators have been proposed to improve cardiovascular health and reduce the burden of cardiovascular disease in the population.However,while these indicators have been proven to reduce the risk of cardiovascular disease,the combination of genetic factors to identify populations more likely to improve the benefits of maintaining favorable CVH has rarely been explored.Hence,this study aims to construct a coronary heart disease PRS applicable to the Chinese population and to evaluate the predictive and stratifying power of the PRS in combination with traditional risk factors in a large prospective cohort.Meanwhile,it explores the benefits of maintaining favorable CVH in the context of different PRS.Subjects and methodsIn this study,PRS was constructed by using a training set(a case-control study consisting of 2055 normal individuals and 2800 patients with coronary heart disease)and validated for evaluation in a prospective cohort containing 41,271 study subjects.All cases in the training set were confirmed by Fuwai Hospital of Chinese Academy of Medical Sciences,and general information such as gender and age were collected.The samples in the control group were from individuals who had no coronary heart disease in the baseline survey and the whole follow-up process randomly selected in the China-PAR study.The training set samples were genotyped by using Multi-Ethnic Genotyping Arrays(MEGA)microarrays.During the validation phase,three sub-cohorts of the Prediction for Atherosclerotic Cardiovascular Disease Risk in China(China-PAR)project were applied.All cohorts had baseline information on demographic information,lifestyle and cardiovascular metabolic indicators collected from study participants based on a uniform questionnaire,laboratory tests and physical examination.This study defined 5 traditional risk factors for coronary heart disease,such as family history of coronary heart disease,high blood pressure,obesity,high total cholesterol and diabetes.In addition,it also defined 7 traditional risk factors for coronary heart disease,which included ideal blood pressure,ideal body mass index(BMI),ideal fasting blood glucose,ideal total cholesterol(TC),ideal smoking status,ideal physical activity,and ideal dietary score.During the follow-up phase,the information on the onset of coronary heart disease was collected by surveying the study subjects themselves or their relatives,which was further verified against case records and death diagnosis certificates for the outcome events.Coronary heart disease was defined as a non-fatal acute myocardial infarction,first occurrence of unstable angina and death due to coronary artery disease.we conducted genotyping of the cohort population by multiplex polymerase chain reaction targeted amplicon sequencing.This study selected 588 previously reported genetic variant loci that reached genomically significant association with coronary heart disease and related phenotypes for PRS construction.Firstly,coronary heart disease and its eight associated phenotypes were selected as subphenotypes for study and GWAS results from East Asian populations were integrated for these subphenotypes.Furthermore,nine candidate PRS were constructed for each subphenotype based on the p-value of the genetic variant effect value.Moreover,the logistic regression model was used to select the optimal score for each subphenotype according to the association size with coronary heart disease in the training set.Lastly,these sub-phenotypic PRS were integrated into a meta-polygenic risk score(metaPRS)by using flexible mesh logistic regression with ten-fold cross-validation.In the validation phase,we fiststy caculated the metaPRS of each sample in the cohort.Subsequently,the cohort population was categorised into three genetic risk groups,low(020%),medium(20-80%)and high(80-100%)based on the level of metaPRS,and into favorable(6-7 ideal indicators),intermediate(4-5 ideal indicators)and unfavorable(0-3 ideal indicators)CVH status based on the number of ideal CVH indicators at baseline.The study used a competing risk model with age as the time scale,adjusting for sex,cohort and the first four principal components to assess:1)The differences in the relative and absolute risk of developing coronary heart disease in different genetic risk groups.2)The stratification effect of combining different genetic backgrounds and traditional risk factors for coronary heart disease on the risk of developing coronary heart disease.3)The relative risk,the lifetime risk at age 80 and the benefit of disease-free years.of maintaining favorable CVH status in different genetic risk backgrounds.ResultsFirstly,subphenotypic PRS were constructed in the training set and integrated to obtain a coronary heart disease metaPRS.A total of 540 genetic variants were included in the final metaPRS for 6 subphenotypic PRS.In regard to the construction scores,we also constructed several coronary heart disease PRS by using European population GWAS effect sizes for comparison-It’s found that the odds ratio(OR)for the association of PRS with coronary heart disease in the training set calculated by European population effect sizes was lower than that calculated based on the East Asian population.As a result,the value of metaPRS in combination with traditional risk factors for predicting and risk stratifying the onset of coronary heart disease was subsequently validated in a prospective cohort.A total of 1303 cases of coronary heart disease occurred in the cohort after an average of 13 years of follow-up.Individual analyses of the metaPRS indicated that each standard deviation(SD)increase in the metaPRS was associated with a 44%increase in the risk of developing coronary heart disease(HR:1.44,95%CI:1.361.52).Both genetic risk and traditional risk factors such as family history of coronary heart disease contributed to the development of coronary heart disease independently of each other.For those who had only a high genetic risk,the lifetime risk of coronary heart disease was 15.9%.For those with both high genetic risk and a family history of coronary heart disease,diabetes,hypertension,obesity,high total cholesterol,and smoking,the lifetime risk of coronary heart disease was 27.7%,23.8%,21.2%,21.1%,20.1%,and 18.1%,respectively.Lastly,the benefit of maintaining favorable CVH status in different genetic backgrounds was evaluated in a prospective cohort.Among the seven indicators of ideal CVH,the most protective effect was seen in maintaining ideal blood pressure,which reduced the risk by 53%(HR 0.47,95%CI:0.40-0.55).After stratification by genetic risk,the protective effect of maintaining ideal blood pressure was higher in the high genetic risk group than in the low genetic risk group,with maintaining ideal blood pressure reducing the relative risk of coronary heart disease by 56%(95%CI:41%-67%)and the lifetime risk by 8%in the high genetic risk group(16.6%in the non-ideal group vs.8.6%in the ideal group).In the low genetic risk group,the relative risk of coronary heart disease was reduced by 32%(95%CI:2%-53%)and the lifetime risk was reduced by 3.3%(6.7%in the non-ideal group vs.3.4%in the ideal group).The P value for the relative risk interaction was 0.030,while the P value for the trend in absolute risk reduction was 0.007.Significantly,maintaining ideal blood pressure in the high genetic risk group reduced the lifetime risk of coronary heart disease in the population to the average of the moderate genetic risk group.Among the low,intermediate and high genetic risk groups,individuals with favorable CVH had a 56%(HR:0.44,95%CI:0.27-0.74),57%(HR:0.43,95%CI:0.33-0.54)and 62%(HR:0.38,95%CI:0.27-0.54)lower risk of developing coronary heart disease compared to unfavorable CVH,respectively.The lifetime risk of coronary heart disease was reduced by 5.1%(8.5%for unfavorable vs.3.4%for favorable),7.9%(13.4%for unfavorable vs.5.5%for favorable)and 12%(20.6%for unfavorable vs.8.6%for favorable),respectively,while the absolute risk benefit was 2.35 times greater in individuals at high genetic risk than in those at low genetic risk,with a trend-tested p-value of 0.009.Eventually,in the analysis of years of delayed onset,we found that individuals with favorable CVH delayed the occurrence of coronary heart disease by 1.0,1.5 and 2.5 years compared to those with unfavorable CVH in the low,intermediate and high genetic risk groups,respectively,at 35 years old.ConclusionOverall,this study established a metaPRS for Chinese populations that can effectively stratify the risk of developing coronary heart disease by integrating traditional risk factors,while screening the population with the greatest benefit from maintaining favorable CVH by this metaPRS.While maintaining favorable CVH has similar relative risk reductions for coronary heart disease across genetic risk groups,individuals with high genetic risk have a greater lifetime risk reduction from maintaining favorable CVH.However,the use of genetic risk information to screen individuals at high risk of coronary heart disease and to guide primary prevention of coronary heart disease in clinical practice requires further validation. |
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