| Background and objectiveCoronary artery disease(CAD),a complex disease driven by both genetic and lifestyle determinants,remains the leading cause of mortality worldwide.Hypercholesterolemia is an independent risk factor for CAD.Eggs are loaded with abundant cholesterol in the yolks,which were reported to elevate serum cholesterol concentrations,increase oxidation susceptibility of low-density lipoprotein(LDL),and enhance the adverse effects of saturated fatty acids.Meanwhile,antioxidant carotenoids and phospholipids contained in the eggs can reduce LDL oxidation and regulate cholesterol absorption,and antihypertensive peptides derived from egg proteins can inhibit angiotensin-converting enzyme activity and stimulate the release of nitric oxide and prostacyclin.Therefore,the association of egg consumption with CAD has long been a topic of intense debate.Several meta-analyses of prospective cohort studies,largely conducted in European and North American countries,reported no significant association between a moderate level of egg consumption(up to 1 egg per day)and risk of the incident CAD.However,due to a relatively lower intake of eggs among the study population,current evidence on the potential adverse effect of higher egg consumption is still insufficient.Lower proportion of dietary cholesterol from eggs and higher percentage energy from saturated fatty acids in the western diet also limited the generalization of the above-mentioned evidence among the Chinese population.Moreover,most previous studies have taken only a one-time measurement on diet and thus have been unable to evaluate changes in egg consumption and subsequent CAD risk.On the other hand,findings from laboratory and clinical trials have suggested that the association of egg intake with serum cholesterol and CAD risk may be modified by genetic susceptibility,while to our knowledge,there is still no evidence from cohort study up to now.Therefore,we conducted this prospective cohort study among Chinese adults to explore the association of egg consumption with incident CAD,especially focusing on the potential effects at a higher level of intake.We further examined the effect of changes in egg consumption from baseline till the first follow-up on the subsequent risk of incident CAD,which has scarcely been studied before.In addition,we investigated the interaction and joint effects of egg consumption with genetic predisposition on incident CAD,as evaluated by the first Chinese CAD meta polygenic risk score(CAD metaPRS).Subjects and methodsThe present study consists of three sub-cohorts with dietary information from the project of Prediction for Atherosclerotic Cardiovascular Disease Risk in China,i.e.,the China Multi-Center Collaborative Study of Cardiovascular Epidemiology 1998(ChinaMUCA 1998),the International Collaborative Study of Cardiovascular Disease in Asia(InterASIA)and the Community Intervention of Metabolic Syndrome in China&Chinese Family Health Study(CIMIC).Baseline surveys for the ChinaMUCA 1998 and the InterASIA were conducted in 1998 and 2000-2001,respectively.The CIMIC was initiated in 2007-2008,during which the above-mentioned two sub-cohorts had their first follow-up.Then,all the three sub-cohorts were followed up twice during 2012-2015 and 2018-2021,with unified protocols and questionnaires.During baseline and follow-up surveys,standardized questionnaires and physical examination were utilized to collect information on demographic characteristics and major risk factors for cardiovascular disease.Fasting peripheral blood samples were collected for laboratory testing and genotyping.Information on diseases and vital status was updated by interviewing participants or their proxies through active follow-up visits and validated with hospital records and death certificates.The incident CAD in our study was defined as a confirmed diagnosis of nonfatal acute myocardial infarction or unstable angina,or mortality from CAD.With time-on-study as timescale,person-years of followup was calculated from the completion of the baseline or the first follow-up survey(for the analysis of changes in egg consumption)till the incidence of CAD,death or last follow-up interview,whichever came first.Retrospective dietary surveys were carried out to investigate the average frequency and quantity of eggs consumed in the last year.For the analysis of associations between egg consumption and incident CAD,participants were classified into five categories according to baseline dietary survey(<1 egg per week,1-<3 eggs per week,3-<6 eggs per week,6-<10 eggs per week,and≥10 eggs per week).To further investigate the effect of maintaining or changing egg consumption on subsequent CAD risk,we classified participants into four groups according to egg consumption at both baseline and the first follow-up survey(maintaining<6 eggs per week,increasing from<6 eggs per week to≥6 eggs per week,decreasing from≥6 eggs per week to<6 eggs per week,and maintaining≥6 eggs per week).In addition,to evaluate the interaction and joint effects of egg consumption with genetic predisposition on incident CAD,participants were firstly stratified by genetic risk,which was assessed with the first Chinese CAD metaPRS(low genetic risk,1st quintile;intermediate genetic risk,2nd-4th quintile;high genetic risk,5th quintile).In each risk strata,we classified individuals into three groups according to baseline egg consumption(<6 eggs per week,6-<10 eggs per week,and>10 eggs per week).Then,participants were further divided into nine groups in the analysis of joint effects according to genetic risk and egg consumption.The cohort-stratified Cox proportional hazard regression model was adopted to estimate the hazard ratios(HRs)and 95%confidence intervals(CIs).Analyses were performed with primary adjustment for age and sex(Model 1),and further adjustment for region,urban or rural resident,per capita household income,education attainment,family history of CAD,smoking,alcohol consumption and physical activity(Model 2),and further adjustment for body mass index(BMI),hypertension,diabetes and hypercholesterolemia(Model 3).We also obtained the adjusted 10-year cumulative incidence of CAD based on Model 3,which was standardized to the average of covariates among the entire study population.The floating absolute risk(FAR)was used to facilitate comparisons across different groups.Restricted cubic splines(RCS)were used to explore the dose-response relationship of egg consumption or metaPRS with incident CAD.Interaction on the multiplicative scale was detected by introducing a cross-product term in the multivariate-adjusted Cox model.Interaction on the additive scale,on the other hand,was quantified with the relative excess risk due to interaction(RERI),the proportion attributable to interaction(AP),and the synergy index(SI).Subgroup analyses were conducted by basic characteristics of participants.To examine the robustness of our results,we performed several sensitivity analyses,mainly including 1)Carrying out analyses in each sub-cohort separately and combing the effects with meta-analyses;2)Adopting Cox proportional hazards models with time-varying covariates,incorporating egg consumptions updated in each follow-up survey;3)Calculating sub-distribution hazard ratios with the Fine-Gray model;4)Treating the 2007-2008 survey as baseline for all three sub-cohorts;5)Excluding incident CAD identified during the first year of follow-up;6)Excluding subjects who took lipidlowering drugs;7)Further adjusting consumptions of red meat,vegetables and fruits.A two-tailed P value of<0.05 was regarded as statistically significant.ResultsFor the analyses between egg consumption and incident CAD,a total of 105,822 participants without history of CAD and other severe chronic diseases at baseline were included.During a mean follow-up of 11.9 years,2,989 cases of incident CAD were documented.The multivariate-adjusted HRs(95%CI)of CAD were 0.98(0.85 to 1.12)for 1-<3 eggs per week,0.93(0.81 to 1.06)for 3-<6 eggs per week,1.15(1.00 to 1.31)for 6-<10 eggs per week,and 1.40(1.23 to 1.60)for≥10 eggs per week,in comparison with consumption of<1 egg per week.Moreover,the RCS curves indicated a nonlinear relationship between egg consumption and incident CAD.Under a moderate level of intake(<6 eggs per week),no significant association was found between egg consumption and incident CAD;while consumption of≥ 6 eggs per week was found to be associated with an elevated risk of CAD in a dose-response manner.To assess the association of changes in egg consumption with subsequent risk of CAD,we included a total of 78,354 participants without history of CAD and other severe chronic diseases during the first follow-up.1,546 cases of incident CAD were documented during a mean follow-up of 6.1 years.Relative to those maintaining consumption of<6 eggs per week(HR,1.00;95%CI,0.90 to 1.11),individuals with increasing consumption from<6 eggs per week to≥6 eggs per week,with decreasing consumption from≥6 eggs per week to<6 eggs per week,and with consistent consumption of ≥6 eggs per week had 17%(HR,1.17;95%CI,1.05 to 1.30),31%(HR,1.31;95%CI,1.18 to 1.47)and 34%(HR,1.34;95%CI,1.20 to 1.50)higher risk for incident CAD,respectively(Model 3,95%CI calculated with FAR method).Moreover,to evaluate the interaction and joint effects of egg consumption with genetic predisposition on incident CAD,39,705 participants with genotyping data and free from CAD as well as other severe chronic diseases at baseline were included.During a mean follow-up of 13 years,1,310 cases of incident CAD were recorded.Both metaPRS(P for trend<0.001)and egg consumption(P for trend=0.001)were found to be positively associated with risks of CAD.When stratifying by genetic predisposition,we found a more significant association between egg consumption and incident CAD among those with high genetic risk.Specifically,among individuals with low genetic risk,the multivariateadjusted HRs(95%CI)of CAD were 1.11(0.75 to 1.64)for 6-<10 eggs per week and 1.21(0.72 to 2.03)for ≥10 eggs per week,in comparison with consumption of<6 eggs per week.The corresponding HRs(95%CI)were 1.11(0.92 to 1.34)and 1.17(0.94 to 1.45)among those with intermediate genetic risk,and 1.21(0.94 to 1.55)and 1.53(1.18 to 1.99)among those with high genetic risk,respectively.The joint effect analysis showed that,in comparison with individuals at low genetic risk with consumption of<6 eggs per week(HR,1.00;95%CI,0.82 to 1.22;adjusted 10-year cumulative CAD rates,1.06±0.11%),the multivariate-adjusted HR(95%CI)was 1.14(0.82 to 1.59)for those at low genetic risk with consumption of 6-<10 eggs per week,0.92(0.60 to 1.41)for those at low genetic risk with consumption of≥10 eggs per week,1.35(1.22 to 1.49)for those at intermediate genetic risk with consumption of<6 eggs per week,1.49(1.27 to 1.75)for those at intermediate genetic risk with consumption of 6-<10 eggs per week,1.54(1.28 to 1.85)for those at intermediate genetic risk with consumption of≥10 eggs per week,2.06(1.80 to 2.36)for those at high genetic risk with consumption of<6 eggs per week,2.48(2.01 to 3.06)for those at high genetic risk with consumption of 6-<10 eggs per week,and 3.55(2.90 to 4.33)for those at high genetic risk with consumption of≥10 eggs per week.The adjusted 10-year cumulative CAD rates,accordingly,were 1.21±0.21%,0.98±0.22%,1.44 ± 0.08%,1.59±0.14%,1.65±0.16%,2.19±0.17%,2.63±0.30%and 3,84±0.41%,respectively.No cross-overs in both HR(95%CI)and adjusted 10-year cumulative CAD rates were found across different genetic risk groups.In addition,we found a significant interaction between genetic risk and egg consumption,either on the multiplicative scale(P=0.04)or the additive scale(RERI,0.59;95%CI,0.17 to 1.01).For those at high genetic risk with consumption of≥10 eggs per week,about 25%(AP,0.25;95%CI,0.10 to 0.41)of the elevated risk could be attributed to the joint effect.The subgroup analyses indicated that the association was not modified by basic characteristics(including age,sex,cardiometabolic health status,and dietary factors)of participants and was consistent across each sub-cohort.All the sensitivity analyses did not considerably alter the significant associations observed in the primary analyses.ConclusionOur findings indicated a J-shaped relationship between egg consumption and incident CAD in a large Chinese cohort population.No significant association was found between egg consumption and incident CAD at a moderate level of intake(about<6 eggs per week);while the increase of egg consumption was positively associated with risks of CAD among individuals with consumption of≥6 eggs per week.Maintaining consumption of≥6 eggs per week was even associated with a greater risk of incident CAD,while it might be modestly attenuated by reducing intakes to<6 eggs per week.In addition,we found a significant interaction between genetic risk and egg consumption on the incidence of CAD.Despite the fact that effects of egg consumption might not completely offset risks decided by the genetic predisposition,individuals at high genetic risk were still expected to gain more cardiovascular health benefits from maintaining consumption of<6 eggs per week compared with those at low or intermediate genetic risk. |
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