| Background and aimsCoronary artery disease(CAD)is the leading cause of disease burden and death worldwide.Low-density lipoprotein cholesterol(LDL-C)is an important risk factor for it,and lowering LDL-C levels can significantly reduce the risk of CAD.Previous studies have found that the clinical benefit of lipid-lowering therapy is that the lower LDL-C,and even the very low level of LDL-C(30 mg/dL)compared with the moderate level of LDL-C(100 mg/dL),can still further reduce the risk of cardiovascular disease.However,it remains unclear to what extent LDL-C can be lowered with respect to cardiovascular benefit.Cholesterol is an important component of the cell membrane,and the side effect of low LDL-C levels is worrisome.Assessment of non-linear relationships between LDLC levels and outcomes could indicate the optimal LDL-C level with respect to cardiovascular benefit and could evaluate the associations of low LDL-C levels with side effects.Therefore,based on two large prospective cohort studies,The Prediction for Atherosclerotic cardiovascular disease Risk in China(China-PAR)and UK Biobank,we performed linear and non-linear Mendelian randomization analyses to evaluate the causal relation between genetically predicted LDL-C levels and cardiovascular and other chronic diseases,providing evidence for the prevention of cardiovascular disease and lipid management.Subjects and MethodsStudy Subjects:The subjects were from the China-PAR project and the UK Biobank.The China-PAR project is a prospective cohort study based on the Chinese population with 113448 participants,including three sub-cohorts:the China Cardiovascular Epidemiology Multi-Center Collaborative Study-1998(ChinaMUCA-1998),the China Cardiovascular Health Multi-Center Collaborative Study(InterASIA),and the China Metabolic Syndrome Community Intervention Study(CIMIC).A total of 41271 subjects were included in the analysis through sub-cohort random sampling.The UK Biobank is a large prospective study based on the UK population.It recruited approximately 500,000 participants at 22 assessment centers in the United Kingdom from 2006 to 2010.All participants completed a series of physical assessments and questionnaires,and blood was collected at baseline for biochemical analysis and genotyping.We restricted the analyses to unrelated participants,who were identified as white British based on selfreport and genetic profiling,and excluded participants with mismatched information between self-reported and genetic sex.Finally,a total of 353,232 participants were included in the analyses.Exposure and Outcomes:We assessed the genetic effect of LDL-C on efficacy and safety outcomes.Specifically,efficacy outcomes included CAD,ischemic stroke,and allcause mortality.Safety outcomes included hemorrhagic stroke,diabetes,overall cancer,non-cardiovascular death,and dementia.In the China-PAR cohort,a uniform survey protocol was used to collect baseline information on participants,including demographic,lifestyle,and personal disease history information,and blood was drawn for biochemical genetic testing.LDL-C levels were estimated by the Friedewald formula.The follow-up information was determined by face-to-face investigation of the subjects themselves and/or their relatives,and case or death registration was obtained through community health service centers,hospitals,population registration,and other means.The follow-up information was finally reviewed by the endpoint evaluation committee.Dementia was defined as prevalence and death,and the remaining outcomes were defined as incidence and death.In the UK Biobank,demographic characteristics,risk factors,and other information were investigated mainly through a self-completed touch-screen questionnaire,a brief computer-assisted interview,physical and functional measures,and the collection of blood.LDL-C levels were determined by a biochemical assay.Outcome information was determined primarily through baseline self-reporting and routinely available national datasets,including death registry data,cancer registry data,hospital inpatient and outpatient data,and primary care.All outcomes were defined as prevalence and death.The construction of genetic risk score:In the China-PAR project,we genotyped 57 single-nucleotide polymorphisms(SNPs)that were of genome-wide significance in association with LDL-C based on previous genome-wide association study(GWAS)in East Asians.We then excluded 19 pleiotropic variants associated with high-density lipoprotein cholesterol(HDL-C)or triglycerides(TG).This process resulted in 38 SNPs being selected for inclusion in the LDL-C PRS instrument.In the UK Biobank,based on the summary statistic of the GWAS of LDL-C in individuals of European ancestry,we selected independent SNPs that passed the genome-wide significance threshold for association with LDL-C.We then excluded pleiotropic variants that were associated with high-density lipoprotein cholesterol(HDL-C)or triglycerides(TG).This process resulted in 57 SNPs being selected for inclusion in the LDL-C PRS instrument in the UK Biobank.Statistical analyses:The statistical analyses were divided into three parts.First,we estimated the linear causal effect between genetically predicted LDL-C levels and outcomes based on the two-stage MR method.Second,we used the non-linear MR method to explore the shape of the causal association between LDL-C and outcomes.Third,the participants were divided into four groups based on LDL-C residual levels with reference to the target values recommended by the guidelines for lipid management(<70 mg/dL,70-100 mg/dL,100-116 mg/dL,≥116 mg/dL)to estimate the causal associations with outcomes under different groups.ResultsCharacteristics of study subjects:A total of 41,271 participants from the China-PAR project and 353,232 participants from the UK Biobank were included in this study.Compared with the UK Biobank,participants in the China-PAR project were younger(mean age 52.3 years vs.56.8 years)and had lower mean LDL-C levels(100.21 mg/dL vs.139.95 mg/dL),with minimum LDL-C levels in the China-PAR and UK Biobank of 20.3 mg/dL and 50.4 mg/dL,respectively.The LDL-C level in the Chinese population was significantly lower than that in the British population.During a mean follow-up of 13.0 years,there were 1303 incident CAD events,2908 ischemic strokes,6215 all-cause deaths,977 hemorrhagic strokes,and 4677 incidences of diabetes in the China-PAR cohort.After a maximum follow-up of 15.5 years in the UK Biobank,37,422 individuals were diagnosed with CAD,6540 with ischemic stroke,23,387 with all-cause death,2887 with hemorrhagic stroke,and 16,833 with diabetes.Linear MR analyses:The results showed a significant causal association between LDL-C level and CAD risk,with each 38.6 mg/dL(1 mmol/L)increase in genetically predicted LDL-C level associated with a 106%increase in CAD risk in the Chinese population(OR,2.06[95%CI,1.20-3.53];P=0.01)and increasing the risk of CAD by 75%in the British population(OR,1.75[95%CI,1.58-1.94];P=7.57×10-52).LDL-C level was positively associated with the risk of ischemic stroke[OR(95%CI),China-PAR:1.10(0.75,1.61);UK Biobank:1.39(1.10,1.76)]and all-cause mortality[OR(95%CI),China-PAR:1.34(1.01,1.77);UK Biobank:1.13(0.99,1.28)]in the Chinese and British.In the safety outcomes,LDL-C level was inversely associated with the risk of diabetes,with an OR(95%CI)of 0.82(0.61,1.11)in the Chinese and 0.85(0.74,0.99)in the British,respectively.However,the associations between LDL-C and other safety outcomes were not significant.Non-linear MR analyses:There were no non-linear causal associations between genetically predicted LDL-C level and outcomes in either the Chinese or the British population(non-linear tests for all outcomes:Cochran Q test P>0.25,quadratic test P>0.04).A linear causal relationship between LDL-C levels and CAD risk was found in both Chinese and British populations.Association of LDL-C groups with outcomes:According to guideline-recommended lipid-lowering targets,the population was divided into four groups based on LDL-C residual levels(<70 mg/dL,70-100 mg/dL,100-116 mg/dL and≥116 mg/dL).In the Chinese population,the mean LDL-C levels in the four groups were 50.49 mg/dL,85.08 mg/dL,108.36 mg/dL and 133.03 mg/dL,respectively.In the British population,the mean LDL-C levels were 57.61 mg/dL,84.01 mg/dL,107.77 mg/dL,and 153.38 mg/dL,respectively.Stratified analyses of LDL-C levels showed that in the low-level LDL-C group(<70 mg/dL)in the UK population,lower LDL-C levels were significantly associated with increased risk of hemorrhagic stroke and dementia,with OR(95%CI)of 0.72(0.54,0.96)and 0.75(0.59,0.97),respectively.The associations of LDL-C levels with other efficacy and safety outcomes were not significant in the group with low LDL-C levels.Compared with the high LDL-C level group(≥116 mg/dL),the risk of all-cause mortality was lower in the low LDL-C level group(<70 mg/dL)in the Chinese population(OR,0.46[95%CI,0.22-0.96]).In the British population,the low-LDL-C group had lower CAD risk(OR,0.25[95%CI,0.13-0.47])and higher diabetes risk(OR,3.54[95%CI,2.11-6.26]).There were no significant differences between the results of the primary analyses and the sensitivity analyses.ConclusionIn this study,a linear causal association between genetically predicted LDL-C level and CAD risk was found in both Chinese and British populations.In addition,lower LDL-C was significantly associated with a reduced risk of all-cause mortality in the Chinese population.In the U.K.population,lower LDL-C levels were significantly associated with a higher risk for adverse events.This study suggests that in both the Chinese and UK populations,sustained reduction of LDL-C levels can be used to maximize cardiovascular benefits,but attention should be paid to potential side effects. |
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