Relationship Between Familial Hypercholesterolemia And Coronary Artery Disease In Chinese Adult

Background and objectiveFamilial hypercholesterolemia（FH）is a metabolic disorder caused by mutations in the low-density lipoprotein receptor（LDLR）gene,leading to the inability to metabolize cholesterol normally and resulting in elevated levels of Low-density Lipoprotein Cholesterol（LDL-C）in the blood,which increases the risk of cardiovascular diseases such as coronary artery disease（CAD）.The main pathogenic mutations causing FH are in the LDLR,Apolipoprotein B（APOB）,and Proprotein Convertase Subtilisin/kexin Type 9（PCSK9）genes.Worldwide,the prevalence of FH is about 1/250,but in specific populations,it can be as high as 1/100.In China,the burden of FH is relatively high,with patients accounting for 8%of the global total,including 2 765 420 to 6 913 550 FH heterozygous carriers and 2 205 to 4 609 FH homozygous carriers.Previous studies based on European and American populations have evaluated the prevalence of FH,single-gene mutations,and their relationship with CAD.However,considering the significant differences in genetic background,CAD,and its risk factors between Chinese and European and American populations,further research is needed to clarify these relationships in the Chinese population.Therefore,this study is based on the Prediction for Atherosclerotic Cardiovascular Disease Risk in China（China-PAR）project to explore the prevalence of FH and its relationship with CAD risk in the study cohort.Using targeted deep sequencing data,the study also aims to explore the types of single-gene mutations in FH in the population and the association between single-gene FH mutations and CAD.Subjects and MethodsThis study is based on three sub-cohorts of the Prediction for Atherosclerotic Cardiovascular Disease Risk in China（China-PAR）project survey,including the China Multi-Center Collaborative Study of Cardiovascular Epidemiology 1998（China MUCA1998）,the International Collaborative Study of Cardiovascular Disease in Asia（InterASIA）China section,and the Community Intervention of Metabolic Syndrome in China and Chinese Family Health Study（CIMIC）.The China MUCA-1998 and InterASIA cohort studies started in 1998 and 2000-2001,respectively,and conducted the first,second,and third follow-ups in 2007-2008,2012-2015,and 2018-2020.The CIMIC cohort was established in 2007-2008 and conducted two follow-ups in 2012-2015 and 2018-2020.Each survey collected demographic characteristics,lifestyle,and medical history information through face-to-face interviews conducted by trained and assessed staff,as well as physical examinations and biochemical tests.Follow-up surveys obtained information on disease incidence and mortality by asking participants or their relatives and collecting hospitalization records and death certificates.Study on the relationship between FH prevalence and CAD risk:The baseline time of the three sub-cohorts was unified to 2007-2008,and a total of 98 885 participants were included.FH was defined according to the "Make Early Diagnosis to Prevent Early Death"（MEDPED）criteria,and the crude and age-sex standardized prevalence of FH was calculated.Based on data from baseline to the last follow-up（2018-2020）,93 180 participants were included after excluding those lost to follow-up and those with cardiovascular disease at baseline.A multivariate Cox proportional hazards model stratified by cohort was used to estimate the association between FH and the incidence of early-onset CAD,CAD,and its major subtypes.Study on the relationship between common single-gene mutations in FH and CAD risk:A total of 6 782 participants who underwent targeted deep sequencing in the three subcohorts were included.Single-gene FH mutations were defined based on loss of function（LoF）mutations in LDLR and variations in LDLR,APOB,or PCSK9 that were annotated as "pathogenic" or "likely pathogenic"in the Clinical Variants（ClinVar）database.Singlegene FH mutations were classified into APOB/PCSK9 mutations,LDLR missense mutations,and LDLR LoF mutations.Propensity score matching was used to match CAD cases and controls,early-onset CAD cases and controls,and hypercholesterolemia cases and controls by age and sex,respectively,to explore the association between single-gene FH mutations and CAD,early-onset CAD,and hypercholesterolemia.ResultsAmong the 98 885 study participants,there were 190 FH patients,with crude and age-sex standardized prevalence rates of 0.19%（95%Confidence Interval（CI）:0.17%-0.22%）and 0.13%（95%CI:0.10%-0.16%）,respectively.The crude prevalence rate of FH was higher in females（0.23%vs.0.13%,P=0.001）than in males.There were differences in crude prevalence rates among different age groups and between males and females.The highest crude prevalence rate was observed in the 60 to<70 age group（0.28%）,while the peak crude prevalence rate in males（0.18%）occurred earlier than that in females（0.4 1%）in the 30 to<40 and 60 to<70 age groups,respectively.During a mean follow-up period of 10.7 years,2,493 participants developed CAD.After multivariate adjustment,compared with those without FH,the hazard ratios（HRs）and 95%CIs for total CAD,AMI,other CAD,and early-onset CAD in FH patients were 2.03（95%CI:1.17-3.51）,2.23（95%CI:1.114.48）,2.32（95%CI:1.15-4.66）,and 2.53（95%CI:1.31-4.89）,respectively.In the second part of the study,among the 6,782 study participants who underwent targeted deep sequencing,255 single-gene FH carriers were identified.The proportions of LDLR,APOB,and PCSK9 mutations were 90.5%,6.3%,and 3.2%,respectively,and 77.8%of the mutations were reported in ClinVar.The missense mutation LDLR（c.570C>G,C190W）accounted for 34.9%of single-gene FH cases,and the functional loss mutation APOB（c.35₃9del,L12Pfs*44）accounted for 21.2%of single-gene FH cases.After multivariate adjustment,the odds ratios（ORs）and 95%CIs for LDLR LoF,LDLR missense,and APOB/PCSK9 mutations were 4.84（95%CI:2.91-8.06）,2.67（95%CI:1.79-3.98）,and 0.89（95%CI:0.41-1.95）for hypercholesterolemia,1.49（95%CI:0.74-3.02）,1.50（95%CI:0.87-2.61）,and 1.18（95%CI:0.53-2.64）for CAD,and 2.68（95%CI:1.09-6.57）,1.43（95%CI:0.67-3.07）,and 0.96（95%CI:0.28-3.32）for early-onset CAD,respectively.ConclusionBased on the data from Chinese cohort population,the crude prevalence rate of FH was 0.19%,and it was significantly associated with an increased risk of total CAD,AMI,other CAD,and early-onset CAD.Among the common single-gene mutations in FH,carriers of LDLR LoF mutations had a significantly increased risk of early-onset CAD,while carriers of LDLR LoF and missense mutations had a significantly increased risk of hypercholesterolemia.Early screening for FH and genetic testing can promote early detection and treatment,which has certain public health significance in reducing the burden of CAD and early-onset CAD.