Khera Amit V, Won Hong-Hee, Peloso Gina M, Lawson Kim S, Bartz Traci M, Deng Xuan, van Leeuwen Elisabeth M, Natarajan Pradeep, Emdin Connor A, Bick Alexander G, Morrison Alanna C, Brody Jennifer A, Gupta Namrata, Nomura Akihiro, Kessler Thorsten, Duga Stefano, Bis Joshua C, van Duijn Cornelia M, Cupples L Adrienne, Psaty Bruce, Rader Daniel J, Danesh John, Schunkert Heribert, McPherson Ruth, Farrall Martin, Watkins Hugh, Lander Eric, Wilson James G, Correa Adolfo, Boerwinkle Eric, Merlini Piera Angelica, Ardissino Diego, Saleheen Danish, Gabriel Stacey, Kathiresan Sekar
Center for Human Genetic Research, Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts.
Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Samsung Medical Center, Seoul, Republic of Korea.
J Am Coll Cardiol. 2016 Jun 7;67(22):2578-89. doi: 10.1016/j.jacc.2016.03.520. Epub 2016 Apr 3.
Approximately 7% of American adults have severe hypercholesterolemia (untreated low-density lipoprotein [LDL] cholesterol ≥190 mg/dl), which may be due to familial hypercholesterolemia (FH). Lifelong LDL cholesterol elevations in FH mutation carriers may confer coronary artery disease (CAD) risk beyond that captured by a single LDL cholesterol measurement.
This study assessed the prevalence of an FH mutation among those with severe hypercholesterolemia and determined whether CAD risk varies according to mutation status beyond the observed LDL cholesterol level.
Three genes causative for FH (LDLR, APOB, and PCSK9) were sequenced in 26,025 participants from 7 case-control studies (5,540 CAD case subjects, 8,577 CAD-free control subjects) and 5 prospective cohort studies (11,908 participants). FH mutations included loss-of-function variants in LDLR, missense mutations in LDLR predicted to be damaging, and variants linked to FH in ClinVar, a clinical genetics database.
Among 20,485 CAD-free control and prospective cohort participants, 1,386 (6.7%) had LDL cholesterol ≥190 mg/dl; of these, only 24 (1.7%) carried an FH mutation. Within any stratum of observed LDL cholesterol, risk of CAD was higher among FH mutation carriers than noncarriers. Compared with a reference group with LDL cholesterol <130 mg/dl and no mutation, participants with LDL cholesterol ≥190 mg/dl and no FH mutation had a 6-fold higher risk for CAD (odds ratio: 6.0; 95% confidence interval: 5.2 to 6.9), whereas those with both LDL cholesterol ≥190 mg/dl and an FH mutation demonstrated a 22-fold increased risk (odds ratio: 22.3; 95% confidence interval: 10.7 to 53.2). In an analysis of participants with serial lipid measurements over many years, FH mutation carriers had higher cumulative exposure to LDL cholesterol than noncarriers.
Among participants with LDL cholesterol ≥190 mg/dl, gene sequencing identified an FH mutation in <2%. However, for any observed LDL cholesterol, FH mutation carriers had substantially increased risk for CAD.
约7%的美国成年人患有严重高胆固醇血症（未经治疗的低密度脂蛋白[LDL]胆固醇≥190mg/dl），这可能是由于家族性高胆固醇血症（FH）所致。FH突变携带者的LDL胆固醇终生升高可能会带来超出单次LDL胆固醇测量所反映的冠状动脉疾病（CAD）风险。
本研究评估了严重高胆固醇血症患者中FH突变的患病率，并确定CAD风险是否会因突变状态而有所不同，且超出观察到的LDL胆固醇水平。
在来自7项病例对照研究（5540例CAD病例受试者、8577例无CAD对照受试者）和5项前瞻性队列研究（11908名参与者）的26025名参与者中，对导致FH的三个基因（LDLR、APOB和PCSK9）进行了测序。FH突变包括LDLR中的功能丧失变异、预测具有损害性的LDLR错义突变，以及临床遗传学数据库ClinVar中与FH相关的变异。
在20485名无CAD对照和前瞻性队列参与者中，1386人（6.7%）的LDL胆固醇≥190mg/dl；其中，只有24人（1.7%）携带FH突变。在任何观察到的LDL胆固醇分层中，FH突变携带者的CAD风险均高于非携带者。与LDL胆固醇<130mg/dl且无突变的参考组相比，LDL胆固醇≥190mg/dl且无FH突变的参与者患CAD的风险高6倍（比值比：6.0；95%置信区间：5.2至6.9），而LDL胆固醇≥190mg/dl且有FH突变的参与者患CAD的风险增加了22倍（比值比：22.3；95%置信区间：10.7至53.2）。在对多年进行系列血脂测量的参与者进行的分析中，FH突变携带者的LDL胆固醇累积暴露量高于非携带者。
在LDL胆固醇≥190mg/dl的参与者中，基因测序发现FH突变的比例<2%。然而，对于任何观察到的LDL胆固醇水平，FH突变携带者患CAD的风险都大幅增加。
