Diagnostic Yield and Clinical Utility of Sequencing Familial Hypercholesterolemia Genes in Patients With Severe Hypercholesterolemia

被引：703

作者：

Khera, Amit V. ^{[1
,2
,3
]}

Won, Hong-Hee ^{[4
]}

Peloso, Gina M. ^{[3
,5
]}

Lawson, Kim S. ^{[6
,7
]}

Bartz, Traci M. ^{[8
]}

Deng, Xuan ^{[5
]}

van Leeuwen, Elisabeth M. ^{[9
]}

Natarajan, Pradeep ^{[1
,2
,3
]}

Emdin, Connor A. ^{[3
]}

Bick, Alexander G. ^{[3
]}

Morrison, Alanna C. ^{[6
,7
]}

Brody, Jennifer A. ^{[10
]}

Gupta, Namrata ^{[3
]}

Nomura, Akihiro ^{[3
,11
]}

Kessler, Thorsten ^{[12
,13
]}

Duga, Stefano ^{[14
,15
]}

Bis, Joshua C. ^{[10
]}

van Duijn, Cornelia M. ^{[9
]}

Cupples, L. Adrienne ^{[5
]}

Psaty, Bruce ^{[10
,16
,17
,18
]}

Rader, Daniel J. ^{[19
]}

Danesh, John ^{[20
,21
,22
]}

Schunkert, Heribert ^{[12
,13
]}

McPherson, Ruth ^{[23
]}

Farrall, Martin ^{[24
,25
]}

Watkins, Hugh ^{[24
,25
]}

Lander, Eric ^{[3
]}

Wilson, James G. ^{[26
]}

Correa, Adolfo ^{[27
]}

Boerwinkle, Eric ^{[6
,7
]}

Merlini, Piera Angelica ^{[28
]}

Ardissino, Diego ^{[29
,30
]}

Saleheen, Danish ^{[31
]}

Gabriel, Stacey ^{[3
]}

Kathiresan, Sekar ^{[1
,2
,3
]}

机构：

[1] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res,Cardiovasc Res Ctr, Boston, MA USA

[2] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA

[3] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA

[4] Sungkyunkwan Univ, Samsung Med Ctr, Samsung Adv Inst Hlth Sci & Technol, Seoul, South Korea

[5] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA

[6] Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Houston, TX 77030 USA

[7] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA

[8] Univ Washington, Dept Biostat, Seattle, WA 98195 USA

[9] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands

[10] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA

[11] Kanazawa Univ, Grad Sch Med Sci, Div Cardiovasc Med, Kanazawa, Ishikawa, Japan

[12] Tech Univ Munich, Deutsch Herzzentrum Munchen, Deutsch Zentrum Herz Kreislauf Forsch, D-80290 Munich, Germany

[13] Munich Heart Alliance, Munich, Germany

[14] Humanitas Univ, Dept Biomed Sci, Milan, Italy

[15] Humanitas Clin & Res Ctr, Milan, Italy

[16] Univ Washington, Dept Med, Seattle, WA USA

[17] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA

[18] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA

[19] Univ Penn, Dept Genet, Philadelphia, PA 19104 USA

[20] Univ Cambridge, Publ Hlth & Primary Care, Cambridge, England

[21] Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Hinxton, England

[22] Univ Cambridge, Natl Inst Hlth Res Blood & Transplant Res Unit Do, Dept Publ Hlth & Primary Care, Cambridge, England

[23] Univ Ottawa, Inst Heart, Ottawa, ON, Canada

[24] Univ Oxford, Radcliffe Dept Med, Div Cardiovasc Med, Oxford, England

[25] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[26] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS USA

[27] Univ Mississippi, Med Ctr, Dept Med, Jackson Heart Study, Jackson, MS USA

[28] Osped Niguarda Ca Granda, Milan, Italy

[29] Univ Parma, Azienda Osped Univ Parma, Div Cardiol, I-43100 Parma, Italy

[30] ASTC Assoc Trombosi Cardiol, Pavia, Italy

[31] Univ Penn, Perelman Sch Med, Biostat & Epidemiol, Philadelphia, PA 19104 USA

来源：

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY | 2016年 / 67卷 / 22期

基金：

美国国家卫生研究院; 英国医学研究理事会; 英国惠康基金; 欧洲研究理事会;

关键词：

coronary artery disease; gene sequencing; genetics; low-density lipoprotein cholesterol; AUTOSOMAL-DOMINANT HYPERCHOLESTEROLEMIA; HEART; POPULATION; MUTATIONS; ASSOCIATION; PREVALENCE; VARIANTS; GUIDANCE; SPECTRUM; LDLR;

D O I：

10.1016/j.jacc.2016.03.520

中图分类号：

R5 [内科学];

学科分类号：

100201 [内科学];

摘要：

BACKGROUND 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. OBJECTIVES 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. METHODS 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. RESULTS 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. CONCLUSIONS 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. (C) 2016 by the American College of Cardiology Foundation.

引用

页码：2578 / 2589

页数：12

共 43 条

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Low Prevalence of Mutations in Known Loci for Autosomal Dominant Hypercholesterolemia in a Multiethnic Patient Cohort [J].