Diagnostic Yield and Clinical Utility of Sequencing Familial Hypercholesterolemia Genes in Patients With Severe Hypercholesterolemia.
Diagnostic Yield and Clinical Utility of Sequencing Familial Hypercholesterolemia Genes in Patients With Severe Hypercholesterolemia.
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DOI：
10.1016/j.jacc.2016.03.520
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发表时间：
2016-06-07
影响因子：
24
通讯作者：
Kathiresan S
中科院分区：
文献类型：
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作者：
Khera AV;Won HH;Peloso GM;Lawson KS;Bartz TM;Deng X;van Leeuwen EM;Natarajan P;Emdin CA;Bick AG;Morrison AC;Brody JA;Gupta N;Nomura A;Kessler T;Duga S;Bis JC;van Duijn CM;Cupples LA;Psaty B;Rader DJ;Danesh J;Schunkert H;McPherson R;Farrall M;Watkins H;Lander E;Wilson JG;Correa A;Boerwinkle E;Merlini PA;Ardissino D;Saleheen D;Gabriel S;Kathiresan S
大约 7% 的美国成年人患有严重高胆固醇血症（未经治疗的 LDL 胆固醇≥190 mg/dl）。如此高的 LDL 水平可能是由于家族性高胆固醇血症 (FH)，这是一种由三个基因中任何一个的单一突变引起的疾病。 FH 突变携带者 LDL 胆固醇终生升高可能会导致 CAD 风险超出单次 LDL 胆固醇测量所捕获的风险。评估严重高胆固醇血症患者中 FH 突变的患病率，并确定 CAD 风险是否根据观察到的 LDL 胆固醇之外的突变状态而变化。对来自 7 项病例对照研究（5,540 例 CAD 病例，8,577 例无 CAD 对照）和 5 项前瞻性队列研究（11,908 名受试者）的 26,025 名受试者的 3 个 FH 致病基因（LDLR、APOB、PCSK9）进行了测序。 FH 突变包括 LDLR 中的功能丧失变异、预计具有破坏性的 LDLR 中的错义突变以及临床遗传学数据库 ClinVar 中与 FH 相关的变异。在 8,577 名无 CAD 对照参与者中，430 名 LDL 胆固醇≥190 mg/dl；其中，只有 8 例 (1.9%) 携带 FH 突变。同样，在来自 5 个前瞻性队列的 11,908 名参与者中，956 人的 LDL 胆固醇≥190 mg/dl，其中只有 16 人 (1.7%) 携带 FH 突变。在任何观察到的 LDL 胆固醇水平中，与非携带者相比，FH 突变携带者患 CAD 的风险较高。与 LDL 胆固醇 <130 mg/dl 且无突变的参考组相比，LDL 胆固醇≥190 mg/dl且无 FH 突变的参与者患 CAD 的风险高出六倍（OR 6.0；95%CI 5.2–6.9），而 LDL 胆固醇≥190 mg/dl 且有 FH 突变的参与者则患 CAD 的风险高出 22 倍（OR 22.3；95%CI 5.2-6.9）。 10.7–53.2）。在 LDL 胆固醇≥190 mg/dl 的个体中，基因测序发现 FH 突变<2%。然而，对于任何给定的观察到的 LDL 胆固醇，FH 突变携带者患 CAD 的风险显着增加。
About 7% of US adults have severe hypercholesterolemia (untreated LDL cholesterol ≥190 mg/dl). Such high LDL levels may be due to familial hypercholesterolemia (FH), a condition caused by a single mutation in any of three genes. Lifelong elevations in LDL cholesterol in FH mutation carriers may confer CAD risk beyond that captured by a single LDL cholesterol measurement. Assess the prevalence of a FH mutation among those with severe hypercholesterolemia and determine whether CAD risk varies according to mutation status beyond the observed LDL cholesterol. Three genes causative for FH (LDLR, APOB, PCSK9) were sequenced in 26,025 participants from 7 case-control studies (5,540 CAD cases, 8,577 CAD-free controls) 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 8,577 CAD-free control participants, 430 had LDL cholesterol ≥190 mg/dl; of these, only eight (1.9%) carried a FH mutation. Similarly, among 11,908 participants from 5 prospective cohorts, 956 had LDL cholesterol ≥190 mg/dl and of these, only 16 (1.7%) carried a FH mutation. Within any stratum of observed LDL cholesterol, risk of CAD was higher among FH mutation carriers when compared with non-carriers. When compared to a reference group with LDL cholesterol <130 mg/dl and no mutation, participants with LDL cholesterol ≥190 mg/dl and no FH mutation had six-fold higher risk for CAD (OR 6.0; 95%CI 5.2–6.9) whereas those with LDL cholesterol ≥190 mg/dl as well as a FH mutation demonstrated twenty-two fold increased risk (OR 22.3; 95%CI 10.7–53.2). Among individuals with LDL cholesterol ≥190 mg/dl, gene sequencing identified a FH mutation in <2%. However, for any given observed LDL cholesterol, FH mutation carriers are at substantially increased risk for CAD.