TY - JOUR T1 - Diagnostic Yield and Clinical Utility of Sequencing Familial Hypercholesterolemia Genes in Patients With Severe Hypercholesterolemia. JF - J Am Coll Cardiol Y1 - 2016 A1 - Khera, Amit V A1 - Won, Hong-Hee A1 - Peloso, Gina M A1 - Lawson, Kim S A1 - Bartz, Traci M A1 - Deng, Xuan A1 - van Leeuwen, Elisabeth M A1 - Natarajan, Pradeep A1 - Emdin, Connor A A1 - Bick, Alexander G A1 - Morrison, Alanna C A1 - Brody, Jennifer A A1 - Gupta, Namrata A1 - Nomura, Akihiro A1 - Kessler, Thorsten A1 - Duga, Stefano A1 - Bis, Joshua C A1 - van Duijn, Cornelia M A1 - Cupples, L Adrienne A1 - Psaty, Bruce A1 - Rader, Daniel J A1 - Danesh, John A1 - Schunkert, Heribert A1 - McPherson, Ruth A1 - Farrall, Martin A1 - Watkins, Hugh A1 - Lander, Eric A1 - Wilson, James G A1 - Correa, Adolfo A1 - Boerwinkle, Eric A1 - Merlini, Piera Angelica A1 - Ardissino, Diego A1 - Saleheen, Danish A1 - Gabriel, Stacey A1 - Kathiresan, Sekar AB -

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.

VL - 67 IS - 22 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27050191?dopt=Abstract ER -