@article {7010, title = {Diagnostic Yield and Clinical Utility of Sequencing Familial Hypercholesterolemia Genes in Patients With Severe Hypercholesterolemia.}, journal = {J Am Coll Cardiol}, volume = {67}, year = {2016}, month = {2016 Jun 7}, pages = {2578-89}, abstract = {

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.

}, issn = {1558-3597}, doi = {10.1016/j.jacc.2016.03.520}, author = {Khera, Amit V and Won, Hong-Hee and Peloso, Gina M and Lawson, Kim S and Bartz, Traci M and Deng, Xuan and van Leeuwen, Elisabeth M and Natarajan, Pradeep and Emdin, Connor A and Bick, Alexander G and Morrison, Alanna C and Brody, Jennifer A and Gupta, Namrata and Nomura, Akihiro and Kessler, Thorsten and Duga, Stefano and Bis, Joshua C and van Duijn, Cornelia M and Cupples, L Adrienne and Psaty, Bruce and Rader, Daniel J and Danesh, John and Schunkert, Heribert and McPherson, Ruth and Farrall, Martin and Watkins, Hugh and Lander, Eric and Wilson, James G and Correa, Adolfo and Boerwinkle, Eric and Merlini, Piera Angelica and Ardissino, Diego and Saleheen, Danish and Gabriel, Stacey and Kathiresan, Sekar} }