03793nas a2200553 4500008004100000022001400041245013800055210006900193260001500262300001200277490000700289520217800296100001902474700001802493700002002511700001902531700002002550700001502570700003002585700002302615700002102638700002302659700002402682700002302706700001902729700002002748700002202768700001802790700001902808700002302827700002502850700001702875700002102892700001702913700002402930700002002954700002002974700001802994700001703012700002103029700001903050700002103069700002903090700002103119700002103140700002003161700002203181856003603203 2016 eng d a1558-359700aDiagnostic Yield and Clinical Utility of Sequencing Familial Hypercholesterolemia Genes in Patients With Severe Hypercholesterolemia.0 aDiagnostic Yield and Clinical Utility of Sequencing Familial Hyp c2016 Jun 7 a2578-890 v673 a
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.
1 aKhera, Amit, V1 aWon, Hong-Hee1 aPeloso, Gina, M1 aLawson, Kim, S1 aBartz, Traci, M1 aDeng, Xuan1 avan Leeuwen, Elisabeth, M1 aNatarajan, Pradeep1 aEmdin, Connor, A1 aBick, Alexander, G1 aMorrison, Alanna, C1 aBrody, Jennifer, A1 aGupta, Namrata1 aNomura, Akihiro1 aKessler, Thorsten1 aDuga, Stefano1 aBis, Joshua, C1 aDuijn, Cornelia, M1 aCupples, Adrienne, L1 aPsaty, Bruce1 aRader, Daniel, J1 aDanesh, John1 aSchunkert, Heribert1 aMcPherson, Ruth1 aFarrall, Martin1 aWatkins, Hugh1 aLander, Eric1 aWilson, James, G1 aCorrea, Adolfo1 aBoerwinkle, Eric1 aMerlini, Piera, Angelica1 aArdissino, Diego1 aSaleheen, Danish1 aGabriel, Stacey1 aKathiresan, Sekar uhttps://chs-nhlbi.org/node/7010