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

TitleDiagnostic Yield and Clinical Utility of Sequencing Familial Hypercholesterolemia Genes in Patients With Severe Hypercholesterolemia.
Publication TypeJournal Article
Year of Publication2016
AuthorsKhera AV, Won H-H, 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, L Cupples A, Psaty B, Rader DJ, Danesh J, Schunkert H, McPherson R, Farrall M, Watkins H, Lander E, Wilson JG, Correa A, Boerwinkle E, Merlini PAngelica, Ardissino D, Saleheen D, Gabriel S
Secondary AuthorsKathiresan S
JournalJ Am Coll Cardiol
Volume67
Issue22
Pagination2578-89
Date Published2016 06 07
ISSN1558-3597
KeywordsApolipoprotein B-100, Case-Control Studies, Cholesterol, LDL, Cohort Studies, Coronary Artery Disease, Female, Genetic Variation, Heterozygote, Humans, Hypercholesterolemia, Hyperlipoproteinemia Type II, Male, Middle Aged, Proprotein Convertase 9, Receptors, LDL, Sequence Analysis
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

CONCLUSIONS: Among participants with LDL cholesterol ≥190 mg/dl, gene sequencing identified an FH mutation in 

DOI10.1016/j.jacc.2016.03.520
Alternate JournalJ Am Coll Cardiol
PubMed ID27050191
PubMed Central IDPMC5405769
Grant ListUC2 HL103010 / HL / NHLBI NIH HHS / United States
HHSN268201100011I / HL / NHLBI NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
K01 HL125751 / HL / NHLBI NIH HHS / United States
HHSN268201200036C / HL / NHLBI NIH HHS / United States
HHSN268201100005I / HL / NHLBI NIH HHS / United States
N01HC85082 / HL / NHLBI NIH HHS / United States
N01HC85080 / HL / NHLBI NIH HHS / United States
RC2 HL102925 / HL / NHLBI NIH HHS / United States
N01HC85081 / HL / NHLBI NIH HHS / United States
HHSN268201100012C / HL / NHLBI NIH HHS / United States
RC2 HL102419 / HL / NHLBI NIH HHS / United States
R01 HL103612 / HL / NHLBI NIH HHS / United States
HHSN268201100009I / HL / NHLBI NIH HHS / United States
RC2 HL102923 / HL / NHLBI NIH HHS / United States
RG/13/13/30194 / BHF_ / British Heart Foundation / United Kingdom
R01 HL120393 / HL / NHLBI NIH HHS / United States
U54 HG003067 / HG / NHGRI NIH HHS / United States
RC2 HL102926 / HL / NHLBI NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
U01 HL080295 / HL / NHLBI NIH HHS / United States
HHSN268201100005G / HL / NHLBI NIH HHS / United States
HHSN268201100008I / HL / NHLBI NIH HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
HHSN268200800007C / HL / NHLBI NIH HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
N02 HL64278 / HL / NHLBI NIH HHS / United States
HHSN268201300048C / HL / NHLBI NIH HHS / United States
R01 HL087652 / HL / NHLBI NIH HHS / United States
R01 HL127564 / HL / NHLBI NIH HHS / United States
N01HC55222 / HL / NHLBI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
N01HC85086 / HL / NHLBI NIH HHS / United States
MR/L003120/1 / MRC_ / Medical Research Council / United Kingdom
N02HL64278 / HL / NHLBI NIH HHS / United States
HHSN268201300049C / HL / NHLBI NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
RC2 HL102924 / HL / NHLBI NIH HHS / United States
HHSN268201300047C / HL / NHLBI NIH HHS / United States
HHSN268201300050C / HL / NHLBI NIH HHS / United States
HHSN268201100009C / HL / NHLBI NIH HHS / United States
N01HC85083 / HL / NHLBI NIH HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
N01HC25195 / HL / NHLBI NIH HHS / United States
RC2 HL103010 / HL / NHLBI NIH HHS / United States
HHSN268201100007I / HL / NHLBI NIH HHS / United States
/ WT_ / Wellcome Trust / United Kingdom
HHSN268201300046C / HL / NHLBI NIH HHS / United States
N01HC85079 / HL / NHLBI NIH HHS / United States
R01 AG023629 / AG / NIA NIH HHS / United States