Diagnostic Yield of Sequencing Familial Hypercholesterolemia Genes in Severe Hypercholesterolemia

By A. Khera, H. Won, G. Peloso, Kim S Lawson, Traci M. Bartz, Xuan Deng, E. V. van Leeuwen, P. Natarajan, C. Emdin, Alexander G. Bick and 25 more. Journal of the American College of Cardiology, 2016

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Background 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. Objectives 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. Methods 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. Results 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). Conclusions 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.

Subfields: Endocrinology, Diabetes and Metabolism, Genetics, Surgery

View Paper: https://www.semanticscholar.org/paper/c6aace07d21e07690850595e5430180a501f5492

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Citations in the corpus

Polygenic prediction of weight and obesity trajectories from birth to adulthood (2019, result): “This observation is consistent with recent large-scale gene sequencing studies across a broad range of complex diseases, including diabetes, cardiovascular disease, and breast cancer (Flannick et al., 2013; Khera et al., 2016; Manickam et al., 2018).”
Genome-wide polygenic score to identify a monogenic risk-equivalent for coronary disease (2017, background): “For example, with respect to coronary disease, ~1:250 individuals carry a rare, large-effect genetic mutation causal for increased low-density lipoprotein cholesterol (1-3).”