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

Amit V Khera, Hong-Hee Won, Gina M Peloso, Kim S Lawson, Traci M Bartz, Xuan Deng, Elisabeth M van Leeuwen, Pradeep Natarajan, Connor A Emdin, Alexander G Bick, Alanna C Morrison, Jennifer A Brody, Namrata Gupta, Akihiro Nomura, Thorsten Kessler, Stefano Duga, Joshua C Bis, Cornelia M van Duijn, L Adrienne Cupples, Bruce Psaty, Daniel J Rader, John Danesh, Heribert Schunkert, Ruth McPherson, Martin Farrall, Hugh Watkins, Eric Lander, James G Wilson, Adolfo Correa, Eric Boerwinkle, Piera Angelica Merlini, Diego Ardissino, Danish Saleheen, Stacey Gabriel, Sekar Kathiresan - Journal of the American College of Cardiology, 2016

Among adults with severe hypercholesterolemia, gene sequencing detected a familial-hypercholesterolemia (FH) mutation in fewer than 2%, yet at the same measured LDL level mutation carriers had far higher coronary-artery-disease risk than non-carriers. Versus a low-LDL no-mutation reference, LDL >=190 mg/dl without a mutation carried a 6-fold higher CAD risk, while LDL >=190 mg/dl with an FH mutation carried a 22-fold higher risk. The mechanism is greater cumulative lifetime LDL exposure in carriers, a natural experiment supporting cumulative LDL burden as causal for CAD.

Key findings

• Among adults with severe hypercholesterolemia (untreated LDL >=190 mg/dl), sequencing of LDLR, APOB, and PCSK9 detected an FH mutation in fewer than 2% (about 1.7%).
• Versus a reference group (LDL <130 mg/dl, no mutation), LDL >=190 mg/dl with no FH mutation carried a 6-fold higher CAD risk (odds ratio 6.0, 95% CI 5.2-6.9).
• LDL >=190 mg/dl WITH an FH mutation carried a 22-fold higher CAD risk (odds ratio 22.3, 95% CI 10.7-53.2) - roughly triple the risk at the same measured LDL.
• FH mutation carriers had higher cumulative lifetime exposure to LDL cholesterol than non-carriers, the mechanism invoked for the excess risk and a natural experiment supporting cumulative LDL burden as causal for CAD.

Population:

26,025 participants from 12 studies: 7 case-control studies (5,540 CAD case subjects, 8,577 CAD-free controls) and 5 prospective cohort studies (11,908 participants). LDLR, APOB, and PCSK9 were sequenced, with analysis focused on those with severe hypercholesterolemia (untreated LDL cholesterol >=190 mg/dl).

Conflicts of interest:

Multiple author disclosures reported. Dr Khera was supported by an ACC/Merck Fellowship and reported consulting fees from Merck and Amarin. Dr Rader reported consulting fees from Aegerion, Alnylam, Eli Lilly, Pfizer, and Novartis, is an inventor on a lomitapide patent owned by the University of Pennsylvania and licensed to Aegerion, and is a co-founder of VascularStrategies and Staten Biotechnology. Dr Kathiresan received grants from Bayer Healthcare, Aegerion, and Regeneron and reported consulting fees from Merck, Quest Diagnostics, Genomics PLC, and Eli Lilly. Several senior authors thus carry industry ties to statin/lipid-lowering and PCSK9-related companies. No retraction or erratum was found.

Funding:

Supported in part by NHLBI/NIH (e.g. Dr Peloso, award K01HL125751) and a DZHK Rotation Grant (Dr Kessler); multiple author-level industry disclosures also apply (see conflicts of interest).