Effect of the LDL receptor mutation type on incident major adverse cardiovascular events in familial hypercholesterolaemia.

Patients with familial hypercholesterolaemia (FH) are at increased risk of cardiovascular disease (CVD) due to extremely high circulating LDL cholesterol (LDL-C) concentrations. Our objective was to study the effect of the type of LDL receptor (LDLR) mutation on the incidence of major adverse cardiovascular events (MACEs). This was a multinational prospective cohort study, which included patients with heterozygous FH aged 18-65 years, without a prior history of CVD, and carrying a pathogenic or likely pathogenic variant in the LDLR gene. A total of 2131 patients (20 535person-years of follow-up) were included in the study, including 1234 subjects carrying a defective mutation in the LDLR and 897 subjects carrying a null mutation. During the follow-up, a first MACE occurred in 79 cases (6%) in the defective group and in 111 cases (12%) in the null group. The mean baseline LDL-C concentration was 17% higher in the null group than in the defective group (7.90 vs. 6.73 mmoL/L, P < 0.0001). In a Cox regression model corrected for traditional cardiovascular risk factors, the presence of a null mutation was associated with a hazard ratio of 2.09 (1.44-3.05), P = 0.0001. Carriers of a null mutation have an independent ∼2-fold increased risk of incident MACE compared with patients carrying a defective mutation. This study highlights the importance of genetic screening in FH in order to improve patient care.

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Déclaration de conflit d'intérêts

Conflict of interest: A.B. received research grants from Akcea, Amgen, Astra Zeneca, Fondation Leducq, Fondation Yvan Morin, Merck Frosst, and Sanofi. He has participated in clinical research protocols from Acasti Pharma Inc., Akcea, Amgen, Astra Zeneca, Ionis Pharmaceuticals Inc., The Medicines Company, Merck Frosst, Novartis, Pfizer, Regeneron Pharmaceuticals Inc., and Sanofi. He has served on advisory boards and received honoraria for symposia from Akcea, Amgen, and Sanofi. S. Ber. has received research grants from Akcea, Fondation Leducq, and Fondation Yvan Morin. She has participated in clinical research protocols from Akcea, Amgen, Ionis Pharmaceuticals Inc., The Medicines Company, Novartis, Pfizer, and Sanofi. She has served on advisory boards for Akcea, Amgen, HLS Therapeutics, Novartis, Novo Nordisk, and Sanofi, and received honoraria for symposia from Akcea, Amgen, Novo Nordisk, and Sanofi. S. Bél. has received honoraria for board, conferences, clinical trial, or congress from Aegerion, Akcea, Elivie, Sanofi, or Amgen. B.C. has received research funding and personal fees from Sanofi and Regeneron Pharmaceuticals Inc.; research funding from Amgen and Pfizer; and honoraria from Abbott, Amgen, Akcea, AstraZeneca, Pierre Fabre, Genfit, Gilead, Eli Lilly, and Company, MSD (Merck & Co.), Novo Nordisk, Sanofi. J.G. Chairs FHCanada (FHCanada.net), a registry of FH patients across Canada. He has received funding from the Canadian Institutes of Health Research for research related to familial hypercholesterolaemia. R.A.H. reports consulting fees from Acasti, Aegerion, Akcea/Ionis, Amgen, and Sanofi. L.R.B. is a Michael Smith Foundation for Health Research Scholar and is a Canada Research Chair in Precision Cardiovascular Disease Prevention and reports receiving honoraria from Amgen, Sanofi, Novartis, and HLS Therapeutics. M.P., M.T., and A.C. have nothing to declare.