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

Martine Paquette; Alain Carrié; Sophie Bernard; Bertrand Cariou; Robert A Hegele; Jacques Genest; Mark Trinder; Liam R Brunham; Sophie Béliard; Alexis Baass

doi:10.1093/eurjpc/zwac188

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

Eur J Prev Cardiol. 2022 Nov 15;29(16):2125-2131. doi: 10.1093/eurjpc/zwac188.

Authors

Martine Paquette¹, Alain Carrié², Sophie Bernard^{1

3}, Bertrand Cariou⁴, Robert A Hegele^{5

6}, Jacques Genest⁷, Mark Trinder⁸, Liam R Brunham⁸, Sophie Béliard⁹, Alexis Baass^{1

10}

Affiliations

¹ Lipids, Nutrition, and Cardiovascular Prevention Clinic of the Montreal Clinical Research Institute, 110 avenue des Pins Ouest, Montreal, QC H2W 1R7, Canada.
² Department of Biochemistry, Obesity and Dyslipidemia Genetics Unit, Hôpital de La Pitié-Salpêtrière, Sorbonne University, Inserm, Institute of Cardiometabolism and Nutrition (ICAN), UMR_S1166, APHP, ICAN, 47-83 boulevard de l'hôpital, 75013 Paris, France.
³ Department of Medicine, Division of Endocrinology, Université de Montreal, Pavillon Roger-Gaudry, 2900 Edouard Montpetit Blvd, Montreal, QC H3T 1J4, Canada.
⁴ Nantes Université, CHU Nantes, CNRS, Inserm, l'institut du thorax, 8 Quai Moncousu, F-44000 Nantes, France.
⁵ Department of Medicine, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond St, London, ON N6A 5C1, Canada.
⁶ Robarts Research Institute, Western University, 100 Perth Dr, London, ON N6A 5K8, Canada.
⁷ Research Institute of the McGill University Health Centre, 1001 Decarie Blvd, Montreal, QC H4A 3J1, Canada.
⁸ Department of Medicine, Faculty of Medicine, University of British Columbia, Centre for Heart and Lung Innovation, University of British Columbia, 1081 Burrard St Room 166, Vancouver, BC V6Z 1Y6, Canada.
⁹ Department of Nutrition, Metabolic Diseases, Endocrinology, Aix Marseille University, INSERM, INRAE, C2VN, La Conception Hospital, 27 Bd Jean Moulin, 13005 Marseille, France.
¹⁰ Department of Medicine, Divisions of Experimental Medicine and Medical Biochemistry, McGill University, 3605 Rue de la Montagne, Montreal, QC H3G 2M1, Canada.

PMID: 36047048
DOI: 10.1093/eurjpc/zwac188

Abstract

Aims: 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).

Methods and results: 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.

Conclusion: 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.

Keywords: Cardiovascular; Defective; Familial hypercholesterolaemia; LDL-C; LDLR; Null.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cardiovascular Diseases* / diagnosis
Cardiovascular Diseases* / epidemiology
Cardiovascular Diseases* / genetics
Cholesterol, LDL
Humans
Hyperlipoproteinemia Type II* / diagnosis
Hyperlipoproteinemia Type II* / genetics
Mutation
Prospective Studies
Receptors, LDL / genetics

Substances

Cholesterol, LDL
Receptors, LDL