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

Martine Paquette1, Alain Carrié2, Sophie Bernard1,3

  • 1Lipids, Nutrition, and Cardiovascular Prevention Clinic of the Montreal Clinical Research Institute, 110 avenue des Pins Ouest, Montreal, QC H2W 1R7, Canada.

European Journal of Preventive Cardiology
|September 1, 2022
PubMed

Insights

Patients with familial hypercholesterolaemia (FH) carrying a null LDL receptor (LDLR) mutation face a doubled risk of major adverse cardiovascular events (MACEs) compared to those with defective mutations. Genetic screening is crucial for improved FH patient care.

Area of Science:

  • Cardiovascular Medicine
  • Genetics
  • Lipidology

Background:

  • Familial hypercholesterolaemia (FH) is characterized by extremely high LDL cholesterol (LDL-C) levels, significantly increasing cardiovascular disease (CVD) risk.
  • The type of mutation in the LDL receptor (LDLR) gene may influence CVD risk in FH patients.

Purpose of the Study:

  • To investigate the impact of different types of LDLR mutations (defective vs. null) on the incidence of major adverse cardiovascular events (MACEs) in patients with heterozygous FH.

Main Methods:

  • A multinational prospective cohort study included 2131 heterozygous FH patients (aged 18-65) without prior CVD.
  • Patients were categorized based on LDLR mutation type: defective (1234) or null (897).
  • Follow-up data over 20,535 person-years were analyzed for MACE incidence using Cox regression, adjusted for cardiovascular risk factors.

Main Results:

  • The null mutation group had a higher incidence of MACE (12%) compared to the defective mutation group (6%).
  • Mean baseline LDL-C was 17% higher in the null mutation group (7.90 mmol/L) versus the defective group (6.73 mmol/L).
  • Null mutation carriers showed a significantly increased risk of MACE (Hazard Ratio: 2.09; P=0.0001) compared to defective mutation carriers.

Conclusions:

  • Carriers of null LDLR mutations have an approximately 2-fold independent increased risk of incident MACE compared to carriers of defective LDLR mutations.
  • These findings underscore the importance of genetic screening in FH management.
  • Understanding LDLR mutation type can help refine risk stratification and personalize patient care for FH.
Abstract

Keywords:
CardiovascularDefectiveFamilial hypercholesterolaemiaLDL-CLDLRNull

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