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LDLR variant classification for improved cardiovascular risk prediction in familial hypercholesterolemia

Shirin Ibrahim1, Merel L Hartgers2, Laurens F Reeskamp1

  • 1Department of Vascular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

Atherosclerosis
|July 31, 2024
PubMed

Insights

Familial hypercholesterolemia (FH) variant classification is improved using LDL cholesterol percentiles. This refined method offers more precise coronary artery disease (CAD) risk prediction for FH patients.

Area of Science:

  • Genetics
  • Cardiovascular Medicine
  • Biochemistry

Background:

  • Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated LDL cholesterol and premature coronary artery disease (CAD) risk.
  • Current classification of LDL receptor gene (LDLR) variants may not fully capture individual variability in LDL cholesterol and CAD risk.
  • A novel approach using variant-specific LDL cholesterol percentiles is proposed to better assess LDLR variant severity.

Purpose of the Study:

  • To develop and validate a novel method for classifying LDLR variants based on their impact on LDL cholesterol levels.
  • To assess the association between these refined variant classifications and coronary artery disease (CAD) risk.
  • To compare the precision of this new classification system with traditional methods for FH patient risk stratification.

Main Methods:

  • Screening of 456 LDLR variants in 35,067 participants from the Dutch FH cascade screening program.
  • Derivation of sex- and age-specific LDL cholesterol percentiles for each LDLR variant carrier.
  • Grouping carriers into distinct LDL cholesterol strata and comparing CAD risk using Cox proportional hazard models.

Main Results:

  • 12,485 LDLR variant carriers were identified, exhibiting a 5-fold higher CAD risk than non-carriers.
  • Coronary artery disease (CAD) risk increased progressively across LDL cholesterol strata, with hazard ratios ranging from 2.2 to 12.0.
  • Carriers of class 1 and non-class 1 LDLR variants showed significantly increased CAD risks (7.3-fold and 3.9-fold, respectively).

Conclusions:

  • A refined approach for classifying LDLR variants based on LDL cholesterol impact has been developed.
  • This method allows for more precise, genotype-specific CAD risk estimation in FH patients.
  • The proposed classification improves upon traditional methods for stratifying FH patient risk.
Abstract

Keywords:
Coronary artery diseaseFamilial hypercholesterolemiaLDLR

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