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Polygenic Contribution to Low-Density Lipoprotein Cholesterol Levels and Cardiovascular Risk in Monogenic Familial

Mark Trinder1,2, Martine Paquette3, Lubomira Cermakova4

  • 1Centre for Heart Lung Innovation (M.T., L.R.B.), University of British Columbia, Vancouver.

Circulation. Genomic and Precision Medicine
|October 20, 2020
PubMed

Insights

Polygenic scores influence low-density lipoprotein cholesterol (LDL-C) levels and atherosclerotic cardiovascular disease (ASCVD) risk in familial hypercholesterolemia (FH). This genetic factor helps explain variations in FH patient outcomes.

Area of Science:

  • Genetics
  • Cardiology
  • Biochemistry

Background:

  • Familial hypercholesterolemia (FH) is a genetic disorder causing high LDL-C and premature ASCVD risk.
  • Significant variability exists in LDL-C levels and ASCVD risk among individuals with monogenic FH.
  • The role of polygenic factors in this variability is not fully understood.

Purpose of the Study:

  • To assess the impact of an LDL-C polygenic score on LDL-C levels in FH patients.
  • To evaluate the association between an LDL-C polygenic score and ASCVD risk in FH patients.
  • To understand the contribution of polygenic factors to FH heterogeneity.

Main Methods:

  • Constructed a weighted LDL-C polygenic score using 28 single-nucleotide variants.
  • Analyzed data from three cohorts: British Columbia FH (n=262), Nutrition, Metabolism and Atherosclerosis Clinic (n=552), and UK Biobank (n=306).
  • Utilized linear regression for LDL-C levels and Cox-proportional hazard models for ASCVD risk, with fixed-effect meta-analyses for combined results.

Main Results:

  • LDL-C levels were significantly associated with the LDL-C polygenic score across cohorts and meta-analysis (β=0.13, P<0.0001).
  • An elevated LDL-C polygenic score (≥80th percentile) showed a trend towards increased ASCVD risk in individual cohorts.
  • The association between elevated LDL-C polygenic score and ASCVD risk was statistically significant in the meta-analysis (HR=1.48, P=0.04).

Conclusions:

  • Polygenic contributions to LDL-C levels significantly influence ASCVD risk in individuals with FH.
  • Genetic polygenic scores help explain the observed heterogeneity in clinical presentation and ASCVD risk among FH patients.
  • These findings highlight the importance of considering polygenic factors in managing FH.
Abstract

Keywords:
coronary artery diseasehypercholesterolemialipidslipoproteinsmetabolism

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