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A polygenic biomarker to identify patients with severe hypercholesterolemia of polygenic origin

Luis G Leal1, Clive Hoggart2, Marjo-Riitta Jarvelin3,4,5,6,7

  • 1Department of Life Sciences, Centre for Integrative Systems Biology and Bioinformatics, Imperial College London, London, United Kingdom.

Molecular Genetics & Genomic Medicine
|April 21, 2020
PubMed

Insights

A new polygenic risk score (PRS) for high LDL cholesterol (LDL-C) shows improved prediction accuracy. This PRS better identifies individuals with severe hypercholesterolemia and aids in risk stratification for better patient management.

Area of Science:

  • Genetics
  • Cardiovascular Disease Epidemiology

Background:

  • Severe hypercholesterolemia (HC), defined as LDL-C > 4.9 mmol/L, impacts over 30 million individuals globally.
  • Accurate identification and risk stratification of HC are crucial for effective patient management and therapeutic strategies.

Purpose of the Study:

  • To validate a novel 36-single nucleotide polymorphism (SNP) polygenic risk score (PRS) for low-density lipoprotein cholesterol (LDL-C).
  • To compare the predictive performance of the new PRS against an existing 12-SNP score for identifying severe HC.

Main Methods:

  • A 36-SNP PRS was developed using summary statistics from the Global Lipid Genome Consortium and genotype data from white Americans.
  • The PRS was validated in a replication cohort of 4,787 Finnish individuals, assessing its association with LDL-C and HC risk.

Main Results:

  • The 36-SNP PRS strongly associated with LDL-C, explaining 8% of its variability (p = 10^-41) in the Finnish cohort.
  • The PRS demonstrated superior performance compared to a 12-SNP score, explaining more LDL-C variability (8% vs. 6%) and reclassifying 54% of severe HC cases initially deemed low-risk.
  • High-risk individuals identified by the PRS had a 4.17-fold increased risk of HC (p < 1x10^-7).

Conclusions:

  • The validated 36-SNP PRS offers enhanced predictive capability for identifying hypercholesterolemia of polygenic origin.
  • This novel PRS can improve patient stratification within diagnostic and therapeutic algorithms for severe hypercholesterolemia.
Abstract

Keywords:
hypercholesterolemialipidspolygenic risk scorerisk stratification

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