Assessment of practical applicability and clinical relevance of a commonly used LDL-C polygenic score in patients with severe hypercholesterolemia

Tycho R Tromp,Arjen J Cupido,Laurens F Reeskamp,Erik S.G Stroes,G Kees Hovingh,Joep C Defesche,Amand F Schmidt,Linda Zuurbier

doi:10.1016/j.atherosclerosis.2021.10.015

Abstract

Background and aimsLow-density lipoprotein cholesterol (LDL-C) levels vary in patients with familial hypercholesterolemia (FH) and can be explained by a single deleterious genetic variant or by the aggregate effect of multiple, common small-effect variants that can be captured in a polygenic score (PS). We set out to investigate the contribution of a previously published PS to the inter-individual LDL-C variation and coronary artery disease (CAD) risk in patients with a clinical FH phenotype. MethodsFirst, in a cohort of 628 patients referred for genetic FH testing, we evaluated the distribution of a PS for LDL-C comprising 12 genetic variants. Next, we determined its association with coronary artery disease (CAD) risk using UK Biobank data. ResultsThe mean PS was higher in 533 FH-variant-negative patients (FH/M-) compared with 95 FH-variant carriers (1.02 vs 0.94, p < 0.001). 39% of all patients had a PS equal to the top 20% from a population-based reference cohort and these patients were less likely to carry an FH variant (OR 0.22, 95% CI 0.10–0.48) compared with patients in the lowest 20%. In UK Biobank data, the PS explained 7.4% of variance in LDL-C levels and was associated with incident CAD. Addition of PS to a prediction model using age and sex and LDL-C did not increase the c-statistic for predicting CAD risk. ConclusionsThis 12-variant PS was higher in FH/M- patients and associated with incident CAD in UK Biobank data. However, the PS did not improve predictive accuracy when added to the readily available characteristics age, sex and LDL-C, suggesting limited discriminative value for CAD.

Highlights

High plasma levels of low-density lipoprotein cholesterol (LDL-C) have been shown to cause50 atherosclerotic cardiovascular disease (CVD) [1]; a leading cause of morbidity and mortality [2].51 Genetic susceptibility to severe hypercholesterolemia may 52 be caused by rare pathogenic variants (“monogenic”) or by the aggregate effect of multiple, common53 small-effect variants (“polygenic”)
First, in a cohort of 628 patients referred for genetic familial hypercholesterolemia (FH) testing, we evaluated the distribution of a polygenic score (PS) for LDL-C comprising 12 variants
The mean PS was higher in 533 FH-variant-negative patients (FH/M-) compared with 95 FHvariant carriers (1.02 vs 0.94, p

Summary

Introduction

High plasma levels of low-density lipoprotein cholesterol (LDL-C) have been shown to cause50 atherosclerotic cardiovascular disease (CVD) [1]; a leading cause of morbidity and mortality [2].51 Genetic susceptibility to severe hypercholesterolemia (generally defined as LDL-C >4.9 mmol/) may 52 be caused by rare pathogenic variants (“monogenic”) or by the aggregate effect of multiple, common53 small-effect variants (“polygenic”). The relatively low number of variants and the consistent association with LDL-C levels, make this PS an inexpensive and easy-to-implement addition to regular FH sequencing methods to identify patients with ‘polygenic hypercholesterolemia’. This original PS (or variations with fewer variants) is used in clinical research settings [7,8,9,10,11,12,13,14,15,16], but its exact relevance and translation to clinically actionable advice. 31 LDL-C variation and coronary artery disease (CAD) risk in patients diagnosed with a clinical FH

Methods

Results

Conclusion