| Title: | Assessment of practical applicability and clinical relevance of a commonly used LDL-C polygenic score in patients with severe hypercholesterolemia |
| Journal: | Atherosclerosis |
| Published: | 2 Nov 2021 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/34774301/ |
| DOI: | https://doi.org/10.1016/j.atherosclerosis.2021.10.015 |
| URL: | http://www.atherosclerosis-journal.com/article/S0021915021014131/pdf |
Publication 4115
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Abstract
BACKGROUND AND AIMS: Low-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.</p>
METHODS: First, 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.</p>
RESULTS: The 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.</p>
CONCLUSIONS: This 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.</p>
7 Keywords
- Cholesterol, LDL
- Heterozygote
- Humans
- Hypercholesterolemia
- Hyperlipoproteinemia Type II
- Multifactorial Inheritance
- Risk Factors
8 Authors
- Tycho R Tromp
- Arjen J Cupido
- Laurens F Reeskamp
- Erik S G Stroes
- G Kees Hovingh
- Joep C Defesche
- Amand F Schmidt
- Linda Zuurbier
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