Abstract
Genetic diagnosis of familial hypercholesterolemia (FH) remains unexplained in 30
to 70% of patients after exclusion of monogenic disease. There is now a growing evidence
that a polygenic burden significantly modulates LDL-cholesterol (LDL-c) concentrations.
Several LDL-c polygenic risk scores (PRS) have been set up. However, the balance between
their diagnosis performance and their practical use in routine practice is not clearly
established. Consequently, we set up new PRS based on our routine panel for sequencing
and compared their diagnostic performance with previously-published PRS. After a meta-analysis,
four new PRS including 165 to 1633 SNP were setup using different softwares. They
were established using two French control cohorts (MONA LISA n=1082 and FranceGenRef
n=856). Then the explained LDL-c variance and the ability of each PRS to discriminate
monogenic negative FH patients (M-) versus healthy controls were compared with 4 previously-described PRS in 785 unrelated FH
patients. Between all PRS, the 165-SNP PRS developed with PLINK showed the best LDL-c
explained variance (adjusted R²=0.19) and the best diagnosis abilities (AUROC=0.77,
95%CI=0.74-0.79): it significantly outperformed all the previously-published PRS (p<1 × 10−4). By using a cut-off at the 75th percentile, 61% of M- patients exhibited a polygenic
hypercholesterolemia with the 165-SNP PRS versus 48% with the previously published 12-SNP PRS (p =3.3 × 10−6). These results were replicated using the UK biobank. This new 165-SNP PRS, usable
in routine diagnosis, exhibits better diagnosis abilities for a polygenic hypercholesterolemia
diagnosis. It would be a valuable tool to optimize referral for whole genome sequencing.
List of human genes
Abbreviations:
FH (familial hypercholesterolemia), LDL (low density lipoprotein), LDL-c (low density lipoprotein cholesterol), ASCVD (Atherosclerotic Cardiovascular Disease), SNP (single nucleotide polymorphism), GWAS (genome-wide association studies), PRS (polygenic risk scores), 2M-SNP (2 million SNP), NGS (next generation sequencing), FGR (FranceGenRef), CNIL (“Commission Nationale de l'Informatique et des Libertés”), DLCN (Dutch Lipid Clinic Network), ACMG (American College of Medical Genetics and Genomic), M+ (monogenic hypercholesterolemia), VUS (variant of uncertain significance), M- (mutation free patients), GLGC (Global Lipids Genetics Consortium), LD (linkage disequilibrium), ROC (receiver-operating characteristic), AUROC (Area under the ROC curve), WGS (Whole Genome Sequencing), CVD (cardio-vascular disease), Lp(a) (lipoprotein (a))To read this article in full you will need to make a payment
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REFERENCES
- Estimating the prevalence of heterozygous familial hypercholesterolaemia: a systematic review and meta-analysis.BMJ Open. 2017; 7e016461https://doi.org/10.1136/bmjopen-2017-016461
- Prevalence of familial hypercholesterolemia among the general population and patients with atherosclerotic cardiovascular disease: a systematic review and meta-analysis.Circulation. 2020; 141: 1742-1759https://doi.org/10.1161/CIRCULATIONAHA.119.044795
- Worldwide prevalence of familial hypercholesterolemia: meta-analyses of 11 million subjects.J Am Coll Cardiol. 2020; 75: 2553-2566https://doi.org/10.1016/j.jacc.2020.03.057
- Genetic testing for familial hypercholesterolaemia - past, present and future.J Lipid Res. 2021; (Published online October 16)100139https://doi.org/10.1016/j.jlr.2021.100139
- Lipid phenotype and heritage pattern in families with genetic hypercholesterolemia not related to LDLR, APOB, PCSK9, or APOE.J Clin Lipidol. 2016; 10 (e2): 1397-1405https://doi.org/10.1016/j.jacl.2016.09.011
- Newly identified loci that influence lipid concentrations and risk of coronary artery disease.Nat Genet. 2008; 40: 161-169https://doi.org/10.1038/ng.76
- Biological, clinical and population relevance of 95 loci for blood lipids.Nature. 2010; 466: 707-713https://doi.org/10.1038/nature09270
- Discovery and refinement of loci associated with lipid levels.Nat Genet. 2013; 45: 1274-1283https://doi.org/10.1038/ng.2797
- Exome-wide association study of plasma lipids in >300,000 individuals.Nat Genet. 2017; 49: 1758-1766https://doi.org/10.1038/ng.3977
- Deep-coverage whole genome sequences and blood lipids among 16,324 individuals.Nat Commun. 2018; 9: 3391https://doi.org/10.1038/s41467-018-05747-8
- Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study.Lancet Lond Engl. 2013; 381: 1293-1301https://doi.org/10.1016/S0140-6736(12)62127-8
- Cardiovascular disease risk associated with familial hypercholesterolemia: a systematic review of the literature.Clin Ther. 2016; 38: 1696-1709https://doi.org/10.1016/j.clinthera.2016.05.006
- Refinement of variant selection for the LDL cholesterol genetic risk score in the diagnosis of the polygenic form of clinical familial hypercholesterolemia and replication in samples from 6 countries.Clin Chem. 2015; 61: 231-238https://doi.org/10.1373/clinchem.2014.231365
- Genetics of blood lipids among ∼300,000 multi-ethnic participants of the Million Veteran Program.Nat Genet. 2018; 50: 1514-1523https://doi.org/10.1038/s41588-018-0222-9
- Risk of Premature Atherosclerotic Disease in Patients With Monogenic Versus Polygenic Familial Hypercholesterolemia.J Am Coll Cardiol. 2019; 74: 512-522https://doi.org/10.1016/j.jacc.2019.05.043
- Polygenic hypercholesterolemia: examples of GWAS results and their replication in the Czech-Slavonic population.Physiol Res. 2017; 66 (Suppl): S101-S111https://doi.org/10.33549/physiolres.933580
- Polygenic Versus Monogenic causes of hypercholesterolemia ascertained clinically.Arterioscler Thromb Vasc Biol. 2016; 36: 2439-2445https://doi.org/10.1161/ATVBAHA.116.308027
- Six years’ experience with LipidSeq: clinical and research learnings from a hybrid, targeted sequencing panel for dyslipidemias.BMC Med Genomics. 2020; 13: 23https://doi.org/10.1186/s12920-020-0669-2
- Familial hypercholesterolemia: experience from France.Curr Opin Lipidol. 2018; 29: 65-71https://doi.org/10.1097/MOL.0000000000000496
- Quantifying the polygenic contribution to variable expressivity in eleven rare genetic disorders.Nat Commun. 2019; 10: 4897https://doi.org/10.1038/s41467-019-12869-0
- Association of monogenic vs polygenic hypercholesterolemia with risk of atherosclerotic cardiovascular disease.JAMA Cardiol. 2020; 5: 390-399https://doi.org/10.1001/jamacardio.2019.5954
- Diagnostic et traitement des hypercholestérolémies familiales (HF) chez l'adulte : recommandations de la Nouvelle société française d'athérosclérose (NSFA).Presse Médicale. 2013; 42 (Part 1): 930-950https://doi.org/10.1016/j.lpm.2013.01.053
- Development of a new expanded next-generation sequencing panel for genetic diseases involved in dyslipidemia.Clin Genet. 2020; 98: 589-594https://doi.org/10.1111/cge.13832
- Probabilistic ancestry maps: a method to assess and visualize population substructures in genetics.BMC Bioinformatics. 2019; 20: 116https://doi.org/10.1186/s12859-019-2680-1
- A global reference for human genetic variation.Nature. 2015; 526: 68-74https://doi.org/10.1038/nature15393
- METAL: fast and efficient meta-analysis of genomewide association scans.Bioinformatics. 2010; 26: 2190-2191https://doi.org/10.1093/bioinformatics/btq340
- PLINK: a tool set for whole-genome association and population-based linkage analyses.Am J Hum Genet. 2007; 81: 559-575https://doi.org/10.1086/519795
- PRSice-2: polygenic risk score software for biobank-scale data.GigaScience. 2019; 8https://doi.org/10.1093/gigascience/giz082
- Polygenic scores via penalized regression on summary statistics.Genet Epidemiol. 2017; 41: 469-480https://doi.org/10.1002/gepi.22050
LDpred2: better, faster, stronger | bioRxiv. Accessed August 10, 2020. https://www.biorxiv.org/content/10.1101/2020.04.28.066720v1
- A large electronic-health-record-based genome-wide study of serum lipids.Nat Genet. 2018; 50: 401-413https://doi.org/10.1038/s41588-018-0064-5
- Association of apolipoprotein e genotypes with lipid levels and coronary risk.JAMA. 2007; 298: 1300https://doi.org/10.1001/jama.298.11.1300
- Genetics, lifestyle, and low-density lipoprotein cholesterol in young and apparently healthy women.Circulation. 2018; 137: 820-831https://doi.org/10.1161/CIRCULATIONAHA.117.032479
- Genetically confirmed familial hypercholesterolemia in patients with acute coronary syndrome.J Am Coll Cardiol. 2017; 70: 1732-1740https://doi.org/10.1016/j.jacc.2017.08.009
- Usefulness of the genetic risk score to identify phenocopies in families with familial hypercholesterolemia?.Eur J Hum Genet. 2018; 26: 570-578https://doi.org/10.1038/s41431-017-0078-y
- Diagnostic yield and clinical utility of sequencing familial hypercholesterolemia genes in patients with severe hypercholesterolemia.J Am Coll Cardiol. 2016; 67: 2578-2589https://doi.org/10.1016/j.jacc.2016.03.520
- Polygenic contribution to low-density lipoprotein cholesterol levels and cardiovascular risk in monogenic familial hypercholesterolemia.Circ Genomic Precis Med. 2020; 13: 515-523https://doi.org/10.1161/CIRCGEN.120.002919
- Polygenic scores to assess atherosclerotic cardiovascular disease risk.Circ Res. 2020; 126: 1159-1177https://doi.org/10.1161/CIRCRESAHA.120.315928
Article info
Publication history
Published online: December 14, 2022
Accepted:
December 9,
2022
Received in revised form:
November 14,
2022
Received:
February 24,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2022 Elsevier Inc. All rights reserved.
