A new 165-SNP low-density lipoprotein cholesterol polygenic risk score based on next generation sequencing outperforms previously published scores in routine diagnostics of familial hypercholesterolemia

• Published in: Translational research : the journal of laboratory and clinical medicine 2023-05, Vol.255, p.119-127
• Main Authors: Vanhoye, Xavier, Bardel, Claire, Rimbert, Antoine, Moulin, Philippe, Rollat-Farnier, Pierre-Antoine, Muntaner, Manon, Marmontel, Oriane, Dumont, Sabrina, Charrière, Sybil, Cornélis, François, Ducluzeau, Pierre Henri, Fonteille, Annie, Nobecourt, Estelle, Peretti, Noël, Schillo, Franck, Wargny, Matthieu, Cariou, Bertrand, Meirhaeghe, Aline, Di Filippo, Mathilde
• Format: Article
• Language: English
• Subjects: APOB, apolipoprotein B; APOE, apolipoprotein E; Cholesterol, LDL - genetics; High-Throughput Nucleotide Sequencing; Humans; Hypercholesterolemia - diagnosis; Hypercholesterolemia - genetics; Hyperlipoproteinemia Type II - diagnosis; Hyperlipoproteinemia Type II - genetics; LDLR, low density lipoprotein receptor; Life Sciences; Mutation; PCSK9, proprotein convertase subtilisin/kexin type 9; Proprotein Convertase 9 - genetics; Receptors, LDL - genetics; Risk Factors
• ISSN: 1931-5244; 1878-1810
• DOI: 10.1016/j.trsl.2022.12.002

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