• Xavier Vanhoye, Claire Bardel, Antoine Rimbert, Philippe Moulin, Pierre-Antoine Rollat-Farnier, Manon Muntaner, Oriane Marmontel, Sabrina Dumont, Sybil Charrière, François Cornélis, Pierre Henri Ducluzeau, Annie Fonteille, Estelle Nobecourt, Noël Peretti, Franck Schillo, Matthieu Wargny, Bertrand Cariou, Aline Meirhaeghe, and Di FilippoMathildeMService de Biochimie et de Biologie Moléculaire, Laboratoire de Biologie Médicale MultiSites, Hospices Civils de Lyon, Bron, France; Laboratoire CarMen, INSERM U1060, INRAE U1397, Oullins, France. Electronic address: mathilde.di-filippo.
• Service de Biochimie et de Biologie Moléculaire, Laboratoire de Biologie Médicale MultiSites, Hospices Civils de Lyon, Bron, France.
• Transl Res. 2023 May 1; 255: 119127119-127.

AbstractGenetic 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.Copyright © 2022 Elsevier Inc. All rights reserved.

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