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.

Autor: Vanhoye X; Service de Biochimie et de Biologie Moléculaire, Laboratoire de Biologie Médicale MultiSites, Hospices Civils de Lyon, Bron, France., Bardel C; Laboratoire de Biométrie et Biologie Evolutive UMR 5558, Université de Lyon, Université Lyon 1, CNRS, Villeurbanne, France; Plateforme de séquençage NGS HCL, Cellule bio-informatique, Hospices Civils de Lyon, Lyon, France., Rimbert A; Institut du thorax, Nantes Université, CHU Nantes, CNRS, Inserm, Nantes, France., Moulin P; Fédération d'endocrinologie, maladies métaboliques, diabète et nutrition, Hôpital Louis Pradel, Hospices Civils de Lyon, Lyon, France; Laboratoire CarMen, INSERM U1060, INRAE U1397, Oullins, France., Rollat-Farnier PA; Plateforme de séquençage NGS HCL, Cellule bio-informatique, Hospices Civils de Lyon, Lyon, France., Muntaner M; Institut Pasteur de Lille, U1167 - RID-AGE - Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Univ. Lille, INSERM, Centre Hospitalo-Universitaire Lille, Lille, France., Marmontel O; Service 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., Dumont S; Service de Biochimie et de Biologie Moléculaire, Laboratoire de Biologie Médicale MultiSites, Hospices Civils de Lyon, Bron, France., Charrière S; Fédération d'endocrinologie, maladies métaboliques, diabète et nutrition, Hôpital Louis Pradel, Hospices Civils de Lyon, Lyon, France; Laboratoire CarMen, INSERM U1060, INRAE U1397, Oullins, France., Cornélis F; Génétique - Oncogénétique Adulte - Prévention, Centre Hospitalo-Universitaire et Université Clermont-Auvergne, Clermont-Ferrand, France., Ducluzeau PH; Unité d'endocrinologie, Centre Hospitalo-Universitaire Bretonneau, Université de Tours, Tours, France., Fonteille A; Infectiologie, Médecine Interne, Médecine des voyages, Centre Hospitalier d'Annecy Genevois, Epagny Metz-Tessy, Annecy, France., Nobecourt E; Service d'Endocrinologie, Diabète et Nutrition et Centre d'Investigation Clinique - Epidémiologie Clinique (CIC-EC) U1410 INSERM, Centre Hospitalo-Universitaire de la Réunion, Saint-Pierre, La Réunion, France., Peretti N; Laboratoire CarMen, INSERM U1060, INRAE U1397, Oullins, France; Service de Gastroentérologie Hépatologie et Nutrition Pédiatrique, GHE, Hospices Civils de Lyon, Lyon, France., Schillo F; Service de Diabétologie-Endocrinologie-Nutrition, Centre Hospitalo-Universitaire Jean Minjoz Besançon France., Wargny M; Institut du thorax, Nantes Université, CHU Nantes, CNRS, Inserm, Nantes, France., Cariou B; Institut du thorax, Nantes Université, CHU Nantes, CNRS, Inserm, Nantes, France., Meirhaeghe A; Institut Pasteur de Lille, U1167 - RID-AGE - Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Univ. Lille, INSERM, Centre Hospitalo-Universitaire Lille, Lille, France., Di Filippo M; Service 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@chu-lyon.fr.
Jazyk: angličtina
Zdroj: Translational research : the journal of laboratory and clinical medicine [Transl Res] 2023 May; Vol. 255, pp. 119-127. Date of Electronic Publication: 2022 Dec 15.
DOI: 10.1016/j.trsl.2022.12.002
Abstrakt: 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.
(Copyright © 2022 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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