Phenotypic Differences Between Polygenic and Monogenic Hypobetalipoproteinemia-Reference-Cited by-同舟云学术

Phenotypic Differences Between Polygenic and Monogenic Hypobetalipoproteinemia

Published:2020-11-19 Issue: Volume: Page:
ISSN:1079-5642
Container-title:Arteriosclerosis, Thrombosis, and Vascular Biology
language:en
Short-container-title:ATVB

Author:

Rimbert Antoine¹,Vanhoye Xavier²^ORCID,Coulibaly Dramane²,Marrec Marie³,Pichelin Matthieu¹³,Charrière Sybil⁴⁵,Peretti Noël⁴⁶,Valéro René⁷,Wargny Matthieu¹³,Carrié Alain⁸⁹,Lindenbaum Pierre¹,Deleuze Jean-François¹⁰,Genin Emmanuelle¹¹^ORCID,Redon Richard¹,Rollat-Farnier Pierre Antoine¹²,Goxe Didier¹³,Degraef Gilles¹⁴,Marmontel Oriane²⁴^ORCID,Divry Eléonore²,Bigot-Corbel Edith¹⁵,Moulin Philippe⁴⁵,Cariou Bertrand¹³^ORCID,Di Filippo Mathilde²⁴^ORCID

Affiliation:

1. Université de Nantes, CNRS, INSERM, l’institut du thorax, France (A.R., M.P., M.W., P.L., R.R., B.C.).

2. Hospices Civils de Lyon, UF Dyslipidémies Service de Biochimie et de Biologie Moléculaire Grand Est, Bron, France (X.V., D.C., O.M., E.D., M.D.F.).

3. L’institut du thorax, CHU NANTES, CIC INSERM 1413, France (M.M., M.P., M.W., B.C.).

4. CarMen Laboratory, INSERM, INRA, INSA Lyon, Université Claude Bernard Lyon 1, Pierre-Bénite, France (S.C., N.P., O.M., P.M., M.D.F.).

5. Hospices Civils de Lyon, Fédération d’endocrinologie, maladies métaboliques, diabète et nutrition, Hôpital Louis Pradel, Bron, France (S.C., P.M.).

6. Hospices Civils de Lyon, Service de Gastroentérologie Hépatologie et Nutrition Pédiatrique, HFME, Bron, France (N.P.).

7. Aix Marseille Univ, APHM, INSERM, INRAE, C2VN, University Hospital La Conception, Department of Nutrition, Metabolic Diseases and Endocrinology, Marseille, France (R.V.).

8. Sorbonne Universite, Inserm UMR_S116, Institute of Cardiometabolism and Nutrition (ICAN), Hopital Pitie-Salpetriere75651 Paris, France (A.C.).

9. UF de génétique de l’Obésité et des Dyslipidémies, Laboratoire de Biochimie Endocrinienne et Oncologique, APHP, Sorbonne Université, Hôpital de la Pitié-salpêtrière, Paris, France (A.C.).

10. Centre National de Recherche en Génomique Humaine, Institut de Génomique, CEA, Evry, France (J.-F.D.).

11. Inserm, Univ Brest, EFS, CHU Brest, UMR 1078, GGB, France (E.G.).

12. Hospices Civils de Lyon, Service de Biostatistique-Bioinformatique, Bron, France (P.A.R.-F.).

13. CPAM, Centre d’examens de santé de la CPAM de la Vendée, La Roche-sur-Yon, France (D.G.).

14. Biolance, Biolance, Nantes, France (G.D.).

15. Laboratoire de Biochimie, CHU de Nantes, Hôpital G et R Laënnec, Bd Jacques Monod, Saint-Herblain (E.B.-C.).

Abstract

Objective: Primary hypobetalipoproteinemia is characterized by LDL-C (low-density lipoprotein cholesterol) concentrations below the fifth percentile. Primary hypobetalipoproteinemia mostly results from heterozygous mutations in the APOB and PCSK9 genes, and a polygenic origin is hypothesized in the remaining cases. Hypobetalipoproteinemia patients present an increased risk of nonalcoholic fatty liver disease and steatohepatitis. Here, we compared hepatic alterations between monogenic, polygenic, and primary hypobetalipoproteinemia of unknown cause. Approach and Results: Targeted next-generation sequencing was performed in a cohort of 111 patients with hypobetalipoproteinemia to assess monogenic and polygenic origins using an LDL-C-dedicated polygenic risk score. Forty patients (36%) had monogenic hypobetalipoproteinemia, 38 (34%) had polygenic hypobetalipoproteinemia, and 33 subjects (30%) had hypobetalipoproteinemia from an unknown cause. Patients with monogenic hypobetalipoproteinemia had lower LDL-C and apolipoprotein B plasma levels compared with those with polygenic hypobetalipoproteinemia. Liver function was assessed by hepatic ultrasonography and liver enzymes levels. Fifty-nine percent of patients with primary hypobetalipoproteinemia presented with liver steatosis, whereas 21% had increased alanine aminotransferase suggestive of liver injury. Monogenic hypobetalipoproteinemia was also associated with an increased prevalence of liver steatosis (81% versus 29%, P <0.001) and liver injury (47% versus 0%) compared with polygenic hypobetalipoproteinemia. Conclusions: This study highlights the importance of genetic diagnosis in the clinical care of primary hypobetalipoproteinemia patients. It shows for the first time that a polygenic origin of hypobetalipoproteinemia is associated with a lower risk of liver steatosis and liver injury versus monogenic hypobetalipoproteinemia. Thus, polygenic risk score is a useful tool to establish a more personalized follow-up of primary hypobetalipoproteinemia patients.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine

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