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PCSK9 rs11591147 R46L Loss-of-Function Variant Protects Against Liver Damage in Individuals with NAFLD

34 Pages Posted: 19 May 2020

See all articles by Stefania Grimaudo

Stefania Grimaudo

University of Palermo - Section of Gastroenterology and Hepatology

Stefano Bartesaghi

AstraZeneca Pharmaceuticals - Bioscience Metabolism, Research and Early Development Cardiovascular, Renal and Metabolism (CVRM)

Raffaela Rametta

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

Fabio Della Marra

University of Parma - Dipartimento di Economia

Rosellina Margherita Mancina

University of Gothenburg - Department of Molecular and Clinical Medicine

Jussi Pihlajamäki

University of Eastern Finland - Department of Clinical Nutrition

Dorota Kakol-Palm

AstraZeneca Pharmaceuticals - Bioscience Metabolism, Research and Early Development Cardiovascular, Renal and Metabolism (CVRM)

Anne-Christine Andréasson

AstraZeneca Pharmaceuticals - Bioscience Cardiovascular, Research and Early Development Cardiovascular, Renal and Metabolism

Paola Dongiovanni

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico - General Medicine and Metabolic Diseases

Anna Ludovica Fracanzani

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

Giulia Lori

University of Florence - Department of Experimental and Clinical Medicine

Ville Männistö

University of Eastern Finland - Department of Medicine

Giovanni Pellegrini

affiliation not provided to SSRN

Mohammad Bohlooly-Y

AstraZeneca Pharmaceuticals - IMED Biotech Unit

Grazia Pennisi

University of Palermo - Section of Gastroenterology and Hepatology

Rosaria Maria Pipitone

University of Palermo - Biomedical Department of Internal and Specialized Medicine (DI.BI.M.I.S.)

Rocco Spagnuolo

Magna Graecia University of Catanzaro - Department of Experimental and Clinical Medicine

Antonio Craxì

University of Palermo - Section of Gastroenterology and Hepatology

Daniel Lindén

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico - General Medicine and Metabolic Diseases

Luca Valenti

University of Milan - Department of Pathophysiology and Transplantation

Stefano Romeo

University of Gothenburg - Department of Molecular and Clinical Medicine

Salvatore Petta

University of Palermo - Section of Gastroenterology and Hepatology

More...

Abstract

Background and Aims: The proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in cholesterol homeostasis, and its inhibition represents an effective therapy to lower LDL-C levels. In this study, we examined the impact of PCSK9 rs11591147 loss-of-function (LOF) variant on liver damage in a multicenter collection of patients at risk of nonalcoholic steatohepatitis (NASH), in clinical samples and experimental models.

Methods: We considered 1,874 consecutive individuals at risk of NASH as determined by histology. The SNP rs11591147, encoding for the p.R46L variant of PCSK9, was genotyped by TaqMan assays. We also evaluated 1) PCSK9 mRNA hepatic expression in human liver, and 2) the impact of a NASH-inducing diet in mice with hepatic overexpression of human PCSK9.

Results: Carriers of PCSK9 rs11591147 had lower circulating LDL-C levels and were protected against NAFLD (OR 0.42;95%C.I0.22-0.81;P=0.01), NASH (OR 0.39;95%C.I.0.20-0.75;P=0.005) and more severe fibrosis (OR 0.44;95%C.I.0.26-0.74;P=0.002) independently of clinical, metabolic and genetic confounding factors. PCSK9 hepatic expression was directly correlated with steatosis (P=0.03). Finally, liver-specific overexpression of human PCSK9 in mice drives NAFLD and fibrosis upon a dietary challenge.

Conclusions: In individuals at risk, PCSK9 was induced with hepatic fat accumulation and PCSK9 rs11591147 LOF variant was protective against liver steatosis, NASH and fibrosis, suggesting PCSK9 inhibition may be a new therapeutic strategy to treat NASH.

Funding Statement: This work was supported by project grant by the Swedish Research Council [Vetenskapsrådet (VR), 2016-01527], the Swedish state under the Agreement between the Swedish government and the county councils (the ALF-agreement) [SU 2018-04276], the Novonordisk Foundation Grant for Excellence in Endocrinology [Excellence Project, 9321- 430], the Swedish Diabetes Foundation [DIA 2017-205], the Swedish Heart Lung Foundation [20120533], the Wallenberg Academy Fellows from the Knut and Alice Wallenberg Foundation [KAW 2017.0203]. LV was supported by MyFirst Grant AIRC n.16888, Ricerca Finalizzata Ministero della Salute [RF-2016-02364358], Ricerca corrente Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Fondazione Sviluppo Cà Granda [PR-0316], the European Union Programme Horizon 2020 [No. 777377].

Declaration of Interests: SR has been consulting for AMGEN, SANOFI, Astra Zeneca, Pfizer, AKCEA, Celgene, Medacorp, Foresite Labs, CAMP4 and received research grants from Astra Zeneca, AMGEN, SANOFI. SB, DK-P, A-CA, GP, MB-Y and DL are AstraZeneca employees. LV reports having received during the last 5 years speaking fees from MSD, Gilead, AlfaSigma, AbbVie, having served as a consultant of: Gilead, Pfizer, Astra Zeneca, Novo Nordisk, Diatech Pharmacogenetics and Intercept, and having received research grants from: Gilead.

Ethics Approval Statement: The study was carried out in accordance with the principles of the Helsinki Declaration, and with local and national laws. Approval was obtained from Internal Review Boards and their Ethics Committees, and written informed consent for the study was obtained from all patients

All animal experiments were performed with humane care and were approved by the Gothenburg Ethics Committee for Experimental Animals in Sweden. The holding facility has received full accreditation from the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC).

Keywords: NASH, NAFLD, FIBROSIS, PCSK9

Suggested Citation

Grimaudo, Stefania and Bartesaghi, Stefano and Rametta, Raffaela and Della Marra, Fabio and Margherita Mancina, Rosellina and Pihlajamäki, Jussi and Kakol-Palm, Dorota and Andréasson, Anne-Christine and Dongiovanni, Paola and Fracanzani, Anna Ludovica and Lori, Giulia and Männistö, Ville and Pellegrini, Giovanni and Bohlooly-Y, Mohammad and Pennisi, Grazia and Pipitone, Rosaria Maria and Spagnuolo, Rocco and Craxì, Antonio and Lindén, Daniel and Valenti, Luca and Romeo, Stefano and Petta, Salvatore, PCSK9 rs11591147 R46L Loss-of-Function Variant Protects Against Liver Damage in Individuals with NAFLD (3/20/2020). Available at SSRN: https://ssrn.com/abstract=3559589 or http://dx.doi.org/10.2139/ssrn.3559589

Stefania Grimaudo

University of Palermo - Section of Gastroenterology and Hepatology

Palermo
Italy

Stefano Bartesaghi

AstraZeneca Pharmaceuticals - Bioscience Metabolism, Research and Early Development Cardiovascular, Renal and Metabolism (CVRM)

Gothenburg
Sweden

Raffaela Rametta

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

Via Manfredo Fanti, 6
Milano, 20122
Italy

Fabio Della Marra

University of Parma - Dipartimento di Economia ( email )

Via Kennedy 6
Parma, Parma 43100
Italy

Rosellina Margherita Mancina

University of Gothenburg - Department of Molecular and Clinical Medicine

PO Box 400
Göteborg, SE405 30
Sweden

Jussi Pihlajamäki

University of Eastern Finland - Department of Clinical Nutrition

Kuopio
Finland

Dorota Kakol-Palm

AstraZeneca Pharmaceuticals - Bioscience Metabolism, Research and Early Development Cardiovascular, Renal and Metabolism (CVRM)

Gothenburg
Sweden

Anne-Christine Andréasson

AstraZeneca Pharmaceuticals - Bioscience Cardiovascular, Research and Early Development Cardiovascular, Renal and Metabolism

Sweden

Paola Dongiovanni

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico - General Medicine and Metabolic Diseases

Via Manfredo Fanti, 6
Milano, 20122
Italy

Anna Ludovica Fracanzani

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

Via Manfredo Fanti, 6
Milano, 20122
Italy

Giulia Lori

University of Florence - Department of Experimental and Clinical Medicine

Florence
Italy

Ville Männistö

University of Eastern Finland - Department of Medicine

Kuopio
Finland

Giovanni Pellegrini

affiliation not provided to SSRN

Mohammad Bohlooly-Y

AstraZeneca Pharmaceuticals - IMED Biotech Unit ( email )

Mölndal
Sweden
+46-31-7064181 (Phone)

Grazia Pennisi

University of Palermo - Section of Gastroenterology and Hepatology

Palermo
Italy

Rosaria Maria Pipitone

University of Palermo - Biomedical Department of Internal and Specialized Medicine (DI.BI.M.I.S.)

Palermo
Italy

Rocco Spagnuolo

Magna Graecia University of Catanzaro - Department of Experimental and Clinical Medicine

Catanzaro, 88100
Italy

Antonio Craxì

University of Palermo - Section of Gastroenterology and Hepatology ( email )

Palermo
Italy

Daniel Lindén

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico - General Medicine and Metabolic Diseases

Milan
Italy

Luca Valenti

University of Milan - Department of Pathophysiology and Transplantation ( email )

Milan, 20122
Italy

Stefano Romeo

University of Gothenburg - Department of Molecular and Clinical Medicine

Viktoriagatan 30
Göteborg, 405 30
Sweden

Salvatore Petta (Contact Author)

University of Palermo - Section of Gastroenterology and Hepatology ( email )

Palermo
Italy