Partitioned polygenic risk scores identify distinct types of metabolic dysfunction-associated steatotic liver disease.

Autor: Jamialahmadi O; Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden. oveis.jamialahmadi@wlab.gu.se., De Vincentis A; Operative Unit of Internal Medicine, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy.; Research Unit of Internal Medicine, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy., Tavaglione F; Operative Unit of Clinical Medicine and Hepatology, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy.; Research Unit of Clinical Medicine and Hepatology, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy., Malvestiti F; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy., Li-Gao R; Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands., Mancina RM; Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden.; Research Unit of Clinical Medicine and Hepatology, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy.; Department of Life Science, Health, and Health Professions, Link Campus University, Rome, Italy., Alvarez M; Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA., Gelev K; Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA., Maurotti S; Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy., Vespasiani-Gentilucci U; Operative Unit of Clinical Medicine and Hepatology, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy.; Research Unit of Clinical Medicine and Hepatology, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy., Rosendaal FR; Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands., Kozlitina J; The Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA., Pajukanta P; Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.; Bioinformatics Interdepartmental Program, UCLA, Los Angeles, CA, USA.; Institute for Precision Health, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA., Pattou F; Service de chirurgie générale et endocrinienne, Centre Hospitalier Universitaire de Lille, Lille, France.; European Genomic Institute for Diabetes, UMR 1190 Translational Research for Diabetes, Inserm, CHU Lille, University of Lille, Lille, France., Valenti L; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.; Precision Medicine - Biological Resource Center, Department of Transfusion Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy., Romeo S; Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden. stefano.romeo@ki.se.; Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden. stefano.romeo@ki.se.; Clinical Nutrition Unit, Department of Medical and Surgical Sciences, University Magna Graecia, Catanzaro, Italy. stefano.romeo@ki.se.; Department of Medicine (H7), Karolinska Institute, Huddinge, Stockholm, Sweden. stefano.romeo@ki.se.; Department of Endocrinology, Karolinska University Hospital, Huddinge, Stockholm, Sweden. stefano.romeo@ki.se.
Jazyk: angličtina
Zdroj: Nature medicine [Nat Med] 2024 Dec; Vol. 30 (12), pp. 3614-3623. Date of Electronic Publication: 2024 Dec 09.
DOI: 10.1038/s41591-024-03284-0
Abstrakt: Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by an excess of lipids, mainly triglycerides, in the liver and components of the metabolic syndrome, which can lead to cirrhosis and liver cancer. While there is solid epidemiological evidence that MASLD clusters with cardiometabolic disease, several leading genetic risk factors for MASLD do not increase the risk of cardiovascular disease, suggesting no causal relationship between MASLD and cardiometabolic derangement. In this work, we leveraged measurements of visceral adiposity identifying 27 previously unknown genetic loci associated with MASLD (n = 36,394), six replicated in four independent cohorts (n = 3,903). Next, we generated two partitioned polygenic risk scores based on the presence of lipoprotein retention in the liver. The two polygenic risk scores suggest the presence of at least two distinct types of MASLD, one confined to the liver resulting in a more aggressive liver disease and one that is systemic and results in a higher risk of cardiometabolic disease. These findings shed light on the heterogeneity of MASLD and have the potential to improve the prediction of clinical trajectories and inform precision medicine approaches.
Competing Interests: Competing interests: S.R. has been consulting for AstraZeneca, GSK, Celgene Corporation, Ribo-cure AB and Pfizer in the last 5 years and received a research grant from AstraZeneca. The funders had no role in the design of the study; in the collection, analyses or interpretation of data; in the writing of the paper or in the decision to publish the results. L.V. has received speaking fees from MSD, Gilead, AlfaSigma and AbbVie, served as a consultant for Gilead, Pfizer, AstraZeneca, Novo Nordisk, Intercept, Diatech Pharmacogenetics, Ionis Pharmaceuticals, Boehringer Ingelheim and Resalis Therapeutics, and received unrestricted research grants from Gilead. R.L.G. is a part-time contractor for Metabolon. O.J. is a part-time consultant to Ribo-cure AB. The other authors declare no competing interests.
(© 2024. The Author(s).)
Databáze: MEDLINE
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