Programmed cell death 1 genetic variant and liver damage in nonalcoholic fatty liver disease
Rosaria M. Pipitone
Sezione di Gastroenterologia e Epatologia, Dipartimento di Promozione della Salute, Materno-Infantile, di Medicina Interna e Specialistica di Eccellenza “G. D'Alessandro”, University of Palermo, Palermo, Italy
Search for more papers by this authorFrancesco Malvestiti
Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
Search for more papers by this authorGrazia Pennisi
Sezione di Gastroenterologia e Epatologia, Dipartimento di Promozione della Salute, Materno-Infantile, di Medicina Interna e Specialistica di Eccellenza “G. D'Alessandro”, University of Palermo, Palermo, Italy
Search for more papers by this authorOveis Jamialahmadi
Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Search for more papers by this authorPaola Dongiovanni
General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
Search for more papers by this authorGiorgio Bertolazzi
Tumor Immunology Unit, University of Palermo School of Medicine, Palermo, Italy
Search for more papers by this authorJussi Pihlajamäki
Department of Clinical Nutrition, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
Search for more papers by this authorHannele Yki-Järvinen
Department of Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
Search for more papers by this authorUmberto Vespasiani-Gentilucci
Clinical Medicine and Hepatology Unit, Department of Internal Medicine and Geriatrics, Campus Bio-Medico University, Rome, Italy
Search for more papers by this authorFederica Tavaglione
Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Clinical Medicine and Hepatology Unit, Department of Internal Medicine and Geriatrics, Campus Bio-Medico University, Rome, Italy
Search for more papers by this authorSamantha Maurotti
Nutrition Unit, Department of Medical and Surgical Sciences, Magna Graecia University Catanzaro, Catanzaro, Italy
Search for more papers by this authorCristiana Bianco
Precision Medicine, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Cà Granda Pad Marangoni, Milan, Italy
Search for more papers by this authorGabriele Di Maria
Precision Medicine, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Cà Granda Pad Marangoni, Milan, Italy
Search for more papers by this authorMarco Enea
Department of Health Promotion Sciences Maternal and Infant Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, Palermo, Italy
Search for more papers by this authorAnna L. Fracanzani
Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
Search for more papers by this authorVesa Kärjä
Department of Clinical Nutrition, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
Search for more papers by this authorGiulia Lupo
Sezione di Gastroenterologia e Epatologia, Dipartimento di Promozione della Salute, Materno-Infantile, di Medicina Interna e Specialistica di Eccellenza “G. D'Alessandro”, University of Palermo, Palermo, Italy
Search for more papers by this authorVille Männistö
Department of Clinical Nutrition, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
Search for more papers by this authorMarica Meroni
General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
Search for more papers by this authorRoberto Piciotti
General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
Search for more papers by this authorSami Qadri
Department of Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
Search for more papers by this authorRossella Zito
Sezione di Gastroenterologia e Epatologia, Dipartimento di Promozione della Salute, Materno-Infantile, di Medicina Interna e Specialistica di Eccellenza “G. D'Alessandro”, University of Palermo, Palermo, Italy
Search for more papers by this authorAntonio Craxì
Sezione di Gastroenterologia e Epatologia, Dipartimento di Promozione della Salute, Materno-Infantile, di Medicina Interna e Specialistica di Eccellenza “G. D'Alessandro”, University of Palermo, Palermo, Italy
Search for more papers by this authorVito Di Marco
Sezione di Gastroenterologia e Epatologia, Dipartimento di Promozione della Salute, Materno-Infantile, di Medicina Interna e Specialistica di Eccellenza “G. D'Alessandro”, University of Palermo, Palermo, Italy
Search for more papers by this authorCalogero Cammà
Sezione di Gastroenterologia e Epatologia, Dipartimento di Promozione della Salute, Materno-Infantile, di Medicina Interna e Specialistica di Eccellenza “G. D'Alessandro”, University of Palermo, Palermo, Italy
Search for more papers by this authorClaudio Tripodo
Tumor Immunology Unit, University of Palermo School of Medicine, Palermo, Italy
Search for more papers by this authorLuca Valenti
Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
Precision Medicine, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Cà Granda Pad Marangoni, Milan, Italy
Search for more papers by this authorStefano Romeo
Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Nutrition Unit, Department of Medical and Surgical Sciences, Magna Graecia University Catanzaro, Catanzaro, Italy
Cardiology Department, Sahlgrenska University Hospital, Gothenburg, Sweden
Search for more papers by this authorCorresponding Author
Salvatore Petta
Sezione di Gastroenterologia e Epatologia, Dipartimento di Promozione della Salute, Materno-Infantile, di Medicina Interna e Specialistica di Eccellenza “G. D'Alessandro”, University of Palermo, Palermo, Italy
Correspondence
Salvatore Petta, Sezione di Gastroenterologia e Epatologia, Di.Bi.M.I.S., Università di Palermo, Piazza delle Cliniche, 2, 90127 Palermo, Italy.
Email: [email protected]
Search for more papers by this authorStefania Grimaudo
Sezione di Gastroenterologia e Epatologia, Dipartimento di Promozione della Salute, Materno-Infantile, di Medicina Interna e Specialistica di Eccellenza “G. D'Alessandro”, University of Palermo, Palermo, Italy
Search for more papers by this authorRosaria M. Pipitone
Sezione di Gastroenterologia e Epatologia, Dipartimento di Promozione della Salute, Materno-Infantile, di Medicina Interna e Specialistica di Eccellenza “G. D'Alessandro”, University of Palermo, Palermo, Italy
Search for more papers by this authorFrancesco Malvestiti
Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
Search for more papers by this authorGrazia Pennisi
Sezione di Gastroenterologia e Epatologia, Dipartimento di Promozione della Salute, Materno-Infantile, di Medicina Interna e Specialistica di Eccellenza “G. D'Alessandro”, University of Palermo, Palermo, Italy
Search for more papers by this authorOveis Jamialahmadi
Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Search for more papers by this authorPaola Dongiovanni
General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
Search for more papers by this authorGiorgio Bertolazzi
Tumor Immunology Unit, University of Palermo School of Medicine, Palermo, Italy
Search for more papers by this authorJussi Pihlajamäki
Department of Clinical Nutrition, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
Search for more papers by this authorHannele Yki-Järvinen
Department of Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
Search for more papers by this authorUmberto Vespasiani-Gentilucci
Clinical Medicine and Hepatology Unit, Department of Internal Medicine and Geriatrics, Campus Bio-Medico University, Rome, Italy
Search for more papers by this authorFederica Tavaglione
Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Clinical Medicine and Hepatology Unit, Department of Internal Medicine and Geriatrics, Campus Bio-Medico University, Rome, Italy
Search for more papers by this authorSamantha Maurotti
Nutrition Unit, Department of Medical and Surgical Sciences, Magna Graecia University Catanzaro, Catanzaro, Italy
Search for more papers by this authorCristiana Bianco
Precision Medicine, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Cà Granda Pad Marangoni, Milan, Italy
Search for more papers by this authorGabriele Di Maria
Precision Medicine, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Cà Granda Pad Marangoni, Milan, Italy
Search for more papers by this authorMarco Enea
Department of Health Promotion Sciences Maternal and Infant Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, Palermo, Italy
Search for more papers by this authorAnna L. Fracanzani
Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
Search for more papers by this authorVesa Kärjä
Department of Clinical Nutrition, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
Search for more papers by this authorGiulia Lupo
Sezione di Gastroenterologia e Epatologia, Dipartimento di Promozione della Salute, Materno-Infantile, di Medicina Interna e Specialistica di Eccellenza “G. D'Alessandro”, University of Palermo, Palermo, Italy
Search for more papers by this authorVille Männistö
Department of Clinical Nutrition, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
Search for more papers by this authorMarica Meroni
General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
Search for more papers by this authorRoberto Piciotti
General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
Search for more papers by this authorSami Qadri
Department of Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
Search for more papers by this authorRossella Zito
Sezione di Gastroenterologia e Epatologia, Dipartimento di Promozione della Salute, Materno-Infantile, di Medicina Interna e Specialistica di Eccellenza “G. D'Alessandro”, University of Palermo, Palermo, Italy
Search for more papers by this authorAntonio Craxì
Sezione di Gastroenterologia e Epatologia, Dipartimento di Promozione della Salute, Materno-Infantile, di Medicina Interna e Specialistica di Eccellenza “G. D'Alessandro”, University of Palermo, Palermo, Italy
Search for more papers by this authorVito Di Marco
Sezione di Gastroenterologia e Epatologia, Dipartimento di Promozione della Salute, Materno-Infantile, di Medicina Interna e Specialistica di Eccellenza “G. D'Alessandro”, University of Palermo, Palermo, Italy
Search for more papers by this authorCalogero Cammà
Sezione di Gastroenterologia e Epatologia, Dipartimento di Promozione della Salute, Materno-Infantile, di Medicina Interna e Specialistica di Eccellenza “G. D'Alessandro”, University of Palermo, Palermo, Italy
Search for more papers by this authorClaudio Tripodo
Tumor Immunology Unit, University of Palermo School of Medicine, Palermo, Italy
Search for more papers by this authorLuca Valenti
Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
Precision Medicine, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Cà Granda Pad Marangoni, Milan, Italy
Search for more papers by this authorStefano Romeo
Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Nutrition Unit, Department of Medical and Surgical Sciences, Magna Graecia University Catanzaro, Catanzaro, Italy
Cardiology Department, Sahlgrenska University Hospital, Gothenburg, Sweden
Search for more papers by this authorCorresponding Author
Salvatore Petta
Sezione di Gastroenterologia e Epatologia, Dipartimento di Promozione della Salute, Materno-Infantile, di Medicina Interna e Specialistica di Eccellenza “G. D'Alessandro”, University of Palermo, Palermo, Italy
Correspondence
Salvatore Petta, Sezione di Gastroenterologia e Epatologia, Di.Bi.M.I.S., Università di Palermo, Piazza delle Cliniche, 2, 90127 Palermo, Italy.
Email: [email protected]
Search for more papers by this authorStefania Grimaudo
Sezione di Gastroenterologia e Epatologia, Dipartimento di Promozione della Salute, Materno-Infantile, di Medicina Interna e Specialistica di Eccellenza “G. D'Alessandro”, University of Palermo, Palermo, Italy
Search for more papers by this authorRosaria Maria Pipitone, Francesco Malvestiti, Grazia Pennisi and Oveis Jamialahmadi equally contributed to the paper.
Luca Valenti, Stefano Romeo, Salvatore Petta and Stefania Grimaudo equally contributed to the paper.
Handling Editor: Alejandro Forner
Abstract
Background and Aims
Programmed cell death 1/programmed cell death-ligand 1 (PD-1/PDL-1) axis has been reported to modulate liver inflammation and progression to hepatocellular carcinoma (HCC) in patients with nonalcoholic fatty liver disease (NAFLD). Here, we examined whether the PDCD1 variation is associated with NAFLD severity in individuals with liver biopsy.
Methods
We examined the impact of PDCD1 gene variants on HCC, as robust severe liver disease phenotype in UK Biobank participants. The strongest genetic association with the rs13023138 G>C variation was subsequently tested for association with liver damage in 2889 individuals who underwent liver biopsy for suspected nonalcoholic steatohepatitis (NASH). Hepatic transcriptome was examined by RNA-Seq in a subset of NAFLD individuals (n = 121). Transcriptomic and deconvolution analyses were performed to identify biological pathways modulated by the risk allele.
Results
The rs13023138 C>G showed the most robust association with HCC in UK Biobank (p = 5.28E-4, OR = 1.32, 95% CI [1.1, 1.5]). In the liver biopsy cohort, rs13023138 G allele was independently associated with severe steatosis (OR 1.17, 95% CI 1.02-1.34; p = .01), NASH (OR 1.22, 95% CI 1.09-1.37; p < .001) and advanced fibrosis (OR 1.26, 95% CI 1.06-1.50; p = .007). At deconvolution analysis, rs13023138 G>C allele was linked to higher hepatic representation of M1 macrophages, paralleled by upregulation of pathways related to inflammation and higher expression of CXCR6.
Conclusions
The PDCD1 rs13023138 G allele was associated with HCC development in the general population and with liver disease severity in patients at high risk of NASH.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflicts of interest.
Supporting Information
| Filename | Description |
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| liv15586-sup-0001-Supplementary Figures.pptxPowerPoint 2007 presentation , 455.3 KB |
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| liv15586-sup-0002-Supplementary Tables 1-2-3-4-5-8.docxWord 2007 document , 88.3 KB |
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| liv15586-sup-0003-Supplementary Table 6.xlsxExcel 2007 spreadsheet , 40.2 KB |
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| liv15586-sup-0004-Supplementary Table 7.xlsxExcel 2007 spreadsheet , 460.1 KB |
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| liv15586-sup-0005-Supplementary Table 9.xlsxExcel 2007 spreadsheet , 58.1 KB |
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