High producer variant of lipoprotein lipase may protect from hepatocellular carcinoma in alcohol-associated cirrhosis
Background & Aims: Progression of alcohol-associated liver disease (ALD) is driven by genetic predisposition. The rs13702 variant in the lipoprotein lipase (LPL) gene is linked to non-alcoholic fatty liver disease. We aimed at clarifying its role in ALD. Methods: Patients with alcohol-associ...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-04-01
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| Series: | JHEP Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589555923000150 |
| _version_ | 1797861067255185408 |
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| author | Franziska Schmalz Janett Fischer Hamish Innes Stephan Buch Christine Möller Madlen Matz-Soja Witigo von Schönfels Benjamin Krämer Bettina Langhans Alexandra Klüners Michael Soyka Felix Stickel Jacob Nattermann Christian P. Strassburg Thomas Berg Philipp Lutz Hans Dieter Nischalke |
| author_facet | Franziska Schmalz Janett Fischer Hamish Innes Stephan Buch Christine Möller Madlen Matz-Soja Witigo von Schönfels Benjamin Krämer Bettina Langhans Alexandra Klüners Michael Soyka Felix Stickel Jacob Nattermann Christian P. Strassburg Thomas Berg Philipp Lutz Hans Dieter Nischalke |
| author_sort | Franziska Schmalz |
| collection | DOAJ |
| description | Background & Aims: Progression of alcohol-associated liver disease (ALD) is driven by genetic predisposition. The rs13702 variant in the lipoprotein lipase (LPL) gene is linked to non-alcoholic fatty liver disease. We aimed at clarifying its role in ALD. Methods: Patients with alcohol-associated cirrhosis, with (n = 385) and without hepatocellular carcinoma (HCC) (n = 656), with HCC attributable to viral hepatitis C (n = 280), controls with alcohol abuse without liver damage (n = 366), and healthy controls (n = 277) were genotyped regarding the LPL rs13702 polymorphism. Furthermore, the UK Biobank cohort was analysed. LPL expression was investigated in human liver specimens and in liver cell lines. Results: Frequency of the LPL rs13702 CC genotype was lower in ALD with HCC in comparison to ALD without HCC both in the initial (3.9% vs. 9.3%) and the validation cohort (4.7% vs. 9.5%; p <0.05 each) and compared with patients with viral HCC (11.4%), alcohol misuse without cirrhosis (8.7%), or healthy controls (9.0%). This protective effect (odds ratio [OR] = 0.5) was confirmed in multivariate analysis including age (OR = 1.1/year), male sex (OR = 3.0), diabetes (OR = 1.8), and carriage of the PNPLA3 I148M risk variant (OR = 2.0). In the UK Biobank cohort, the LPL rs13702 C allele was replicated as a risk factor for HCC. Liver expression of LPL mRNA was dependent on LPL rs13702 genotype and significantly higher in patients with ALD cirrhosis compared with controls and alcohol-associated HCC. Although hepatocyte cell lines showed negligible LPL protein expression, hepatic stellate cells and liver sinusoidal endothelial cells expressed LPL. Conclusions: LPL is upregulated in the liver of patients with alcohol-associated cirrhosis. The LPL rs13702 high producer variant confers protection against HCC in ALD, which might help to stratify people for HCC risk. Impact and implications: Hepatocellular carcinoma is a severe complication of liver cirrhosis influenced by genetic predisposition. We found that a genetic variant in the gene encoding lipoprotein lipase reduces the risk for hepatocellular carcinoma in alcohol-associated cirrhosis. This genetic variation may directly affect the liver, because, unlike in healthy adult liver, lipoprotein lipase is produced from liver cells in alcohol-associated cirrhosis. |
| first_indexed | 2024-04-09T21:56:05Z |
| format | Article |
| id | doaj.art-281715ab1def4e8eae95e524cbb821c1 |
| institution | Directory Open Access Journal |
| issn | 2589-5559 |
| language | English |
| last_indexed | 2024-04-09T21:56:05Z |
| publishDate | 2023-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | JHEP Reports |
| spelling | doaj.art-281715ab1def4e8eae95e524cbb821c12023-03-24T04:23:16ZengElsevierJHEP Reports2589-55592023-04-0154100684High producer variant of lipoprotein lipase may protect from hepatocellular carcinoma in alcohol-associated cirrhosisFranziska Schmalz0Janett Fischer1Hamish Innes2Stephan Buch3Christine Möller4Madlen Matz-Soja5Witigo von Schönfels6Benjamin Krämer7Bettina Langhans8Alexandra Klüners9Michael Soyka10Felix Stickel11Jacob Nattermann12Christian P. Strassburg13Thomas Berg14Philipp Lutz15Hans Dieter Nischalke16Department of Internal Medicine I, University Hospital, University of Bonn, GermanyDivision of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, GermanySchool of Health and Life Sciences, Glasgow Caledonian University, Glasgow, UKMedical Department 1, University Hospital Dresden, Technische Universität Dresden, Dresden, GermanyDepartment of Internal Medicine I, University Hospital, University of Bonn, GermanyDivision of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, GermanyDepartment of General, Visceral-, Thoracic-, Transplantation- and Pediatric Surgery, University Medical Center Schleswig-Holstein (UKSH), Campus Kiel, and Christian-Albrecht University (CAU), Kiel, GermanyDepartment of Internal Medicine I, University Hospital, University of Bonn, GermanyDepartment of Internal Medicine I, University Hospital, University of Bonn, GermanyDepartment of Internal Medicine I, University Hospital, University of Bonn, GermanyPsychiatric Hospital, Ludwig Maximilians University, Munich, GermanyDepartment of Gastroenterology and Hepatology, University Hospital of Zürich, SwitzerlandDepartment of Internal Medicine I, University Hospital, University of Bonn, GermanyDepartment of Internal Medicine I, University Hospital, University of Bonn, GermanyDivision of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, GermanyDepartment of Internal Medicine I, University Hospital, University of Bonn, Germany; Corresponding author. Address: Department of Internal Medicine I, University of Bonn, Venusberg Campus 1, D 53127, Bonn, Germany. Tel.: +49-228-287-51417Department of Internal Medicine I, University Hospital, University of Bonn, GermanyBackground & Aims: Progression of alcohol-associated liver disease (ALD) is driven by genetic predisposition. The rs13702 variant in the lipoprotein lipase (LPL) gene is linked to non-alcoholic fatty liver disease. We aimed at clarifying its role in ALD. Methods: Patients with alcohol-associated cirrhosis, with (n = 385) and without hepatocellular carcinoma (HCC) (n = 656), with HCC attributable to viral hepatitis C (n = 280), controls with alcohol abuse without liver damage (n = 366), and healthy controls (n = 277) were genotyped regarding the LPL rs13702 polymorphism. Furthermore, the UK Biobank cohort was analysed. LPL expression was investigated in human liver specimens and in liver cell lines. Results: Frequency of the LPL rs13702 CC genotype was lower in ALD with HCC in comparison to ALD without HCC both in the initial (3.9% vs. 9.3%) and the validation cohort (4.7% vs. 9.5%; p <0.05 each) and compared with patients with viral HCC (11.4%), alcohol misuse without cirrhosis (8.7%), or healthy controls (9.0%). This protective effect (odds ratio [OR] = 0.5) was confirmed in multivariate analysis including age (OR = 1.1/year), male sex (OR = 3.0), diabetes (OR = 1.8), and carriage of the PNPLA3 I148M risk variant (OR = 2.0). In the UK Biobank cohort, the LPL rs13702 C allele was replicated as a risk factor for HCC. Liver expression of LPL mRNA was dependent on LPL rs13702 genotype and significantly higher in patients with ALD cirrhosis compared with controls and alcohol-associated HCC. Although hepatocyte cell lines showed negligible LPL protein expression, hepatic stellate cells and liver sinusoidal endothelial cells expressed LPL. Conclusions: LPL is upregulated in the liver of patients with alcohol-associated cirrhosis. The LPL rs13702 high producer variant confers protection against HCC in ALD, which might help to stratify people for HCC risk. Impact and implications: Hepatocellular carcinoma is a severe complication of liver cirrhosis influenced by genetic predisposition. We found that a genetic variant in the gene encoding lipoprotein lipase reduces the risk for hepatocellular carcinoma in alcohol-associated cirrhosis. This genetic variation may directly affect the liver, because, unlike in healthy adult liver, lipoprotein lipase is produced from liver cells in alcohol-associated cirrhosis.http://www.sciencedirect.com/science/article/pii/S2589555923000150CirrhosisAlcohol-associated liver diseaseHCCLPLrs13702rs328 |
| spellingShingle | Franziska Schmalz Janett Fischer Hamish Innes Stephan Buch Christine Möller Madlen Matz-Soja Witigo von Schönfels Benjamin Krämer Bettina Langhans Alexandra Klüners Michael Soyka Felix Stickel Jacob Nattermann Christian P. Strassburg Thomas Berg Philipp Lutz Hans Dieter Nischalke High producer variant of lipoprotein lipase may protect from hepatocellular carcinoma in alcohol-associated cirrhosis JHEP Reports Cirrhosis Alcohol-associated liver disease HCC LPL rs13702 rs328 |
| title | High producer variant of lipoprotein lipase may protect from hepatocellular carcinoma in alcohol-associated cirrhosis |
| title_full | High producer variant of lipoprotein lipase may protect from hepatocellular carcinoma in alcohol-associated cirrhosis |
| title_fullStr | High producer variant of lipoprotein lipase may protect from hepatocellular carcinoma in alcohol-associated cirrhosis |
| title_full_unstemmed | High producer variant of lipoprotein lipase may protect from hepatocellular carcinoma in alcohol-associated cirrhosis |
| title_short | High producer variant of lipoprotein lipase may protect from hepatocellular carcinoma in alcohol-associated cirrhosis |
| title_sort | high producer variant of lipoprotein lipase may protect from hepatocellular carcinoma in alcohol associated cirrhosis |
| topic | Cirrhosis Alcohol-associated liver disease HCC LPL rs13702 rs328 |
| url | http://www.sciencedirect.com/science/article/pii/S2589555923000150 |
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