Habeeb Salameh1, Evan Raff2, Angelika Erwin3, Devanshi Seth4, Hans Dieter Nischalke5, Edmondo Falleti6, Maria Antonella Burza7, Julian Leathert8, Stefano Romeo9, Antonio Molinaro7, Stefano Ginanni Corradini10, Pierluigi Toniutto11, Ulrich Spengler, Spengler Ulrich5, Ann Daly12, Christopher P Day12, Yong-Fang Kuo13, Ashwani K Singal14. 1. Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA. 2. Department of Internal Medicine, University of Alabama, Birmingham, Alabama, USA. 3. Genomic Medicine Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA. 4. 1] Drug Health Services, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia [2] Centenary Institute of Cancer Medicine and Cell Biology, Camperdown, New South Wales, Australia [3] Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia. 5. Department of Internal Medicine, University of Bonn, Bonn, Germany. 6. Laboratory Medicine-Istituto Patologia Clinica, Azienda Ospedaliero Universitaria, Udine, Italy. 7. Institute of Medicine, Department of Molecular and Clinical Medicine, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden. 8. Institute of Cellular Medicine, Newcastle University Medical School, Newcastle upon Tyne, UK. 9. 1] Institute of Medicine, Department of Molecular and Clinical Medicine, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden [2] Department of Medical and Surgical Science, University Magna Grecia of Catanzaro, Clinical Nutrition Unit, Germaneto, Catanzaro, Italy. 10. Department of Clinical Medicine, Division of Gastroenterology, Sapienza University of Rome, Rome, Italy. 11. Department of Medical Sciences Experimental and Clinical, Medical Liver Transplantation Unit, University of Udine, Udine, Italy. 12. Faculty of Medical Sciences, Newcastle University Medical School, Newcastle upon Tyne, UK. 13. Department of Biostatistics, University of Texas Medical Branch, Galveston, Texas, USA. 14. Division of Gastroenterology and Hepatology, University of Alabama, Birmingham, Alabama, USA.
Abstract
OBJECTIVES: The genetic polymorphism with an isoleucine-to-methionine substitution at position 148 (rs738409 C>G) in the patatin-like phospholipase domain protein 3 (PNPLA3) gene confers risk of steatosis. PNPLA3 polymorphism is shown to be associated with alcoholic liver disease (ALD). We performed a systematic review and meta-analysis to examine association of this genetic polymorphism with ALD spectrum and its severity. METHODS: Medline, Embase, and Cochrane Library were searched for studies on association of PNPLA3 polymorphism and ALD spectrum: alcoholic fatty liver (AFL), alcoholic liver injury (ALI), alcoholic cirrhosis (AC), and hepatocellular carcinoma (HCC). Pooled data are reported as odds ratio (OR) with 95% confidence interval. Heterogeneity was assessed using the I(2) statistics and publication bias using Egger's test and Begg and Mazumdar's test. Individual participant data obtained from five studies were used for subgroup analyses. RESULTS: Among 10 studies included in this pooled analysis, compared with controls, OR for rs738409 CG and GG among ALI patients was 1.45 (1.24-1.69) and 2.22 (1.50-3.28), respectively, compared with CC. Respective OR among AC patients was 2.09 (1.79-2.44) and 3.37 (2.49-4.58) and among AC patients with HCC was 2.87 (1.61-5.10) and 12.41 (6.99-22.03). Data for AFL were inconsistent. Among ALD patients, OR of CG and GG genotypes was 2.62 (1.73-3.97) and 8.45 (2.52-28.37), respectively, for AC compared with fatty liver (FL) patients. Similar OR for AC compared with ALI was 1.98 (1.24-3.17) and 3.86 (1.18-12.60). The OR for CG and GG genotypes among AC patients for HCC occurrence was 1.43 (0.76-2.72) and 2.81 (1.57-5.01), respectively. Individual participant data analysis showed age to predispose to AC among ALI patients. CONCLUSIONS: PNPLA3 genetic polymorphism (rs738409 C>G) is associated with increased risk for the entire spectrum of ALD among drinkers including ALI, AC, and HCC. Studies are needed to clarify association of PNPLA3 polymorphism and steatosis in alcoholics. PNPLA3 gene may potentially be a therapeutic target in ALD.
OBJECTIVES: The genetic polymorphism with an isoleucine-to-methionine substitution at position 148 (rs738409 C>G) in the patatin-like phospholipase domain protein 3 (PNPLA3) gene confers risk of steatosis. PNPLA3 polymorphism is shown to be associated with alcoholic liver disease (ALD). We performed a systematic review and meta-analysis to examine association of this genetic polymorphism with ALD spectrum and its severity. METHODS: Medline, Embase, and Cochrane Library were searched for studies on association of PNPLA3 polymorphism and ALD spectrum: alcoholic fatty liver (AFL), alcoholic liver injury (ALI), alcoholic cirrhosis (AC), and hepatocellular carcinoma (HCC). Pooled data are reported as odds ratio (OR) with 95% confidence interval. Heterogeneity was assessed using the I(2) statistics and publication bias using Egger's test and Begg and Mazumdar's test. Individual participant data obtained from five studies were used for subgroup analyses. RESULTS: Among 10 studies included in this pooled analysis, compared with controls, OR for rs738409 CG and GG among ALI patients was 1.45 (1.24-1.69) and 2.22 (1.50-3.28), respectively, compared with CC. Respective OR among AC patients was 2.09 (1.79-2.44) and 3.37 (2.49-4.58) and among AC patients with HCC was 2.87 (1.61-5.10) and 12.41 (6.99-22.03). Data for AFL were inconsistent. Among ALDpatients, OR of CG and GG genotypes was 2.62 (1.73-3.97) and 8.45 (2.52-28.37), respectively, for AC compared with fatty liver (FL) patients. Similar OR for AC compared with ALI was 1.98 (1.24-3.17) and 3.86 (1.18-12.60). The OR for CG and GG genotypes among AC patients for HCC occurrence was 1.43 (0.76-2.72) and 2.81 (1.57-5.01), respectively. Individual participant data analysis showed age to predispose to AC among ALI patients. CONCLUSIONS:PNPLA3 genetic polymorphism (rs738409 C>G) is associated with increased risk for the entire spectrum of ALD among drinkers including ALI, AC, and HCC. Studies are needed to clarify association of PNPLA3 polymorphism and steatosis in alcoholics. PNPLA3 gene may potentially be a therapeutic target in ALD.
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