title: PNPLA3 Gene Polymorphism Is Associated With Predisposition to and Severity of Alcoholic Liver Disease.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Habeeb
authors.initials: H
authors.lastname: Salameh
authors.affiliation: Department of Internal Medicine, University of Alabama, Birmingham, Alabama, USA.
authors.forename: Evan
authors.initials: E
authors.lastname: Raff
authors.affiliation: Genomic Medicine Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA.
authors.forename: Angelika
authors.initials: A
authors.lastname: Erwin
authors.affiliation: 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.
authors.forename: Devanshi
authors.initials: D
authors.lastname: Seth
authors.affiliation: Department of Internal Medicine, University of Bonn, Bonn, Germany.
authors.forename: Hans Dieter
authors.initials: HD
authors.lastname: Nischalke
authors.affiliation: Laboratory Medicine-Istituto Patologia Clinica, Azienda Ospedaliero Universitaria, Udine, Italy.
authors.forename: Edmondo
authors.initials: E
authors.lastname: Falleti
authors.affiliation: Institute of Medicine, Department of Molecular and Clinical Medicine, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Maria Antonella
authors.initials: MA
authors.lastname: Burza
authors.affiliation: Institute of Cellular Medicine, Newcastle University Medical School, Newcastle upon Tyne, UK.
authors.forename: Julian
authors.initials: J
authors.lastname: Leathert
authors.affiliation: 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.
authors.forename: Stefano
authors.initials: S
authors.lastname: Romeo
authors.affiliation: Institute of Medicine, Department of Molecular and Clinical Medicine, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Antonio
authors.initials: A
authors.lastname: Molinaro
authors.affiliation: Department of Clinical Medicine, Division of Gastroenterology, Sapienza University of Rome, Rome, Italy.
authors.forename: Stefano Ginanni
authors.initials: SG
authors.lastname: Corradini
authors.affiliation: Department of Medical Sciences Experimental and Clinical, Medical Liver Transplantation Unit, University of Udine, Udine, Italy.
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Toniutto
authors.forename: Ulrich
authors.initials: U
authors.lastname: Spengler
authors.affiliation: Department of Internal Medicine, University of Bonn, Bonn, Germany.
authors.forename: Spengler
authors.initials: S
authors.lastname: Ulrich
authors.affiliation: Faculty of Medical Sciences, Newcastle University Medical School, Newcastle upon Tyne, UK.
authors.forename: Ann
authors.initials: A
authors.lastname: Daly
authors.affiliation: Faculty of Medical Sciences, Newcastle University Medical School, Newcastle upon Tyne, UK.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Day
authors.affiliation: Department of Biostatistics, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Yong-Fang
authors.initials: YF
authors.lastname: Kuo
authors.affiliation: Division of Gastroenterology and Hepatology, University of Alabama, Birmingham, Alabama, USA.
authors.forename: Ashwani K
authors.initials: AK
authors.lastname: Singal
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000235:genetics*; D002492:Central Nervous System Depressants / Q000009:adverse effects; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000235:genetics*; D000431:Ethanol / Q000009:adverse effects; D005235:Fatty Liver, Alcoholic / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008049:Lipase / Q000235:genetics*; D008104:Liver Cirrhosis, Alcoholic / Q000235:genetics*; D008108:Liver Diseases, Alcoholic / Q000235:genetics; D008113:Liver Neoplasms / Q000139:chemically induced / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012720:Severity of Illness Index; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
chemical_list: D002492:Central Nervous System Depressants; D000431:Ethanol; D008049:Lipase; D008565:Membrane Proteins; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent