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• W2315490633 abstract "The human patatin-like phospholipase domain-containing-3 (PNPLA3) gene rs738409 C>G polymorphism is associated with several types of liver disease. The aim of this meta-analysis was to assess the risk of cirrhosis on the basis of rs738409 allele frequency and genotype. Medline, the Cochrane Library, EMBASE, and Google Scholar were searched for prospective and retrospective studies assessing the effect of the rs738409 polymorphism on liver cirrhosis. Seven studies, involving 2,023 patients with cirrhosis, were included. The G allele was associated with a significantly increased risk of cirrhosis versus the C allele [pooled odds ratio (OR) = 1.86, 95% confidence interval (CI) = 1.64–2.12, Z = 9.55, P < 0.001]. Both the GC and GG genotypes were associated with a significantly increased risk of cirrhosis versus the CC genotype (GC vs. CC: pooled OR = 1.73, 95% CI = 1.51–1.98, Z = 7.86, P < 0.001; GG vs. CC: pooled OR = 3.41, 95% CI = 2.77–4.18, Z = 11.65, P < 0.001). There was no evidence of publication bias. Our findings suggest that patients at risk for liver cirrhosis may benefit from PNPLA3 genotyping and thus more intensive monitoring if the rs738409 C>G polymorphism is identified. The human patatin-like phospholipase domain-containing-3 (PNPLA3) gene rs738409 C>G polymorphism is associated with several types of liver disease. The aim of this meta-analysis was to assess the risk of cirrhosis on the basis of rs738409 allele frequency and genotype. Medline, the Cochrane Library, EMBASE, and Google Scholar were searched for prospective and retrospective studies assessing the effect of the rs738409 polymorphism on liver cirrhosis. Seven studies, involving 2,023 patients with cirrhosis, were included. The G allele was associated with a significantly increased risk of cirrhosis versus the C allele [pooled odds ratio (OR) = 1.86, 95% confidence interval (CI) = 1.64–2.12, Z = 9.55, P < 0.001]. Both the GC and GG genotypes were associated with a significantly increased risk of cirrhosis versus the CC genotype (GC vs. CC: pooled OR = 1.73, 95% CI = 1.51–1.98, Z = 7.86, P < 0.001; GG vs. CC: pooled OR = 3.41, 95% CI = 2.77–4.18, Z = 11.65, P < 0.001). There was no evidence of publication bias. Our findings suggest that patients at risk for liver cirrhosis may benefit from PNPLA3 genotyping and thus more intensive monitoring if the rs738409 C>G polymorphism is identified. Liver cirrhosis is the 12th leading cause of death in the United States, with about half of these deaths being associated with alcohol (1National Institutes of Health. Surveillance report #93: liver cirrhosis mortality in the United States, 1970–2009. Accessed September 10, 2013, at http://pubs.niaaa.nih.gov/publications/Surveillance93/Cirr09.htm.Google Scholar). The precise worldwide incidence of liver cirrhosis is unknown; however, epidemiological data from Europe suggest that there are 15 to 133 cases per 100,000 population per year (2Blachier M. Leleu H. Peck-Radosavljevic M. Valla D.C. Roudot-Thoraval F. The burden of liver disease in Europe: a review of available epidemiological data.J. Hepatol. 2013; 58: 593-608Abstract Full Text Full Text PDF PubMed Scopus (925) Google Scholar). Although alcohol use increases the risk of cirrhosis, there appear to be other factors that influence disease progression as only 10–20% of heavy drinkers develop cirrhosis (3Teli M.R. Day C.P. Burt A.D. Bennett M.K. James O.F. Determinants of progression to cirrhosis or fibrosis in pure alcoholic fatty liver.Lancet. 1995; 346: 987-990Abstract PubMed Scopus (409) Google Scholar). Other factors purported to affect the development of cirrhosis include gender, insulin resistance, steatosis, environmental factors, body mass index, chronic viral infection, and genetics (4Becker U. Deis A. Sorensen T.I. Gronbaek M. Borch-Johnsen K. Muller C.F. Schnohr P. Jensen G. Prediction of risk of liver disease by alcohol intake, sex, and age: a prospective population study.Hepatology. 1996; 23: 1025-1029Crossref PubMed Google Scholar, 5Naveau S. Giraud V. Borotto E. Aubert A. Capron F. Chaput J.C. Excess weight risk factor for alcoholic liver disease.Hepatology. 1997; 25: 108-111Crossref PubMed Scopus (535) Google Scholar, 6Raynard B. Balian A. Fallik D. Capron F. Bedossa P. Chaput J.C. Naveau S. Risk factors of fibrosis in alcohol-induced liver disease.Hepatology. 2002; 35: 635-638Crossref PubMed Scopus (321) Google Scholar, 7Mathurin P. Beuzin F. Louvet A. Carrie-Ganne N. Balian A. Trinchet J.C. Dalsoglio D. Prevot S. Naveau S. Fibrosis progression occurs in a subgroup of heavy drinkers with typical histological features.Aliment. Pharmacol. Ther. 2007; 25: 1047-1054Crossref PubMed Scopus (111) Google Scholar, 8Nishiguchi S. Kuroki T. Yabusako T. Seki S. Kobayashi K. Monna T. Otani S. Sakurai M. Shikata T. Yamamoto S. Detection of hepatitis C virus antibodies and hepatitis C virus RNA in patients with alcoholic liver disease.Hepatology. 1991; 14: 985-989Crossref PubMed Scopus (108) Google Scholar, 9Mann R.E. Smart R.G. Govoni R. The epidemiology of alcoholic liver disease.Alcohol Res. Health. 2003; 27: 209-219PubMed Google Scholar, 10Stickel F. Osterreicher C.H. The role of genetic polymorphisms in alcoholic liver disease.Alcohol Alcohol. 2006; 41: 209-224Crossref PubMed Scopus (100) Google Scholar, 11Romeo S. Kozlitina J. Xing C. Pertsemlidis A. Cox D. Pennacchio L.A. Boerwinkle E. Cohen J.C. Hobbs H.H. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease.Nat. Genet. 2008; 40: 1461-1465Crossref PubMed Scopus (2233) Google Scholar, 12Yuan X. Waterworth D. Perry J.R. Lim N. Song K. Chambers J.C. Zhang W. Vollenweider P. Stirnadel H. Johnson T. et al.Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes.Am. J. Hum. Genet. 2008; 83: 520-528Abstract Full Text Full Text PDF PubMed Scopus (330) Google Scholar). One such genetic factor is the patatin-like phospholipase domain-containing-3 (PNPLA3) gene, also known as adiponutrin. Although the precise physiological role of PNPLA3 in the liver is currently unclear (13Dongiovanni P. Donati B. Fares R. Lombardi R. Mancina R.M. Romeo S. Valenti L. PNPLA3 I148M polymorphism and progressive liver disease.World J. Gastroenterol. 2013; 19: 6969-6978Crossref PubMed Scopus (171) Google Scholar), the PNPLA3 gene encodes a 481-amino-acid protein that contains a highly conserved patatin-like domain with lipolytic activity toward triglycerides (13Dongiovanni P. Donati B. Fares R. Lombardi R. Mancina R.M. Romeo S. Valenti L. PNPLA3 I148M polymorphism and progressive liver disease.World J. Gastroenterol. 2013; 19: 6969-6978Crossref PubMed Scopus (171) Google Scholar, 14Wilson P.A. Gardner S.D. Lambie N.M. Commans S.A. Crowther D.J. Characterization of the human patatin-like phospholipase family.J. Lipid Res. 2006; 47: 1940-1949Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar). Biochemical analysis indicates that the PNPLA3 protein exerts lipase activity and may play a role in the hydrolysis of glycerolipids, with maximum enzymatic activity against triglycerides, diacylglyerol, and monacylglycerol (15Huang Y. Cohen J.C. Hobbs H.H. Expression and characterization of a PNPLA3 protein isoform (I148M) associated with nonalcoholic fatty liver disease.J. Biol. Chem. 2011; 286: 37085-37093Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar). A genome-wide association study of a multiethnic population found that a single rs738409 C>G polymorphism of PNPLA3, which encodes I148M, is strongly associated with hepatic fat content and conferred susceptibility to nonalcoholic fatty liver disease (NAFLD) (11Romeo S. Kozlitina J. Xing C. Pertsemlidis A. Cox D. Pennacchio L.A. Boerwinkle E. Cohen J.C. Hobbs H.H. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease.Nat. Genet. 2008; 40: 1461-1465Crossref PubMed Scopus (2233) Google Scholar). Other studies have substantiated and extended these findings by demonstrating an association of rs738409 with fatty liver and alcoholic liver diseases (16Kantartzis K. Peter A. Machicao F. Machann J. Wagner S. Konigsrainer I. Konigsrainer A. Schick F. Fritsche A. Haring H.U. et al.Dissociation between fatty liver and insulin resistance in humans carrying a variant of the patatin-like phospholipase 3 gene.Diabetes. 2009; 58: 2616-2623Crossref PubMed Scopus (245) Google Scholar, 17Kotronen A. Johansson L.E. Johansson L.M. Roos C. Westerbacka J. Hamsten A. Bergholm R. Arkkila P. Arola J. Kiviluoto T. et al.A common variant in PNPLA3, which encodes adiponutrin, is associated with liver fat content in humans.Diabetologia. 2009; 52: 1056-1060Crossref PubMed Scopus (243) Google Scholar, 18Romeo S. Sentinelli F. Dash S. Yeo G.S. Savage D.B. Leonetti F. Capoccia D. Incani M. Maglio C. Iacovino M. et al.Morbid obesity exposes the association between PNPLA3 I148M (rs738409) and indices of hepatic injury in individuals of European descent.Int. J. Obes. (Lond.). 2010; 34: 190-194Crossref PubMed Scopus (156) Google Scholar, 19Sookoian S. Castano G.O. Burgueno A.L. Gianotti T.F. Rosselli M.S. Pirola C.J. A nonsynonymous gene variant in the adiponutrin gene is associated with nonalcoholic fatty liver disease severity.J. Lipid Res. 2009; 50: 2111-2116Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar, 20Krawczyk M. Grunhage F. Zimmer V. Lammert F. Variant adiponutrin (PNPLA3) represents a common fibrosis risk gene: non-invasive elastography-based study in chronic liver disease.J. Hepatol. 2011; 55: 299-306Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar, 21Trépo E. Gustot T. Degré D. Lemmers A. Verset L. Demetter P. Ouziel R. Quertinmont E. Vercruysse V. Amininejad L. et al.Common polymorphism in the PNPLA3/adiponutrin gene confers higher risk of cirrhosis and liver damage in alcoholic liver disease.J. Hepatol. 2011; 55: 906-912Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar, 22Tian C. Stokowski R.P. Kershenobich D. Ballinger D.G. Hinds D.A. Variant in PNPLA3 is associated with alcoholic liver disease.Nat. Genet. 2010; 42: 21-23Crossref PubMed Scopus (348) Google Scholar). Further to this, several studies have investigated the influence of rs738409 on the clinical, biochemical, and histological parameters of liver diseases across different patient populations (20Krawczyk M. Grunhage F. Zimmer V. Lammert F. Variant adiponutrin (PNPLA3) represents a common fibrosis risk gene: non-invasive elastography-based study in chronic liver disease.J. Hepatol. 2011; 55: 299-306Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar, 21Trépo E. Gustot T. Degré D. Lemmers A. Verset L. Demetter P. Ouziel R. Quertinmont E. Vercruysse V. Amininejad L. et al.Common polymorphism in the PNPLA3/adiponutrin gene confers higher risk of cirrhosis and liver damage in alcoholic liver disease.J. Hepatol. 2011; 55: 906-912Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar, 22Tian C. Stokowski R.P. Kershenobich D. Ballinger D.G. Hinds D.A. Variant in PNPLA3 is associated with alcoholic liver disease.Nat. Genet. 2010; 42: 21-23Crossref PubMed Scopus (348) Google Scholar, 23Nischalke H.D. Berger C. Luda C. Berg T. Muller T. Grunhage F. Lammert F. Coenen M. Kramer B. Korner C. et al.The PNPLA3 rs738409 148M/M genotype is a risk factor for liver cancer in alcoholic cirrhosis but shows no or weak association in hepatitis C cirrhosis.PLoS ONE. 2011; 6: e27087Crossref PubMed Scopus (100) Google Scholar, 24Stickel F. Buch S. Lau K. Meyer zu Schwabedissen H. Berg T. Ridinger M. Rietschel M. Schafmayer C. Braun F. Hinrichsen H. et al.Genetic variation in the PNPLA3 gene is associated with alcoholic liver injury in Caucasians.Hepatology. 2011; 53: 86-95Crossref PubMed Scopus (236) Google Scholar, 25Falleti E. Fabris C. Cmet S. Cussigh A. Bitetto D. Fontanini E. Fornasiere E. Bignulin S. Fumolo E. Bignulin E. et al.PNPLA3 rs738409C/G polymorphism in cirrhosis: relationship with the aetiology of liver disease and hepatocellular carcinoma occurrence.Liver Int. 2011; 31: 1137-1143Crossref PubMed Scopus (101) Google Scholar, 26Valenti L. Nobili V. PNPLA3 I148M polymorphism and liver damage in obese children.J. Pediatr. 2011; 159: 876Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar, 27Valenti L. Rumi M. Galmozzi E. Aghemo A. Del Menico B. De Nicola S. Dongiovanni P. Maggioni M. Fracanzani A.L. Rametta R. et al.Patatin-like phospholipase domain-containing 3 I148M polymorphism, steatosis, and liver damage in chronic hepatitis C.Hepatology. 2011; 53: 791-799Crossref PubMed Scopus (221) Google Scholar, 28Sookoian S. Pirola C.J. Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease.Hepatology. 2011; 53: 1883-1894Crossref PubMed Scopus (672) Google Scholar). The rs738409 variant has been reported to be associated with fibrosis (20Krawczyk M. Grunhage F. Zimmer V. Lammert F. Variant adiponutrin (PNPLA3) represents a common fibrosis risk gene: non-invasive elastography-based study in chronic liver disease.J. Hepatol. 2011; 55: 299-306Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar, 29Valenti L. Al-Serri A. Daly A.K. Galmozzi E. Rametta R. Dongiovanni P. Nobili V. Mozzi E. Roviaro G. Vanni E. et al.Homozygosity for the patatin-like phospholipase-3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease.Hepatology. 2010; 51: 1209-1217Crossref PubMed Scopus (497) Google Scholar, 30Rotman Y. Koh C. Zmuda J.M. Kleiner D.E. Liang T.J. The association of genetic variability in patatin-like phospholipase domain-containing protein 3 (PNPLA3) with histological severity of nonalcoholic fatty liver disease.Hepatology. 2010; 52: 894-903Crossref PubMed Scopus (368) Google Scholar, 31Speliotes E.K. Butler J.L. Palmer C.D. Voight B.F. Hirschhorn J.N. PNPLA3 variants specifically confer increased risk for histologic nonalcoholic fatty liver disease but not metabolic disease.Hepatology. 2010; 52: 904-912Crossref PubMed Scopus (292) Google Scholar), histological disease severity (19Sookoian S. Castano G.O. Burgueno A.L. Gianotti T.F. Rosselli M.S. Pirola C.J. A nonsynonymous gene variant in the adiponutrin gene is associated with nonalcoholic fatty liver disease severity.J. Lipid Res. 2009; 50: 2111-2116Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar, 29Valenti L. Al-Serri A. Daly A.K. Galmozzi E. Rametta R. Dongiovanni P. Nobili V. Mozzi E. Roviaro G. Vanni E. et al.Homozygosity for the patatin-like phospholipase-3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease.Hepatology. 2010; 51: 1209-1217Crossref PubMed Scopus (497) Google Scholar, 30Rotman Y. Koh C. Zmuda J.M. Kleiner D.E. Liang T.J. The association of genetic variability in patatin-like phospholipase domain-containing protein 3 (PNPLA3) with histological severity of nonalcoholic fatty liver disease.Hepatology. 2010; 52: 894-903Crossref PubMed Scopus (368) Google Scholar, 31Speliotes E.K. Butler J.L. Palmer C.D. Voight B.F. Hirschhorn J.N. PNPLA3 variants specifically confer increased risk for histologic nonalcoholic fatty liver disease but not metabolic disease.Hepatology. 2010; 52: 904-912Crossref PubMed Scopus (292) Google Scholar, 32Valenti L. Alisi A. Galmozzi E. Bartuli A. Del Menico B. Alterio A. Dongiovanni P. Fargion S. Nobili V. I148M patatin-like phospholipase domain-containing 3 gene variant and severity of pediatric nonalcoholic fatty liver disease.Hepatology. 2010; 52: 1274-1280Crossref PubMed Scopus (231) Google Scholar), steatosis (29Valenti L. Al-Serri A. Daly A.K. Galmozzi E. Rametta R. Dongiovanni P. Nobili V. Mozzi E. Roviaro G. Vanni E. et al.Homozygosity for the patatin-like phospholipase-3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease.Hepatology. 2010; 51: 1209-1217Crossref PubMed Scopus (497) Google Scholar), and elevated levels of liver enzymes in healthy adults (12Yuan X. Waterworth D. Perry J.R. Lim N. Song K. Chambers J.C. Zhang W. Vollenweider P. Stirnadel H. Johnson T. et al.Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes.Am. J. Hum. Genet. 2008; 83: 520-528Abstract Full Text Full Text PDF PubMed Scopus (330) Google Scholar, 21Trépo E. Gustot T. Degré D. Lemmers A. Verset L. Demetter P. Ouziel R. Quertinmont E. Vercruysse V. Amininejad L. et al.Common polymorphism in the PNPLA3/adiponutrin gene confers higher risk of cirrhosis and liver damage in alcoholic liver disease.J. Hepatol. 2011; 55: 906-912Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar). Of note, a number of studies have reported that rs738409 is also a risk factor for cirrhosis (20Krawczyk M. Grunhage F. Zimmer V. Lammert F. Variant adiponutrin (PNPLA3) represents a common fibrosis risk gene: non-invasive elastography-based study in chronic liver disease.J. Hepatol. 2011; 55: 299-306Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar, 21Trépo E. Gustot T. Degré D. Lemmers A. Verset L. Demetter P. Ouziel R. Quertinmont E. Vercruysse V. Amininejad L. et al.Common polymorphism in the PNPLA3/adiponutrin gene confers higher risk of cirrhosis and liver damage in alcoholic liver disease.J. Hepatol. 2011; 55: 906-912Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar, 22Tian C. Stokowski R.P. Kershenobich D. Ballinger D.G. Hinds D.A. Variant in PNPLA3 is associated with alcoholic liver disease.Nat. Genet. 2010; 42: 21-23Crossref PubMed Scopus (348) Google Scholar, 23Nischalke H.D. Berger C. Luda C. Berg T. Muller T. Grunhage F. Lammert F. Coenen M. Kramer B. Korner C. et al.The PNPLA3 rs738409 148M/M genotype is a risk factor for liver cancer in alcoholic cirrhosis but shows no or weak association in hepatitis C cirrhosis.PLoS ONE. 2011; 6: e27087Crossref PubMed Scopus (100) Google Scholar, 24Stickel F. Buch S. Lau K. Meyer zu Schwabedissen H. Berg T. Ridinger M. Rietschel M. Schafmayer C. Braun F. Hinrichsen H. et al.Genetic variation in the PNPLA3 gene is associated with alcoholic liver injury in Caucasians.Hepatology. 2011; 53: 86-95Crossref PubMed Scopus (236) Google Scholar, 25Falleti E. Fabris C. Cmet S. Cussigh A. Bitetto D. Fontanini E. Fornasiere E. Bignulin S. Fumolo E. Bignulin E. et al.PNPLA3 rs738409C/G polymorphism in cirrhosis: relationship with the aetiology of liver disease and hepatocellular carcinoma occurrence.Liver Int. 2011; 31: 1137-1143Crossref PubMed Scopus (101) Google Scholar, 27Valenti L. Rumi M. Galmozzi E. Aghemo A. Del Menico B. De Nicola S. Dongiovanni P. Maggioni M. Fracanzani A.L. Rametta R. et al.Patatin-like phospholipase domain-containing 3 I148M polymorphism, steatosis, and liver damage in chronic hepatitis C.Hepatology. 2011; 53: 791-799Crossref PubMed Scopus (221) Google Scholar, 33Valenti L. Maggioni P. Piperno A. Rametta R. Pelucchi S. Mariani R. Dongiovanni P. Fracanzani A.L. Fargion S. Patatin-like phospholipase domain containing-3 gene I148M polymorphism, steatosis, and liver damage in hereditary hemochromatosis.World J. Gastroenterol. 2012; 18: 2813-2820Crossref PubMed Scopus (38) Google Scholar). Interestingly, the magnitude and strength of the effect of this variant on cirrhosis varied among studies, with odds ratios (ORs) ranging from 1.47 (27Valenti L. Rumi M. Galmozzi E. Aghemo A. Del Menico B. De Nicola S. Dongiovanni P. Maggioni M. Fracanzani A.L. Rametta R. et al.Patatin-like phospholipase domain-containing 3 I148M polymorphism, steatosis, and liver damage in chronic hepatitis C.Hepatology. 2011; 53: 791-799Crossref PubMed Scopus (221) Google Scholar) to 3.26 (33Valenti L. Maggioni P. Piperno A. Rametta R. Pelucchi S. Mariani R. Dongiovanni P. Fracanzani A.L. Fargion S. Patatin-like phospholipase domain containing-3 gene I148M polymorphism, steatosis, and liver damage in hereditary hemochromatosis.World J. Gastroenterol. 2012; 18: 2813-2820Crossref PubMed Scopus (38) Google Scholar). The differences across the studies likely reflect differences in patient characteristics. No meta-analysis to date has examined the association between the aforementioned rs738409 variant and cirrhosis. Therefore, to gain a more comprehensive understanding of the strength of this association, we reviewed the available published literature and carried out meta-analysis to assess the risk of cirrhosis on the basis of rs738409 allele frequency (C vs. G) and genotype (CC vs. GG vs. GC). The literature search, data extraction, review, and data analysis were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (34Moher D. Liberati A. Tetzlaff J. Altman D.G. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.Int. J. Surg. 2010; 8: 336-341Crossref PubMed Scopus (7263) Google Scholar). Medline, the Cochrane Library, EMBASE, and Google Scholar were searched for articles published up to August 2013 that assessed the effect of the rs738409 (also called I148) variant in the PNPLA3 gene on cirrhosis using a differing combination of the following terms: PNPLA3, I148, rs738409, adiponutrin, and cirrhosis. Prospective and retrospective studies were included if subjects were 18 years of age and older and had liver cirrhosis, regardless of cause. All studies had to be in English. Excluded studies included letters, comments, editorials, or case reports. Two independent reviewers screened potentially relevant studies, and both had to agree for inclusion of an article. If there was disagreement between reviewers, it was resolved by a third reviewer. The following information was extracted from the included studies: the name of the first author, year of publication, study design, number of participants in each genotype group, participants' age and gender, diagnoses, and number or association with cirrhosis. The data were extracted by two reviewers. A third reviewer collated and checked the pooled data prior to the data being assessed by a statistician. The quality of included studies was evaluated using the Newcastle-Ottawa Scale, which is a validated technique to assess the quality of nonrandomized studies (35Wells, G. A., Shea, B., O'Connell, D., Peterson, J., Welch, V., Losos, M., Tugwell, P. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Accessed September 10, 2013, at http://www.medicine.mcgill.ca/rtamblyn/Readings/The%20Newcastle%20-%20Scale%20for%20assessing%20the%20quality%20of%20nonrandomised%20studies%20in%20meta-analyses.pdf.Google Scholar). The assessed outcomes for the seven included studies are listed in Table 1.TABLE 1.Summary of basic characteristics of studies included in the meta-analysisFirst Author (Year)RaceStudy GroupsaData presented as cirrhosis group versus control group.NaData presented as cirrhosis group versus control group.SexaData presented as cirrhosis group versus control group. (M/F)AgeaData presented as cirrhosis group versus control group.PNPLA3 GenotypeaData presented as cirrhosis group versus control group.MAFOR (95% CI)Newcastle-Ottawa Scale ScoreCCGCGGG versus CGC versus CCGG versus CCDutta (2013)North IndianAlcoholic cirrhosis Versus healthy control60 versus 100NA49.5 (10.3) versus 32.9 (9.5)24 versus 6221 versus 6915 versus 9G: 42.5%gIndicates that the allele frequencies were in Hardy-Weinberg equilibrium (Fisher's exact test).2.41 (1.48, 3.92)1.87 (0.90, 3.89)4.31 (1.66, 11.15)8Nischalke (2011)CaucasianAlcoholic or HCV cirrhosis versus healthy control322 versus 190230/92 versus 106/8456 (37–82) versus 40.5 (20–86)cMedian (range).134 versus 112142 versus 6946 versus 9G: 36.3%gIndicates that the allele frequencies were in Hardy-Weinberg equilibrium (Fisher's exact test).1.92 (1.44, 2.56)1.72 (1.17, 2.52)4.27 (2.00, 9.11)7Falleti (2011)CaucasianCirrhosis versus healthy control483 versus 428344/139 versus 314/11457 (22–86) versus 49 (18–77)cMedian (range).168 versus 218220 versus 17595 versus 35G: 42.4%gIndicates that the allele frequencies were in Hardy-Weinberg equilibrium (Fisher's exact test).1.84 (1.51, 2.24)1.63 (1.23, 2.16)3.52 (2.28, 5.44)7Trépo (2011)CaucasianALD with cirrhosis versus healthy control265 versus 328NANA100 versus 181130 versus 11835 versus 29G: 37.7%gIndicates that the allele frequencies were in Hardy-Weinberg equilibrium (Fisher's exact test).1.65 (1.29, 2.12)1.99 (1.41, 2.83)2.18 (1.26, 3.78)7Stickel (2011)CaucasianAlcoholic cirrhosis versus alcoholic control210 versus 439167/43 versus 439/050 (43–55) versus 39 (34–45)dMedian [25th percentile and 75th percentile (Q1–Q3)].90 versus 26493 versus 15327 versus 22G: 35.0%gIndicates that the allele frequencies were in Hardy-Weinberg equilibrium (Fisher's exact test).1.86 (1.44, 2.40)1.78 (1.25, 2.53)3.60 (1.95, 6.64)8Krawczyk (2011)NACLD cirrhosisfCLD patients with cirrhosis were defined by liver stiffness values ≥13.0 kPa.versus CLD control201 versus 698547/35250 (17–83)cMedian (range).91 versus 39490 versus 26120 versus 43G: 32.3%gIndicates that the allele frequencies were in Hardy-Weinberg equilibrium (Fisher's exact test).1.45 (1.14, 1.84)1.49 (1.07, 2.08)2.01 (1.13, 3.59)8Tian (2010)Mestizo MexicansbMixed European and Native American ancestry.Alcoholic cirrhosis versus alcoholic control482 versus 305411/71 versus 257/4852 (11.6) versus 39 (12.7)eMean (standard deviation).59 versus 83264 versus 198371 versus 111C: 27.5%gIndicates that the allele frequencies were in Hardy-Weinberg equilibrium (Fisher's exact test).2.28 (1.90, 2.74)1.88 (1.28, 2.75)4.70 (3.17, 6.98)8ALD, alcoholic liver disease; CI, confidence interval; CLD, chronic liver disease; F, female; HCV, hepatitis C virus; M, male; MAF, minor allele frequency; NA, not available.a Data presented as cirrhosis group versus control group.b Mixed European and Native American ancestry.c Median (range).d Median [25th percentile and 75th percentile (Q1–Q3)].e Mean (standard deviation).f CLD patients with cirrhosis were defined by liver stiffness values ≥13.0 kPa.g Indicates that the allele frequencies were in Hardy-Weinberg equilibrium (Fisher's exact test). Open table in a new tab ALD, alcoholic liver disease; CI, confidence interval; CLD, chronic liver disease; F, female; HCV, hepatitis C virus; M, male; MAF, minor allele frequency; NA, not available. The primary outcome measure was the association of rs738409 with cirrhosis. The OR with 95% CI was calculated for the primary outcome in the cirrhosis group compared with the control group. Heterogeneity among the eligible studies was assessed by determining the Cochran Q and the I2 statistic. For the Q statistic, P < 0.10 was considered to indicate statistically significant heterogeneity. For the I2 statistic, which indicates the percentage of the observed between-study variability due to heterogeneity rather than chance, no heterogeneity was indicated by 0% to 25%, moderate heterogeneity was indicated by 25% to 50%, large heterogeneity was indicated by 50% to 75%, and extreme heterogeneity was indicated by 75% to 100%. Because the random effects model assumes that different studies may contain different underlying effects and takes into consideration both within- and between-study variation, the random effects model was adopted for the current study. Hence, pooled OR of the outcome was calculated by the DerSimonian-Laird method (36DerSimonian R. Laird N. Meta-analysis in clinical trials.Control. Clin. Trials. 1986; 7: 177-188Abstract Full Text PDF PubMed Scopus (29196) Google Scholar). Allele frequencies of the PNPLA3 I148M were tested for consistency with Hardy-Weinberg equilibrium (HWE) using the Fisher's exact test. A two-sided P value < 0.05 indicated statistical significance. All statistical analyses were performed using the statistical software Comprehensive Meta-Analysis, version 2.0 (Biostat, Englewood, NJ). We identified 147 potential studies and excluded 135 for not being relevant or not meeting the inclusion criteria (Fig. 1). Of the 12 remaining studies, 2 were excluded due to lack of details of subjects needed for the analysis, another 2 did not have a suitable control arm, and 1 contained preliminary unpublished data. A total of seven studies were included; all were prospective in design (20Krawczyk M. Grunhage F. Zimmer V. Lammert F. Variant adiponutrin (PNPLA3) represents a common fibrosis risk gene: non-invasive elastography-based study in chronic liver disease.J. Hepatol. 2011; 55: 299-306Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar, 21Trépo E. Gustot T. Degré D. Lemmers A. Verset L. Demetter P. Ouziel R. Quertinmont E. Vercruysse V. Amininejad L. et al.Common polymorphism in the PNPLA3/adiponutrin gene confers higher risk of cirrhosis and liver damage in alcoholic liver disease.J. Hepatol. 2011; 55: 906-912Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar, 22Tian C. Stokowski R.P. Kershenobich D. Ballinger D.G. Hinds D.A. Variant in PNPLA3 is associated with alcoholic liver disease.Nat. Genet. 2010; 42: 21-23Crossref PubMed Scopus (348) Google Scholar, 23Nischalke H.D. Berger C. Luda C. Berg T. Muller T. Grunhage F. Lammert F. Coenen M. Kramer B. Korner C. et al.The PNPLA3 rs738409 148M/M genotype is a risk factor for liver cancer in alcoholic cirrhosis but shows no or weak association in hepatitis C cirrhosis.PLoS ONE. 2011; 6: e27087Crossref PubMed Scopus (100) Google Scholar, 24Stickel F. Buch S. Lau K. Meyer zu Schwabedissen H. Berg T. Ridinger M. Rietschel M. Schafmayer C. Braun F. Hinrichsen H. et al.Genetic variation in the PNPLA3 gene is associated with alcoholic liver injury in Caucasians.Hepatology. 201" @default.
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• W2315490633 title "The rs738409 (I148M) variant of the PNPLA3 gene and cirrhosis: a meta-analysis" @default.
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