PNPLA3 gene polymorphism is associated with predisposition to and severity of alcoholic liver disease

Habeeb Salameh, Evan Raff, Angelika Erwin, Devanshi Seth, Hans Dieter Nischalke, Edmondo Falleti, Maria Antonella Burza, Julian Leathert, Stefano Romeo, Antonio Molinaro, Stefano Ginanni Corradini, Pierluigi Toniutto, Spengler Ulrich, Ann Daly, Christopher P. Day, Yong Fang Kuo, Ashwani K. Singal

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)846-856
Number of pages11
JournalAmerican Journal of Gastroenterology
Volume110
Issue number6
DOIs
StatePublished - Jun 10 2015

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Alcoholic Liver Cirrhosis
Alcoholic Liver Diseases
Phospholipases
Odds Ratio
Hepatocellular Carcinoma
Proteins
Genetic Polymorphisms
Alcoholic Fatty Liver
Wounds and Injuries
Liver
Genotype
Publication Bias
Protein Domains
Isoleucine
Fatty Liver
Alcoholics
Methionine
Libraries
Meta-Analysis
Confidence Intervals

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Salameh, H., Raff, E., Erwin, A., Seth, D., Nischalke, H. D., Falleti, E., ... Singal, A. K. (2015). PNPLA3 gene polymorphism is associated with predisposition to and severity of alcoholic liver disease. American Journal of Gastroenterology, 110(6), 846-856. https://doi.org/10.1038/ajg.2015.137

PNPLA3 gene polymorphism is associated with predisposition to and severity of alcoholic liver disease. / Salameh, Habeeb; Raff, Evan; Erwin, Angelika; Seth, Devanshi; Nischalke, Hans Dieter; Falleti, Edmondo; Burza, Maria Antonella; Leathert, Julian; Romeo, Stefano; Molinaro, Antonio; Corradini, Stefano Ginanni; Toniutto, Pierluigi; Ulrich, Spengler; Daly, Ann; Day, Christopher P.; Kuo, Yong Fang; Singal, Ashwani K.

In: American Journal of Gastroenterology, Vol. 110, No. 6, 10.06.2015, p. 846-856.

Research output: Contribution to journalArticle

Salameh, H, Raff, E, Erwin, A, Seth, D, Nischalke, HD, Falleti, E, Burza, MA, Leathert, J, Romeo, S, Molinaro, A, Corradini, SG, Toniutto, P, Ulrich, S, Daly, A, Day, CP, Kuo, YF & Singal, AK 2015, 'PNPLA3 gene polymorphism is associated with predisposition to and severity of alcoholic liver disease', American Journal of Gastroenterology, vol. 110, no. 6, pp. 846-856. https://doi.org/10.1038/ajg.2015.137
Salameh, Habeeb ; Raff, Evan ; Erwin, Angelika ; Seth, Devanshi ; Nischalke, Hans Dieter ; Falleti, Edmondo ; Burza, Maria Antonella ; Leathert, Julian ; Romeo, Stefano ; Molinaro, Antonio ; Corradini, Stefano Ginanni ; Toniutto, Pierluigi ; Ulrich, Spengler ; Daly, Ann ; Day, Christopher P. ; Kuo, Yong Fang ; Singal, Ashwani K. / PNPLA3 gene polymorphism is associated with predisposition to and severity of alcoholic liver disease. In: American Journal of Gastroenterology. 2015 ; Vol. 110, No. 6. pp. 846-856.
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title = "PNPLA3 gene polymorphism is associated with predisposition to and severity of alcoholic liver disease",
abstract = "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.",
author = "Habeeb Salameh and Evan Raff and Angelika Erwin and Devanshi Seth and Nischalke, {Hans Dieter} and Edmondo Falleti and Burza, {Maria Antonella} and Julian Leathert and Stefano Romeo and Antonio Molinaro and Corradini, {Stefano Ginanni} and Pierluigi Toniutto and Spengler Ulrich and Ann Daly and Day, {Christopher P.} and Kuo, {Yong Fang} and Singal, {Ashwani K.}",
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T1 - PNPLA3 gene polymorphism is associated with predisposition to and severity of alcoholic liver disease

AU - Salameh, Habeeb

AU - Raff, Evan

AU - Erwin, Angelika

AU - Seth, Devanshi

AU - Nischalke, Hans Dieter

AU - Falleti, Edmondo

AU - Burza, Maria Antonella

AU - Leathert, Julian

AU - Romeo, Stefano

AU - Molinaro, Antonio

AU - Corradini, Stefano Ginanni

AU - Toniutto, Pierluigi

AU - Ulrich, Spengler

AU - Daly, Ann

AU - Day, Christopher P.

AU - Kuo, Yong Fang

AU - Singal, Ashwani K.

PY - 2015/6/10

Y1 - 2015/6/10

N2 - 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.

AB - 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.

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