The effect of PNPLA3 on fibrosis progression and development of hepatocellular carcinoma: a meta-analysis.
OBJECTIVE
The PNPLA3 rs738409 single-nucleotide polymorphism is known to promote nonalcoholic steatohepatitis (NASH), but its association with fibrosis severity and hepatocellular carcinoma (HCC) risk is less well-defined. The objectives of this study were to determine the association between PNPLA3 and liver fibrosis severity, HCC risk, and HCC prognosis among patients with liver disease.


METHODS
We performed a systematic literature review using the Medline, PubMed, Scopus, and Embase databases through May 2013 and a manual search of national meeting abstracts from 2010 to 2012. Two investigators independently extracted data on patient populations, study methods, and results using standardized forms. Pooled odds ratios (ORs), according to PNPLA3 genotype, were calculated using the DerSimonian and Laird method for a random effects model.


RESULTS
Among 24 studies, with 9,915 patients, PNPLA3 was associated with fibrosis severity (OR 1.32, 95% confidence interval (CI) 1.20-1.45), with a consistent increased risk across liver disease etiologies. Among nine studies, with 2,937 patients, PNPLA3 was associated with increased risk of HCC in patients with cirrhosis (OR 1.40, 95% CI 1.12-1.75). On subgroup analysis, increased risk of HCC was demonstrated in patients with NASH or alcohol-related cirrhosis (OR 1.67, 95% CI 1.27-2.21) but not in those with other etiologies of cirrhosis (OR 1.33, 95% CI 0.96-1.82). Three studies, with 463 patients, do not support an association between PNPLA3 and HCC prognosis but are limited by heterogeneous outcome measures. For all outcomes, most studies were conducted in homogenous Caucasian populations, and studies among racially diverse cohorts are needed.


CONCLUSIONS
PNPLA3 is associated with an increased risk of advanced fibrosis among patients with a variety of liver diseases and is an independent risk factor for HCC among patients with nonalcoholic steatohepatitis or alcohol-related cirrhosis.
1] Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA [2] Harold C. Simmons Cancer Center, UT Southwestern Medical Center, Dallas, Texas, USA.
Amit G
AG
Singal
Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA.
Hema
H
Manjunath
1] Harold C. Simmons Cancer Center, UT Southwestern Medical Center, Dallas, Texas, USA [2] Department of Surgery, UT Southwestern Medical Center, Dallas, Texas, USA.
Adam C
AC
Yopp
Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA.
Muhammad S
MS
Beg
1] Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA [2] Harold C. Simmons Cancer Center, UT Southwestern Medical Center, Dallas, Texas, USA.
Jorge A
JA
Marrero
Department of Pathology, UT Southwestern Medical Center, Dallas, Texas, USA.
Purva
P
Gopal
1] Veterans Affairs Center for Clinical Management Research, Ann Arbor, Michigan, USA [2] Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Akbar K
AK
Waljee
D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D018450:Disease Progression; D020022:Genetic Predisposition to Disease; D006801:Humans; D008049:Lipase / Q000235:genetics*; D008103:Liver Cirrhosis / Q000175:diagnosis / Q000235:genetics*; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D018570:Risk Assessment; D012307:Risk Factors; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
D008049:Lipase; D008565:Membrane Proteins; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent