PNPLA3 Gene Polymorphism is Associated with Alcohol-Related Liver Injury with Increased Progression to Cirrhosis and Hepatocellular Carcinoma

Abstract

Purpose: Alcohol abuse is a common cause of liver disease (ALD) and indication for liver transplantation in the US. Clinical spectrum of ALD may range from simple steatosis or fatty liver (FL), alcoholic hepatitis, alcoholic cirrhosis (AC), and hepatocellular carcinoma (HCC). Only 10-20% of heavy drinkers develop alcoholic cirrhosis (AC), implicating the role of other factors in development of ALD and progression to AC and HCC. Recently, a genetic polymorphism with an isoleucine to methionine substitution at position 148 (rs738409 C>G) in the palatin-like phospholipase domain (PNPLA3) gene has been shown to predispose to steatosis. Data has shown association of this genetic polymorphism with ALD and its progression to more advanced disease. We performed a systematic review and meta-analysis of studies evaluating association of this polymorphism (G instead of C) in ALD. Methods: Search of electronic databases revealed six studies examining association of PNPLA3 gene polymorphism and ALD. Data were reported as pooled odds ratio (OR), with 95% confidence interval (CI). Fixed effects model of comprehensive meta-analysis program software was used to pool data. I2 statistics and Egger's tests were used to assess data heterogeneity and publication bias, respectively. Results: Compared to non-drinkers, drinkers were assessed for risk of AC in five studies, ALD in three, HCC in two, and FL in one. Among alcohol drinkers, association of PNPLA3 genetic polymorphism was assessed for risk of AC compared to ALD or to FL (one study each), and risk of HCC occurrence in AC in two studies. Pooled data shown in Table 1 were homogeneous, without any publication bias.Table 1Conclusion: PNPLA3 genetic polymorphism (rs738409 C>G) confers an increased risk for the development of ALD among drinkers, and an increased propensity for AC and HCC in those with ALD. Studies are needed to clarify association of PNPLA3 and steatosis in alcohol drinkers. PNPLA3 gene may be a potential therapeutic target in ALD and in selecting donor organs for transplanting patients with ALD.