PNPLA3 in end-stage liver disease: Alcohol consumption, hepatocellular carcinoma development, and transplantation-free survival

Background and Aims: The rs738409 variant (I148M) of the patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene is associated with several liver malfunctions. Its impact on end-stage liver disease has not been addressed yet. Methods: The I148M polymorphism was genotyped in a well-characterized cohort of 421 Caucasian patients and retrospectively analyzed from the time of enrollment at Eurotransplant. Results: The G allele of the I148M variant was significantly overrepresented in patients with alcoholic liver disease (ALD, P < 0.001) and associated with hepatocellular carcinoma (HCC) development (odds ratio [OR] = 2.399; 95% confidence interval [CI]: 1.292-4.455; P = 0.008) while not affecting the other liver disease entities. Time until hydropic decompensation (P = 0.04) and hepatic encephalopathy (P = 0.043) was significantly impaired for ALD patients carrying either one or two mutated G alleles. Actuarial survival free of liver transplantation was further reduced for ALD carriers of the I148M variant (CC = 30.7 months +/- 7.9, 95% CI: 15.1-46.2 vs CG/GG: 17.1 months +/- 3.3, 95% CI: 3.3-10.6; P = 0.012) compared with wild-type patients. Cox multivariate analysis identified the PNPLA3 I148M genotype as an independent predictor actuarial survival free of liver transplantation (OR = 1.77; 95% CI: 1.27-2.47; P = 0.001). Conclusions: In end-stage liver disease patients, we identified ALD to be predominantly affected by the PNPLA3 I148M variant resulting in an increased risk of HCC and reduced transplantation free survival. Genetic testing of the I148M genotype in ALD patients awaiting liver transplantation might be beneficial for these patients.