Abstract
Alcoholic liver cirrhosis (ALC) is the most common indication for liver transplantation (LT) in Croatia and presents a risk factor for the development of hepatocellular carcinoma (HCC). However, genetic susceptibility has not yet been systematically studied. We aimed to investigate the contribution of the risk polymorphisms PNPLA3 rs738409, EGF rs4444903, TM6SF2 rs58542926, MTHFR rs1801133, previously identified in other populations and, additionally, the contribution of Notch-related polymorphisms (NOTCH1 rs3124591, NOTCH3 rs1043996 and rs1044116, NOTCH4 rs422951). The study included 401 patients. The ALC group consisted of 260 LT candidates, 128 of whom had histopathologically confirmed HCC, and 132 of whom were without HCC. The control group included 141 patients without liver disease. Genotyping was performed by PCR using Taqman assays. The patients’ susceptibility to ALC was significantly associated with PNPLA3 rs738409, TM6SF2 rs58542926, and NOTCH3 rs1043996 polymorphisms. These polymorphisms remained significantly associated with ALC occurrence in a logistic regression model, even after additional model adjustment for sex and age. Cirrhotic patients with the PNPLA3 GG genotype demonstrated higher activity of ALT aminotransferases than patients with CC or CG genotypes. The susceptibility to the development of HCC in ALC was significantly associated with PNPLA3 rs738409 and EGF rs4444903 polymorphisms, and logistic regression confirmed these polymorphisms as independent predictors.
Highlights
End-stage alcoholic liver disease is one of the leading indications for liver transplantation (LT), and patients with alcoholic liver cirrhosis (ALC) are at higher risk for developing hepatocellular carcinoma (HCC) [1,2,3]
We aimed to investigate the contribution of previously implicated genetic risk factors (PNPLA3, transmembrane 6 superfamily member 2 (TM6SF2), epidermal growth factor (EGF), methylenetetrahydrofolate reductase (MTHFR)) for the development of cirrhosis and HCC
To further establish the additional genetic risk factors for ALC, we investigated the possible contribution of polymorphisms in Notch receptors and found that NOTCH3 rs1043996 GG carriers have a reduced probability of developing ALC that is independent of the PNPLA3 or TM6SF2 genotypes
Summary
End-stage alcoholic liver disease is one of the leading indications for liver transplantation (LT), and patients with alcoholic liver cirrhosis (ALC) are at higher risk for developing hepatocellular carcinoma (HCC) [1,2,3]. Genetic predisposition contributes to both liver fibrosis and its progression to HCC The findings of both genome-wide association studies and candidate gene approach studies, conducted in the last decade, point to the patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 G allele and the transmembrane 6 superfamily member 2 (TM6SF2) rs58542926 T allele as the major genetic factors that increase susceptibility to the fibrosis [4,5,6,7,8]. Their role as a risk factor for the development of cirrhosis or HCC has not yet been investigated
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