PNPLA3 p.I148M and TM6SF2 p.E167K variants do not predispose to liver injury in cholestatic liver diseases: A prospective analysis of 178 patients with PSC.

Beata Kruk,Marcin Krawczyk,Frank Lammert,Joanna Raszeja-Wyszomirska,Małgorzata Milkiewicz,Ewa Wunsch,Piotr Milkiewicz,Roman Liebe,Matias A Avila

doi:10.1371/journal.pone.0202942

Abstract

BackgroundThe adiponutrin (PNPLA3) p.I148M and transmembrane 6 superfamily member 2 (TM6SF2) p.E167K variants represent major genetic risk factors for progressive liver injury in nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD) and chronic viral hepatitis. The aim of this study was to find out whether these variants have a detrimental impact on the progression of chronic liver disease in patients with prolonged cholestasis induced by primary sclerosing cholangitis (PSC).MethodsWe prospectively recruited 178 PSC patients (112 male, age range 17–75 years, 55 with liver cirrhosis, 94 with ulcerative colitis, 48 transplanted during follow-up). PNPLA3 rs738409 and TM6SF2 rs58542926 polymorphisms were genotyped using dedicated TaqMan assays. Associations between genotypes, biochemical and clinical phenotypes were analyzed using contingency tables.ResultsAllele and genotype distribution of both variants were consistent with Hardy-Weinberg equilibrium. No significant differences in the genotype distribution of PNPLA3 (P = 0.90) or TM6SF2 (P = 0.72) were observed between patients with cirrhosis and patients without cirrhosis. Serum liver enzyme activities were not modified by the presence of PNPLA3 (ALT P = 0.88, AST P = 0.77) or TM6SF2 (ALT P = 0.92, AST P = 0.49) risk variants. Increasing number of risk alleles had no impact on serum liver enzyme activities, as demonstrated by a separate analysis of patients carrying 0 (n = 99), 1 (n = 64), 2 (n = 12) or 3 (n = 3) risk alleles (P>0.05). No impact of PNPLA3 or TM6SF2 risk variants was detectable in patients with PSC and ulcerative colitis, and none of the variants increased the odds of transplantation.ConclusionsNeither PNPLA3 nor TM6SF2 polymorphisms seem to contribute significantly towards an increased risk for deterioration of liver function in patients with PSC. These results underscore the divergent mechanisms of liver damage in cholestatic conditions as compared to metabolic and viral liver diseases.

Highlights

No impact of patatin-like phospholipase domaincontaining protein 3TM6SF2 (PNPLA3) or transmembrane 6 superfamily member 2 (TM6SF2) risk variants was detectable in patients with primary sclerosing cholangitis (PSC) and ulcerative colitis, and none of the variants increased the odds of transplantation
Primary sclerosing cholangitis (PSC) is a progressive cholestatic liver disease characterized by ongoing inflammation and destruction of intrahepatic and extrahepatic bile ducts [1], and resulting in chronic liver damage leading to hepatic fibrosis
The PNPLA3 "M" variant has been associated with increased hepatic steatosis and fibrosis in patients with viral hepatitis, non-alcoholic fatty liver disease (NAFLD) [2] and alcoholic liver disease (ALD) [3], [4], [5], [6]

Summary

Introduction

Primary sclerosing cholangitis (PSC) is a progressive cholestatic liver disease characterized by ongoing inflammation and destruction of intrahepatic and extrahepatic bile ducts [1], and resulting in chronic liver damage leading to hepatic fibrosis. Friedrich et al [10] studied 121 German and 347 Norwegian PSC patients and postulated that the disease-associated minor PNPLA3 allele modifies the course of the disease among carriers of dominant stenosis in bile ducts. They found that risk allele carriers were more prone to require liver transplantation and had shorter survival. Italian researchers demonstrated recently that patients with inflammatory bowel disease (IBD) carrying the PNPLA3 "M" allele are at increased risk of developing hepatic steatosis and increased liver enzymes [11] They postulated that this variant might modulate the degree of liver injury in patients with PSC and ulcerative colitis [11]. The aim of this study was to find out whether these variants have a detrimental impact on the progression of chronic liver disease in patients with prolonged cholestasis induced by primary sclerosing cholangitis (PSC)

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