Background:
Chronic liver diseases lead to liver fibrosis. The adiponutrin (PNPLA3) p.I148 M and transmembrane 6 superfamily member 2 (TM6SF2) p.E167K variants represent major genetic risk factors for increased liver injury in patients with fatty liver (NAFLD), viral hepatitis and alcoholic liver disease (ALD) (Anstee et al. Gastroenterology 2016, Krawczyk et al. J Lipid Res 2017). Here we aim to investigate whether these two variants enhance liver injury in the setting of chronic cholestasis as well.
Methods:
Starting in 2012, we prospectively recruited 178 PSC patients (112 men, age range 17 – 75 years, 62 biopsied, 94 with ulcerative colitis). Cirrhosis was present in 55 patients, and 48 patients were transplanted during the 4-year follow-up. The PNPLA3 rs738409 and TM6SF2 rs58542926 polymorphisms were genotyped using TaqMan assays.
Results:
Allele and genotype distributions of both variants were consistent with Hardy-Weinberg equilibrium (both P > 0.05), and minor allele frequencies (MAF) were within the ExAC database ranges. Overall, we did not detect any differences in the PNPLA3 (P = 0.90) or TM6SF2 (P = 0.72) genotype distributions between patients with cirrhosis (PNPLA3 MAF = 0.22, TM6SF2 MAF = 0.04) and patients without cirrhosis (PNPLA3 MAF = 0.20, TM6SF2 MAF = 0.06). In addition, serum liver enzyme activities were not modified by neither PNPLA3 (ALT P = 0.88, AST P = 0.77) nor TM6SF2 (ALT P = 0.92, AST P = 0.49) variants. Liver function tests did not increase with the number of risk alleles as demonstrated by a separate analysis of patients carrying 0 (n = 99), 1 (n = 64), 2 (n = 12) or 3 (n = 3) minor alleles (P > 0.05). The effects of the PNPLA3 or TM6SF2 variants were also not apparent in patients with concomitant ulcerative colitis, and none of the variants increased the odds of liver transplantation.
Conclusions:
Based on the large number of previous studies demonstrating associations of the PNPLA3 and TM6SF2 variants with chronic liver injury in NAFLD, ALD and viral hepatitis, one could expect similar results in PSC as well. Here we demonstrate however, that neither PNPLA3 nor TM6SF2 polymorphisms confer a major risk for deterioration of liver function in the setting of chronic cholestasis. This observation underscores distinct modulation of liver fibrogenesis in cholestatic conditions as compared to metabolic and viral liver diseases.
