PNPLA3 and SERPINA1 Variants Are Associated with Severity of Fatty Liver Disease at First Referral to a Tertiary Center.

Georg Semmler,Lorenz Balcar,Bernhard Paulweber,Elmar Aigner,Hannes Oberkofler,Christian Datz,Michael Strasser,Pavel Strnad,David Niederseer,Felix Stickel,Alexandra Feldman,Stephan Zandanell

doi:10.3390/jpm11030165

Abstract

Single nucleotide polymorphisms (SNPs), including PNPLA3 rs738409 and SERPINA1 rs17580, have been identified as risk modifiers in the progression fatty liver disease (alcoholic (ALD) or non-alcoholic (NAFLD)). While PNPLA3 has been studied in various settings, the value of both SNPs has so far not been addressed in a real-world cohort of subjects referred for a diagnostic work-up of liver disease. Thus, liver disease severity was assessed in 1257 consecutive patients with suspected ALD or NAFLD at the time of referral to a tertiary center. Advanced chronic liver disease (ACLD) was present in 309 (24.6%) patients and clinically significant portal hypertension (CSPH) was present in 185 (14.7%) patients. The PNPLA3 G-allele was independently associated with a higher liver stiffness measurement (LSM; adjusted B: 2.707 (1.435–3.979), p < 0.001), and higher odds of ACLD (adjusted odds ratio (aOR): 1.971 (1.448–2.681), p < 0.001) and CSPH (aOR: 1.685 (1.180–2.406), p = 0.004). While the SERPINA1 Z-allele was not associated with a higher LSM or the presence of ACLD, it was independently associated with higher odds of CSPH (aOR: 2.122 (1.067–4.218), p = 0.032). Associations of the PNPLA3 G-allele and the SERPINA1 Z-allele with CSPH were maintained independently of each other. The presence of both risk variants further increased the likelihood of ACLD and CSPH.

Highlights

Following genome-wide association studies, several single nucleotide polymorphisms (SNPs) have been identified as modifiers in the progression of chronic liver disease (CLD)
non-alcoholic fatty liver disease (NAFLD) was the more common etiology (n = 1048, 83.4%), while a smaller proportion was classified as alcoholic liver disease (ALD) (n = 209, 16.6%)
The recent findings by Strnad et al [13] showed that the SERPINA1 Z-allele was associated with disease severity and an increased risk of developing cirrhosis in patients with NAFLD and ALD, which was significant as the association was independent of PNPLA3, TM6SF2 and MBOAT7, and was numerically stronger than that of other risk variants for the development of NAFLD/ALD cirrhosis

Summary

Introduction

Following genome-wide association studies, several single nucleotide polymorphisms (SNPs) have been identified as modifiers in the progression of chronic liver disease (CLD). Strnad et al [13] reported that the SERPINA1 Pi*Zallele was associated with disease severity and an increased risk of developing cirrhosis in patients with NAFLD and ALD This association was independent of PNPLA3, TM6SF2 (Transmembrane 6 superfamily 2 rs58542926) and MBOAT7 (membrane-bound O-acyltransferase domain-containing protein 7 rs641738), and the association with the development of NAFLD/ALD cirrhosis was stronger than that of other risk variants (including PNPLA3) [14]. These findings raise questions about the impact and clinical usefulness of these variants on the severity of liver disease in clinical practice. We aimed to assess these questions in a cohort of consecutive subjects who had been referred to a tertiary referral center for a diagnostic work-up of liver disease

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