Combined effects of PNPLA3, TM6SF2 and HSD17B13 variants on severity of biopsy-proven non-alcoholic fatty liver disease

Rafael Paternostro,Petra Munda,Katharina Staufer,Elias Laurin Meyer ,Af Stättermayer ,Mattias Mandorfer,Péter Ferenci ,Fritz Wrba,Christian Datz,Emina Halilbasic,Jochen Hampe,Omar Keritam,Stefan Traussnigg,Judith Stift,Ali Canbay,Martin Schlattjan,Gerhard Prager,Felix Stickel,Bence Sipos,Clemens Schafmayer,Elmar Aigner,Michael Trauner

doi:10.1007/s12072-021-10200-y

Abstract

ObjectiveSeveral single-nucleotide polymorphisms have been identified to be disadvantageous or protective in regard to disease severity in patients with non-alcoholic fatty liver disease (NAFLD). However, it is unclear, whether including genetic risk factor(s) either alone or combined into risk stratification algorithms for NAFLD actually provides incremental benefit over clinical risk factors.DesignPatients with biopsy-proven NAFLD were genotyped for the PNPLA3-rs738409(minor allele:G), TM6SF2-rs58542926(minor allele:T) and HSD17B13- rs72613567 (minor allele:TA) variants. The NAFLD activity score (NAS) and fibrosis stage (F0–F4) were used to grade and stage all liver biopsy samples. Patients from seven centers throughout Central Europe were considered for the study.Results703 patients were included: NAS ≥ 5:173(24.6%); Fibrosis: F3–4:81(11.5%). PNPLA3 G/G genotype was associated with a NAS ≥ 5(aOR 2.23, p = 0.007) and advanced fibrosis (aOR-3.48, p < 0.001).TM6SF2 T/- was associated with advanced fibrosis (aOR 1.99, p = 0.023). HSD17B13 TA/- was associated with a lower probability of NAS ≥ 5(TA/T: aOR 0.65, p = 0.041, TA/TA: aOR 0.40, p = 0.033). Regarding the predictive capability for NAS ≥ 5, well-known risk factors (age, sex, BMI, diabetes, and ALT; baseline model) had an AUC of 0.758, Addition of PNPLA3(AUC 0.766), HSB17B13(AUC 0.766), and their combination(AUC 0.775), but not of TM6SF2(AUC 0.762), resulted in a higher diagnostic accuracy of the model. Addition of genetic markers for the prediction of advanced fibrosis (baseline model: age, sex, BMI, diabetes: AUC 0.777) resulted in a higher AUC if PNPLA3(AUC 0.789), and TM6SF2(AUC 0.786) but not if HSD17B13(0.777) were added.ConclusionIn biopsy-proven NAFLD, PNPLA3 G/-, TM6SF2 T/- and HSD17B13 TA/- carriage are associated with severity of NAFLD. Incorporating these genetic risk factors into risk stratification models might improve their predictive accuracy for severity of NAFLD and/or advanced fibrosis on liver biopsy.

Highlights

In recent years, several genetic risk factors associated with the susceptibility to and progression of chronic liver disease have been identified [1]
A study evaluating the combined effect of PNPLA3 and transmembrane 6 superfamily member 2 (TM6SF2) polymorphisms in non-alcoholic fatty liver disease (NAFLD) found variants of PNPLA3 and TM6SF2 to be independently associated with hepatic steatosis, while PNPLA3 but not TM6SF2 was associated with liver fibrosis in a multivariable model
Grade 2 ballooning was significantly more often seen in G-allele carriers (G/−: 60 [17.4%] vs. C/C: 37 [10.3%], p = 0.007), while severity of inflammation was not different between G-allele carriers and C/C genotypes (p = 0.676)

Summary

Introduction

Several genetic risk factors associated with the susceptibility to and progression of chronic liver disease have been identified [1]. A study evaluating the combined effect of PNPLA3 and TM6SF2 polymorphisms in NAFLD found variants of PNPLA3 and TM6SF2 to be independently associated with hepatic steatosis, while PNPLA3 but not TM6SF2 was associated with liver fibrosis in a multivariable model. These findings suggest combined disease-modifying effects of these polymorphisms [11]

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Results

Conclusion