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

Abstract

Objective Several 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. Design Patients 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. Results 703 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. Conclusion In 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.

HSD17B13: A Potential Therapeutic Target for NAFLD

“…In addition, Stender's group has recently reported that an unweighted genetic risk score combining three genetic variants including PNPLA3p.I148M, TM6SF2 p.E167K and HSD17B13 rs72613567 for fatty liver disease conferred up to a 12-fold higher risk of cirrhosis and up to a 29-fold higher risk of HCC in individuals from the general population in Europe (Gellert-Kristensen et al, 2020). Moreover, in patients with biopsyproven NAFLD, PNPLA3 G/-, TM6SF2 T/-and HSD17B13 TA/-carriage were found to be associated with the severity of NAFLD, and combining PNPLA3 (rs738409, p 0.0076), HSD17B13 (rs72613567), and TM6SF2(rs10401969, p 0.0076), MBOAT7 (rs641738) with clinical data further increased the accuracy for predicting the severity of NASH and/or advanced fibrosis (Ioannou, 2021;Paternostro et al, 2021). Meanwhile, another study explored the impact of the HSD17B13 variant in 1,153 non-Hispanic NASH patients in the United States.…”

Discovery of a Novel Potent and Selective HSD17B13 Inhibitor, BI-3231, a Well-Characterized Chemical Probe Available for Open Science

“…A link between HSD17B13 and liver disease was first indicated by genome-wide association studies (GWAS) that revealed a strong association between a loss-of-function (LoF) SNP rs72613567 and levels of serum alanine aminotransferase (ALT), a clinical biomarker of liver dysfunction . The initial observation has been reinforced by multiple studies of diverse cohorts, demonstrating an association between this and other LoF SNPs and risk for NASH, alcoholic liver disease, cirrhosis, and hepatocellular carcinoma. − Primarily expressed in hepatocytes, HSD17B13 is upregulated in the liver of NAFLD patients and, preclinically, AAV-mediated HSD17B13 overexpression in mouse liver promoted lipid accumulation, indicating a strong association of HSD17B13 with fatty acid metabolism . Direct clinical support for HSD17B13 as a therapeutic target was generated when a hepatocyte-directed small interfering RNA (siRNA) designed to deplete HSD17B13 in human liver was found to decrease serum alanine aminotransferase (ALT) activity in five patients with presumed NAFLD…”

Genetic variants associated with steatohepatitis and liver fibrosis in HIV-infected patients with NAFLD

“…It would have been interesting to have a control group of patients with steatohepatitis who were not HIV-infected, unfortunately we were unable to include patients with these characteristics. Nevertheless, our results for the association between CG/GG in PNPLA3 and presence of steatohepatitis and fibrosis in the general population are well documented ( Krawczyk et al, 2017 ; Mazo et al, 2019 ; Paternostro et al, 2021 ) and the main interest of our study was that we explored whether findings previously reported in other populations can also be found in populations coinfected by HIV without coinfection by HCV. Our results also show an independent association between CG/GG in PNPLA3 and the presence of steatohepatitis and liver fibrosis in this population.…”