HSD17B13 and MARC1 - Understanding genetic protection from non-alcoholic fatty liver disease

• Applicant: Professorin Dr. Carolin Victoria Schneider
• Subject Area: Gastroenterology ; Human Genetics
• Term: from 2020 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 448210878

• Final Report Year: 2022

Final Report Abstract

The non-alcoholic fatty liver disease (NAFLD) pandemic has reached alarming magnitudes, affecting nearly 2 billion people worldwide. My postdoctoral fellowship’s goal was to understand the impact of genetic variants that protect from NAFLD to develop interventional strategies, thereby avoiding complications of the ever-increasing thread of liver diseases. Despite the COVID19 pandemic, I was able to (Aim 1) determine that the common MTARC1 rs2642438 variant is associated with a healthier liver phenotype without raising the risk of cardiovascular disorders and (Aim 2) to identify the metabolic consequences MTARC1 pLoF variants, highlighting MTARC1 as a potential target for NAFLD treatment. To complete Aim 1 and 2, we used a genome-first approach and explored a range of metabolic phenotypes and outcomes associated with MTARC1 p.Ala165Thr in diverse population-based datasets, the UKBiobank (UKB, >500k) and the Penn-Medicine BioBank (PMBB, >60k). It was not possible to perform recall by genotype studies in PMBB, due to the COVID 19 pandemic. However, we found creative ways to answer the proposed research questions and substituted this missing data with data from the population-based datasets. Next, we focused on pLOF variants in HSD17B13 and MTARC1 and their relationship with liver-related mortality. We build a multivariable model including known genetic risk variants as well as lifestyle dependent factors. Here, we confirmed the association of the MTARC1 pLOF variant with liver-related mortality, independent of other known risk genes and saw a less pronounced effect in HSD17B13 rs72613567 carriers. To determine whether the observed phenotypical alterations are linked to changes in the cellular metabolism, we analyzed non-targeted metabolomics of patients with HSD17B13 or MTARC1 pLoF variants and matched controls. The observed metabolomic pattern is consistent with the reduced MTARC1 activity leading to increased hepatic secretion of a TG-enriched very-low-density lipoprotein (VLDL). Despite the setbacks of the pandemic, we were able to dissect the effects of pLOF variants in MTARC1 and HSD17B13 on NAFLD, liver-related mortality and lipid metabolism and we highlighted MTARC1 as a potential target for NAFLD therapy. Together, our data highlight MTARC1 as an important liver disease modifier that influences plasma lipids in an allele-dose dependent manner without increasing cardiovascular outcomes. Our results point toward potential mechanisms and reveal a remarkable association with liver-related mortality. In aim 3 we found biomarkers that predict liver disease progression in the general population. The Early prediction of decompensation (EPOD) score is a new score for the prediction of liver cirrhosis progression and is calculated from 3 routinely measured blood parameters (albumin, bilirubin, platelets). The score was evaluated using the IBM Explorys database, the PMBB and the UKB. It outperforms the well-known MELD and Child-Pugh score in predicting decompensation. We are the first to model a risk score predicting decompensation of cirrhosis and validate it in a diverse range of population-based datasets. Lastly, as the focus of my postdoctoral fellowship shifted from basic science to computational science, due to the possibilities in the COVID19 pandemic, I analyzed mortality and morbidity in the to-date largest, population-based dataset of telomer length. Interestingly, I also found an association of telomere shortening with liver diseases and liver-related mortality, which ties this project to the other proposed projects of my application. This highlights that spontaneity and perseverance even during a pandemic are sometimes rewarded. The numerous associations with telomere shortening, will probably be economically used in the future.

Publications

• A genome-first approach to mortality and metabolic phenotypes in MTARC1 p.Ala165Thr (rs2642438) heterozygotes and homozygotes. Med, 2(7), 851-863.e3.
  Schneider, Carolin V.; Schneider, Kai Markus; Conlon, Donna M.; Park, Joseph; Vujkovic, Marijana; Zandvakili, Inuk; Ko, Yi-An; Trautwein, Christian; Carr, Rotonya M.; Strnad, Pavel; Thaiss, Christoph A. & Rader, Daniel J.
  
• Mortality in Patients With Genetic and Environmental Risk of Liver Disease. American Journal of Gastroenterology, 116(8), 1741-1745.
  Schneider, Carolin V.; Fromme, Malin; Schneider, Kai Markus; Bruns, Tony & Strnad, Pavel
  
• Association of Telomere Length With Risk of Disease and Mortality. JAMA Internal Medicine, 182(3), 291.
  Schneider, Carolin V.; Schneider, Kai Markus; Teumer, Alexander; Rudolph, Karl Lenhard; Hartmann, Daniel; Rader, Daniel J. & Strnad, Pavel
  
• Early prediction of decompensation (EPOD) score: Non‐invasive determination of cirrhosis decompensation risk. Liver International, 42(3), 640-650.
  Schneider, Annika R. P.; Schneider, Carolin V.; Schneider, Kai Markus; Baier, Vanessa; Schaper, Steffen; Diedrich, Christian; Coboeken, Katrin; Mayer, Hannah; Gu, Wenyi; Trebicka, Jonel; Blank, Lars M.; Burghaus, Rolf; Lippert, Joerg; Rader, Daniel J.; Thaiss, Christoph A.; Schlender, Jan‐Frederik; Trautwein, Christian & Kuepfer, Lars