Carolin V Schneider1, Kai Markus Schneider2,3,4, Donna M Conlon1, Joseph Park1, Marijana Vujkovic1, Inuk Zandvakili5, Yi-An Ko1, Christian Trautwein6, Regerneron Center7, Rotonya M Carr5, Pavel Strnad6, Christoph A Thaiss2,3,4, Daniel J Rader1,8. 1. Division of Translational Medicine and Human Genetics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. 2. Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. 3. Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. 4. Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. 5. Division of Gastroenterology and Hepatology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. 6. Medical Clinic III, Gastroenterology, Metabolic diseases and Intensive Care, University Hospital RWTH Aachen, 52072 Aachen, Germany. 7. Regeneron Genetics Center, Tarrytown, New York, USA. 8. Department of Genetics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Abstract
BACKGROUND: A coding variant in MTARC1 (rs2642438; p.Ala165Thr) was recently associated with protection from cirrhosis in European individuals. However, its impact on overall and cause-specific mortality remained elusive. METHODS: Using a genome-first approach, we explored a range of metabolic phenotypes and outcomes associated with MTARC1 p.Ala165Thr in the UKBiobank and the Penn-Medicine BioBank. FINDINGS: MTARC1 p.Ala165Thr was significantly associated with higher triglycerides, lower total cholesterol, lower LDL-C, lower ApoB, lower HDL-C, lower ApoA-I and higher IGF-1. Per each minor allele, the risk of NAFLD was reduced by ~15%. The ALT-lowering and NAFLD-protective effect of MTARC1 p.Ala165Thr was amplified by obesity, diabetes mellitus and presence of PNPLA3 rs738409:G. In African-American and Black-British individuals, the allele frequency of MTARC1 p.Ala165Thr was lower, but carriers showed the same distinctive lipid phenotype. Importantly, MTARC1 p.Ala165Thr carriers did not show higher cardiovascular disease burden as evidenced by cardiac MRI and carotid ultrasound. In prospective analyses, the homozygous minor allele was associated with up to 39% lower rates of liver-related mortality, while no risk of increased overall or cardiovascular death could be observed. Strikingly, liver-related mortality was more than 50% reduced in diabetic participants or carriers of PNPLA3 rs738409:G. CONCLUSIONS: Together these 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 calling for future studies exploring its therapeutic potential. FUNDING: This study was funded by the German Research Foundation (DFG).
BACKGROUND: A coding variant in MTARC1 (rs2642438; p.Ala165Thr) was recently associated with protection from cirrhosis in European individuals. However, its impact on overall and cause-specific mortality remained elusive. METHODS: Using a genome-first approach, we explored a range of metabolic phenotypes and outcomes associated with MTARC1 p.Ala165Thr in the UKBiobank and the Penn-Medicine BioBank. FINDINGS: MTARC1 p.Ala165Thr was significantly associated with higher triglycerides, lower total cholesterol, lower LDL-C, lower ApoB, lower HDL-C, lower ApoA-I and higher IGF-1. Per each minor allele, the risk of NAFLD was reduced by ~15%. The ALT-lowering and NAFLD-protective effect of MTARC1 p.Ala165Thr was amplified by obesity, diabetes mellitus and presence of PNPLA3 rs738409:G. In African-American and Black-British individuals, the allele frequency of MTARC1 p.Ala165Thr was lower, but carriers showed the same distinctive lipid phenotype. Importantly, MTARC1 p.Ala165Thr carriers did not show higher cardiovascular disease burden as evidenced by cardiac MRI and carotid ultrasound. In prospective analyses, the homozygous minor allele was associated with up to 39% lower rates of liver-related mortality, while no risk of increased overall or cardiovascular death could be observed. Strikingly, liver-related mortality was more than 50% reduced in diabetic participants or carriers of PNPLA3 rs738409:G. CONCLUSIONS: Together these 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 calling for future studies exploring its therapeutic potential. FUNDING: This study was funded by the German Research Foundation (DFG).
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