TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease

Yang-Lin Liu, Helen L. Reeves, Alastair D. Burt, Dina Tiniakos, Stuart McPherson, Julian B. S. Leathart, Michael E. D. Allison, Graeme J. Alexander, Anne-Christine Piguet, Rodolphe Anty, Peter Donaldson, Guruprasad P. Aithal, Sven Francque, Luc Van Gaal, Karine Clement, Vlad Ratziu, Jean-Francois Dufour, Christopher P. Day, Ann K. Daly and Quentin M. Anstee ()
Additional contact information
Yang-Lin Liu: Institute of Cellular Medicine, The Medical School, Newcastle University
Helen L. Reeves: Northern Institute for Cancer Research, The Medical School, Newcastle University
Alastair D. Burt: Institute of Cellular Medicine, The Medical School, Newcastle University
Dina Tiniakos: Institute of Cellular Medicine, The Medical School, Newcastle University
Stuart McPherson: Institute of Cellular Medicine, The Medical School, Newcastle University
Julian B. S. Leathart: Institute of Cellular Medicine, The Medical School, Newcastle University
Michael E. D. Allison: Liver Unit, Addenbrooke’s Hospital
Graeme J. Alexander: Liver Unit, Addenbrooke’s Hospital
Anne-Christine Piguet: University Clinic of Visceral Surgery and Medicine, Inselspital Bern
Rodolphe Anty: Institute of Cellular Medicine, The Medical School, Newcastle University
Peter Donaldson: Institute of Cellular Medicine, The Medical School, Newcastle University
Guruprasad P. Aithal: NIHR Nottingham Digestive Diseases Biomedical Research Unit, Nottingham University Hospitals NHS Trust and University of Nottingham
Sven Francque: Diabetology and Metabolism, Antwerp University Hospital, Wilrijkstraat 10
Luc Van Gaal: Diabetology and Metabolism, Antwerp University Hospital, Wilrijkstraat 10
Karine Clement: Institute of Cardiometabolism and Nutrition, Pitié-Salpêtrière Hospital
Vlad Ratziu: Institute of Cardiometabolism and Nutrition, Pitié-Salpêtrière Hospital
Jean-Francois Dufour: University Clinic of Visceral Surgery and Medicine, Inselspital Bern
Christopher P. Day: Institute of Cellular Medicine, The Medical School, Newcastle University
Ann K. Daly: Institute of Cellular Medicine, The Medical School, Newcastle University
Quentin M. Anstee: Institute of Cellular Medicine, The Medical School, Newcastle University

Nature Communications, 2014, vol. 5, issue 1, 1-6

Abstract: Abstract Non-alcoholic fatty liver disease (NAFLD) is an increasingly common condition, strongly associated with the metabolic syndrome, that can lead to progressive hepatic fibrosis, cirrhosis and hepatic failure. Subtle inter-patient genetic variation and environmental factors combine to determine variation in disease progression. A common non-synonymous polymorphism in TM6SF2 (rs58542926 c.449 C>T, p.Glu167Lys) was recently associated with increased hepatic triglyceride content, but whether this variant promotes clinically relevant hepatic fibrosis is unknown. Here we confirm that TM6SF2 minor allele carriage is associated with NAFLD and is causally related to a previously reported chromosome 19 GWAS signal that was ascribed to the gene NCAN. Furthermore, using two histologically characterized cohorts encompassing steatosis, steatohepatitis, fibrosis and cirrhosis (combined n=1,074), we demonstrate a new association, independent of potential confounding factors (age, BMI, type 2 diabetes mellitus and PNPLA3 rs738409 genotype), with advanced hepatic fibrosis/cirrhosis. These findings establish new and important clinical relevance to TM6SF2 in NAFLD.

Date: 2014
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DOI: 10.1038/ncomms5309

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