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Nat Commun. 2014 Jun 30;5:4309. doi: 10.1038/ncomms5309.

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

Author information

1
Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
2
Northern Institute for Cancer Research, The Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
3
1] Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK [2].
4
Liver Unit, Department of Medicine, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
5
University Clinic of Visceral Surgery and Medicine, Inselspital Bern, 3010 Bern, Switzerland.
6
1] Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK [2] Institut National de la Santé et de la Recherche Médicale (INSERM), U1065, Team 8, Nice F-06204, Cedex 3, France.
7
NIHR Nottingham Digestive Diseases Biomedical Research Unit, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham NG7 2UH, UK.
8
Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, Wilrijkstraat 10, B-2650 Edegem, Antwerp, Belgium.
9
Institute of Cardiometabolism and Nutrition, Pitié-Salpêtrière Hospital, 75013 Paris, France.

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.

PMID:
24978903
PMCID:
PMC4279183
DOI:
10.1038/ncomms5309
[Indexed for MEDLINE]
Free PMC Article

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