title: TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease.
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.
authors: Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors: Yang-Lin
authors: YL
authors: Liu
authors: Northern Institute for Cancer Research, The Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors: Helen L
authors: HL
authors: Reeves
authors: 1] Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK [2].
authors: Alastair D
authors: AD
authors: Burt
authors: Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors: Dina
authors: D
authors: Tiniakos
authors: Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors: Stuart
authors: S
authors: McPherson
authors: Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors: Julian B S
authors: JB
authors: Leathart
authors: Liver Unit, Department of Medicine, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors: Michael E D
authors: ME
authors: Allison
authors: Liver Unit, Department of Medicine, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors: Graeme J
authors: GJ
authors: Alexander
authors: University Clinic of Visceral Surgery and Medicine, Inselspital Bern, 3010 Bern, Switzerland.
authors: Anne-Christine
authors: AC
authors: Piguet
authors: 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.
authors: Rodolphe
authors: R
authors: Anty
authors: Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors: Peter
authors: P
authors: Donaldson
authors: NIHR Nottingham Digestive Diseases Biomedical Research Unit, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham NG7 2UH, UK.
authors: Guruprasad P
authors: GP
authors: Aithal
authors: Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, Wilrijkstraat 10, B-2650 Edegem, Antwerp, Belgium.
authors: Sven
authors: S
authors: Francque
authors: Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, Wilrijkstraat 10, B-2650 Edegem, Antwerp, Belgium.
authors: Luc
authors: L
authors: Van Gaal
authors: Institute of Cardiometabolism and Nutrition, Pitié-Salpêtrière Hospital, 75013 Paris, France.
authors: Karine
authors: K
authors: Clement
authors: Institute of Cardiometabolism and Nutrition, Pitié-Salpêtrière Hospital, 75013 Paris, France.
authors: Vlad
authors: V
authors: Ratziu
authors: University Clinic of Visceral Surgery and Medicine, Inselspital Bern, 3010 Bern, Switzerland.
authors: Jean-Francois
authors: JF
authors: Dufour
authors: Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors: Christopher P
authors: CP
authors: Day
authors: 1] Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK [2].
authors: Ann K
authors: AK
authors: Daly
authors: 1] Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK [2].
authors: Quentin M
authors: QM
authors: Anstee
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D011508:Chondroitin Sulfate Proteoglycans / Q000235:genetics / Q000378:metabolism; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D058580:Neurocan; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020641:Polymorphism, Single Nucleotide
chemical_list: D011508:Chondroitin Sulfate Proteoglycans; D037181:Lectins, C-Type; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D058580:Neurocan; C419195:TM6SF2 protein, human; C076817:NCAN protein, human