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

By Yang-Lin Liu, H. Reeves, A. Burt, D. Tiniakos, S. McPherson, J. Leathart, M. Allison, G. Alexander, A. Piguet, R. Anty and 10 more. Nature Communications, 2014

596 citations recorded by the source corpus.

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. Non-alcoholic fatty liver disease (NAFLD) is characterized by increased hepatic triglyceride content (HTGC) in the absence of high alcohol consumption. Here the authors show that a genetic variant in TM6SF2, which is known to be associated with HTGC, is a clinically relevant modifier of hepatic fibrogenesis and increases the risk of progressive NAFLD.

Subfields: Cell Biology, Endocrinology, Diabetes and Metabolism, Epidemiology

View Paper: https://www.semanticscholar.org/paper/fff77952b5698c13b8308aa3908ff076fcb11dd0

How researchers see this paper

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In Endocrinology, Diabetes and Metabolism

1. Z. Younossi
2. Q. Anstee
3. M. Rinella
4. K. Cusi
5. A. Sanyal
6. M. Pinzani
7. E. Tsochatzis
8. C. Day

In Epidemiology

1. Z. Younossi
2. M. Rinella
3. A. Sanyal
4. K. Cusi
5. Q. Anstee
6. E. Brunt
7. J. Lavine
8. C. Day

Citations in the corpus

• The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). (2016, background): “[98] Liu YL, Reeves HL, Burt AD, et al.”
• Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management. (2015, background): “This variability is in part due to subtle individual genetic differences that modify response to environmental factors and lifestyle, and so determine disease phenotype [14–16].”
• Metabolism Disrupting Chemicals and Metabolic Disorders (2016, unknown): “located on chromosome 19 and associated with increased hepatic triglyceride content and lower serum lipoproteins [54, 55].”
• The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases (2018, background): “Recent genome-wide association studies have associated several genetic polymorphisms, notably PNPLA-3 variants, with SH and advanced fibrosis in patients with NAFLD.((112-121)) However, testing for these genetic variants in routine clinical care is currently not advocated.”