Diverse impacts of the rs58542926 E167K variant in TM6SF2 on viral and metabolic liver disease phenotypes

Mohammed Eslam, Alessandra Mangia, Thomas Berg, Henry Lik Yuen Chan, William L. Irving, Gregory J. Dore, Maria Lorena Abate, Elisabetta Bugianesi, Leon A. Adams, Mustafa A M Najim, Luca Miele, Martin Weltman, Lindsay Mollison, Wendy Cheng, Stephen Riordan, Janett Fischer, Manuel Romero-Gomez, Ulrich Spengler, Jacob Nattermann, Antony RahmeDavid Sheridan, David R. Booth, Duncan McLeod, Elizabeth Powell, Christopher Liddle, Mark W. Douglas, David van der Poorten, Jacob George, Rose White, Angela Rojas, Rocio Gallego-Duran, Margaret Bassendine, Vincent W S Wong, Chiara Rosso, Lavinia Mezzabotta, Reynold Leung, Barbara Malik, Gail Matthews, Tanya Applegate, Jason Grebely, Vincenzo Fragomeli, Julie R. Jonsson, Rosanna Santoro

Research output: Contribution to journalArticle

Abstract

A genome-wide exome association study has identified the transmembrane 6 superfamily member 2 (TM6SF2) rs58542926 variant encoding an E167K substitution as a genetic determinant of hepatic steatosis in nonalcoholic fatty liver disease (NAFLD). The roles of this variant across a spectrum of liver diseases and pathologies and on serum lipids comparing viral hepatitis to NAFLD and viral load in chronic viral hepatitis, as well as its intrahepatic molecular signature, have not been well characterized. We undertook detailed analyses in 3260 subjects with viral and nonviral liver diseases and in healthy controls. Serum inflammatory markers and hepatic expression of TM6SF2 and genes regulating lipid metabolism were assessed in a subset with chronic hepatitis C (CHC). The rs58542926 T allele was more prevalent in 502 NAFLD patients than controls (P = 0.02) but not different in cohorts with CHC (n = 2023) and chronic hepatitis B (n = 507). The T allele was associated with alterations in serum lipids and hepatic steatosis in all diseases and with reduced hepatic TM6SF2 and microsomal triglyceride transfer protein expression. Interestingly, the substitution was associated with reduced CHC viral load but increased hepatitis B virus DNA. The rs58542926 T allele had no effect on inflammation, impacted ≥F2 fibrosis in CHC and NAFLD assessed cross-sectionally (odds ratio = 1.39, 95% confidence interval 1.04-1.87, and odds ratio = 1.62, 95% confidence interval 1.03-2.52, respectively; P < 0.03 for both), but had no effect on fibrosis progression in 1174 patients with CHC and a known duration of infection. Conclusion: The TM6SF2 E167K substitution promotes steatosis and lipid abnormalities in part by altering TM6SF2 and microsomal triglyceride transfer protein expression and differentially impacts CHC and chronic hepatitis B viral load, while effects on fibrosis are marginal. (Hepatology 2016;64:34–46).

Original languageEnglish
Pages (from-to)34-46
Number of pages13
JournalHepatology
Volume64
Issue number1
DOIs
Publication statusPublished - Jul 1 2016

ASJC Scopus subject areas

  • Medicine(all)
  • Hepatology

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    Eslam, M., Mangia, A., Berg, T., Chan, H. L. Y., Irving, W. L., Dore, G. J., Abate, M. L., Bugianesi, E., Adams, L. A., Najim, M. A. M., Miele, L., Weltman, M., Mollison, L., Cheng, W., Riordan, S., Fischer, J., Romero-Gomez, M., Spengler, U., Nattermann, J., ... Santoro, R. (2016). Diverse impacts of the rs58542926 E167K variant in TM6SF2 on viral and metabolic liver disease phenotypes. Hepatology, 64(1), 34-46. https://doi.org/10.1002/hep.28475