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 Rahme & 23 others David 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

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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

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Metabolic Diseases
Chronic Hepatitis C
Liver Diseases
Phenotype
Viral Load
Fibrosis
Liver
Alleles
Chronic Hepatitis B
Lipids
Odds Ratio
Confidence Intervals
Exome
Genome-Wide Association Study
Gastroenterology
Chronic Hepatitis
Serum
Lipid Metabolism
Hepatitis B virus
Hepatitis

ASJC Scopus subject areas

  • Medicine(all)
  • Hepatology

Cite this

Diverse impacts of the rs58542926 E167K variant in TM6SF2 on viral and metabolic liver disease phenotypes. / Eslam, Mohammed; Mangia, Alessandra; Berg, Thomas; Chan, Henry Lik Yuen; Irving, William L.; Dore, Gregory J.; Abate, Maria Lorena; Bugianesi, Elisabetta; Adams, Leon A.; Najim, Mustafa A M; Miele, Luca; Weltman, Martin; Mollison, Lindsay; Cheng, Wendy; Riordan, Stephen; Fischer, Janett; Romero-Gomez, Manuel; Spengler, Ulrich; Nattermann, Jacob; Rahme, Antony; Sheridan, David; Booth, David R.; McLeod, Duncan; Powell, Elizabeth; Liddle, Christopher; Douglas, Mark W.; van der Poorten, David; George, Jacob; White, Rose; Rojas, Angela; Gallego-Duran, Rocio; Bassendine, Margaret; Wong, Vincent W S; Rosso, Chiara; Mezzabotta, Lavinia; Leung, Reynold; Malik, Barbara; Matthews, Gail; Applegate, Tanya; Grebely, Jason; Fragomeli, Vincenzo; Jonsson, Julie R.; Santoro, Rosanna.

In: Hepatology, Vol. 64, No. 1, 01.07.2016, p. 34-46.

Research output: Contribution to journalArticle

Eslam, M, Mangia, A, Berg, T, Chan, HLY, Irving, WL, Dore, GJ, Abate, ML, Bugianesi, E, Adams, LA, Najim, MAM, Miele, L, Weltman, M, Mollison, L, Cheng, W, Riordan, S, Fischer, J, Romero-Gomez, M, Spengler, U, Nattermann, J, Rahme, A, Sheridan, D, Booth, DR, McLeod, D, Powell, E, Liddle, C, Douglas, MW, van der Poorten, D, George, J, White, R, Rojas, A, Gallego-Duran, R, Bassendine, M, Wong, VWS, Rosso, C, Mezzabotta, L, Leung, R, Malik, B, Matthews, G, Applegate, T, Grebely, J, Fragomeli, V, Jonsson, JR & Santoro, R 2016, 'Diverse impacts of the rs58542926 E167K variant in TM6SF2 on viral and metabolic liver disease phenotypes', Hepatology, vol. 64, no. 1, pp. 34-46. https://doi.org/10.1002/hep.28475
Eslam, Mohammed ; Mangia, Alessandra ; Berg, Thomas ; Chan, Henry Lik Yuen ; Irving, William L. ; Dore, Gregory J. ; Abate, Maria Lorena ; Bugianesi, Elisabetta ; Adams, Leon A. ; Najim, Mustafa A M ; Miele, Luca ; Weltman, Martin ; Mollison, Lindsay ; Cheng, Wendy ; Riordan, Stephen ; Fischer, Janett ; Romero-Gomez, Manuel ; Spengler, Ulrich ; Nattermann, Jacob ; Rahme, Antony ; Sheridan, David ; Booth, David R. ; McLeod, Duncan ; Powell, Elizabeth ; Liddle, Christopher ; Douglas, Mark W. ; van der Poorten, David ; George, Jacob ; White, Rose ; Rojas, Angela ; Gallego-Duran, Rocio ; Bassendine, Margaret ; Wong, Vincent W S ; Rosso, Chiara ; Mezzabotta, Lavinia ; Leung, Reynold ; Malik, Barbara ; Matthews, Gail ; Applegate, Tanya ; Grebely, Jason ; Fragomeli, Vincenzo ; Jonsson, Julie R. ; Santoro, Rosanna. / Diverse impacts of the rs58542926 E167K variant in TM6SF2 on viral and metabolic liver disease phenotypes. In: Hepatology. 2016 ; Vol. 64, No. 1. pp. 34-46.
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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).",
author = "Mohammed Eslam and Alessandra Mangia and Thomas Berg and Chan, {Henry Lik Yuen} and Irving, {William L.} and Dore, {Gregory J.} and Abate, {Maria Lorena} and Elisabetta Bugianesi and Adams, {Leon A.} and Najim, {Mustafa A M} and Luca Miele and Martin Weltman and Lindsay Mollison and Wendy Cheng and Stephen Riordan and Janett Fischer and Manuel Romero-Gomez and Ulrich Spengler and Jacob Nattermann and Antony Rahme and David Sheridan and Booth, {David R.} and Duncan McLeod and Elizabeth Powell and Christopher Liddle and Douglas, {Mark W.} and {van der Poorten}, David and Jacob George and Rose White and Angela Rojas and Rocio Gallego-Duran and Margaret Bassendine and Wong, {Vincent W S} and Chiara Rosso and Lavinia Mezzabotta and Reynold Leung and Barbara Malik and Gail Matthews and Tanya Applegate and Jason Grebely and Vincenzo Fragomeli and Jonsson, {Julie R.} and Rosanna Santoro",
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T1 - Diverse impacts of the rs58542926 E167K variant in TM6SF2 on viral and metabolic liver disease phenotypes

AU - Eslam, Mohammed

AU - Mangia, Alessandra

AU - Berg, Thomas

AU - Chan, Henry Lik Yuen

AU - Irving, William L.

AU - Dore, Gregory J.

AU - Abate, Maria Lorena

AU - Bugianesi, Elisabetta

AU - Adams, Leon A.

AU - Najim, Mustafa A M

AU - Miele, Luca

AU - Weltman, Martin

AU - Mollison, Lindsay

AU - Cheng, Wendy

AU - Riordan, Stephen

AU - Fischer, Janett

AU - Romero-Gomez, Manuel

AU - Spengler, Ulrich

AU - Nattermann, Jacob

AU - Rahme, Antony

AU - Sheridan, David

AU - Booth, David R.

AU - McLeod, Duncan

AU - Powell, Elizabeth

AU - Liddle, Christopher

AU - Douglas, Mark W.

AU - van der Poorten, David

AU - George, Jacob

AU - White, Rose

AU - Rojas, Angela

AU - Gallego-Duran, Rocio

AU - Bassendine, Margaret

AU - Wong, Vincent W S

AU - Rosso, Chiara

AU - Mezzabotta, Lavinia

AU - Leung, Reynold

AU - Malik, Barbara

AU - Matthews, Gail

AU - Applegate, Tanya

AU - Grebely, Jason

AU - Fragomeli, Vincenzo

AU - Jonsson, Julie R.

AU - Santoro, Rosanna

PY - 2016/7/1

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N2 - 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).

AB - 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).

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