Response to: liver fat content, non-alcoholic fatty liver disease, and ischaemic heart disease

Response to: liver fat content, non-alcoholic fatty liver disease, and ischaemic heart disease DISCUSSION FORUM European Heart Journal (2018) 00,1 doi:10.1093/eurheartj/ehy250 Response to: liver fat content, non-alcoholic fatty liver disease, and ischaemic heart disease Stefan Stender and Anne Tybjaerg-Hansen* Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark This commentary refers to ‘Liver fat content, non-alcoholic both NAFLD (outcome) and liver cirrhosis (outcome), and we con- fatty liver disease, and risk of ischaemic heart disease’, by . firm this for IHD in a very large meta-analysis. C.D. Byrne and G. Targher, doi: 10.1093/eurheartj/ehy237. . We concur that PNPLA3 I148M explains a small fraction of the . overall variation in hepatic fat content and risk of NAFLD. Individual We thank Drs Byrne and Targher for their interest in our Mendelian . common genetic variants rarely have large phenotypic effects. randomization (MR) study examining the relationship between liver . Despite this, the large sample size of our study (n = 279 013) ensured fat content, non-alcoholic fatty liver disease (NAFLD), and ischaemic . sufficient power to rule out an association between PNPLA3 I148M 1 . heart disease (IHD). Our responses are as follows: . and increased risk of IHD. The most likely explanation for the low prevalence of ICD-defined . A key assumption of our study is that PNPLA3 I148M is a valid NAFLD in our general population cohort is that the definition (ICD- . proxy for hepatic steatosis and NAFLD per se. As noted by Targher code received in a hospital setting) mainly captures individuals with . and Byrne, it has been hypothesized that distinct forms of NAFLD symptomatic NAFLD. We agree that a subset of this cohort is likely . exist (obese/metabolic vs. PNPLA3-associated). If true, this would in- to have undiagnosed NAFLD, however, this is unlikely to impact the . validate the use of PNPLA3 I148M as a proxy for NAFLD per se. conclusion of the article. . However, a simple and more likely explanation is that in obese/meta- In MR, the genotype acts as a proxy for the exposure of interest. In . bolic NAFLD, the associated risk of IHD is caused by common risk other words, MR does not necessarily depend on having measured factors for NAFLD and IHD (confounding), such as higher plasma the exposure of interest, as long as the genetic proxy associates ro- levels of atherogenic LDL cholesterol and remnant cholesterol in bustly and specifically with it. This is a reasonable assumption in the triglyceride-rich lipoproteins. That this is likely the case, is in fact case of PNPLA3 I148M and NAFLD, given the large effect of PNPLA3 what the present study suggests. Finally, we agree that more studies I148M on the entire spectrum of NAFLD in numerous cohorts, on the relationship between NAFLD and IHD are needed. including a highly significant association in the subset of individuals Conflict of interest: none declared. with measured hepatic fat content in our study. Therefore, we do not fail to show an association with risk of IHD in 1439 individuals Reference with liver fat content detected by computerized tomography scan, . 1. Lauridsen BK, Stender S, Kristensen TS, Kofoed KF, Kober L, Nordestgaard BG, we fail to show an association between lifelong increased liver fat Tybjærg-Hansen A. Liver fat content, non-alcoholic fatty liver disease, and content (exposure) and risk of IHD (outcome) in 94 708 individuals ischaemic heart disease: Mendelian randomization and meta-analysis of 279013 of whom 10 897 had IHD, despite confirming causal associations with individuals. Eur Heart J 2017;39:385–393. * Corresponding author. Tel: þ45 3545 4159, Fax: þ45 3545 4160, Email: anne.tybjaerg.hansen@regionh.dk Published on behalf of the European Society of Cardiology. All rights reserved. V The Author(s) 2018. For permissions, please email: journals.permissions@oup.com. Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy250/4992676 by Ed 'DeepDyve' Gillespie user on 08 June 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Heart Journal Oxford University Press

Response to: liver fat content, non-alcoholic fatty liver disease, and ischaemic heart disease

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Oxford University Press
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.
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0195-668X
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1522-9645
D.O.I.
10.1093/eurheartj/ehy250
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Abstract

DISCUSSION FORUM European Heart Journal (2018) 00,1 doi:10.1093/eurheartj/ehy250 Response to: liver fat content, non-alcoholic fatty liver disease, and ischaemic heart disease Stefan Stender and Anne Tybjaerg-Hansen* Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark This commentary refers to ‘Liver fat content, non-alcoholic both NAFLD (outcome) and liver cirrhosis (outcome), and we con- fatty liver disease, and risk of ischaemic heart disease’, by . firm this for IHD in a very large meta-analysis. C.D. Byrne and G. Targher, doi: 10.1093/eurheartj/ehy237. . We concur that PNPLA3 I148M explains a small fraction of the . overall variation in hepatic fat content and risk of NAFLD. Individual We thank Drs Byrne and Targher for their interest in our Mendelian . common genetic variants rarely have large phenotypic effects. randomization (MR) study examining the relationship between liver . Despite this, the large sample size of our study (n = 279 013) ensured fat content, non-alcoholic fatty liver disease (NAFLD), and ischaemic . sufficient power to rule out an association between PNPLA3 I148M 1 . heart disease (IHD). Our responses are as follows: . and increased risk of IHD. The most likely explanation for the low prevalence of ICD-defined . A key assumption of our study is that PNPLA3 I148M is a valid NAFLD in our general population cohort is that the definition (ICD- . proxy for hepatic steatosis and NAFLD per se. As noted by Targher code received in a hospital setting) mainly captures individuals with . and Byrne, it has been hypothesized that distinct forms of NAFLD symptomatic NAFLD. We agree that a subset of this cohort is likely . exist (obese/metabolic vs. PNPLA3-associated). If true, this would in- to have undiagnosed NAFLD, however, this is unlikely to impact the . validate the use of PNPLA3 I148M as a proxy for NAFLD per se. conclusion of the article. . However, a simple and more likely explanation is that in obese/meta- In MR, the genotype acts as a proxy for the exposure of interest. In . bolic NAFLD, the associated risk of IHD is caused by common risk other words, MR does not necessarily depend on having measured factors for NAFLD and IHD (confounding), such as higher plasma the exposure of interest, as long as the genetic proxy associates ro- levels of atherogenic LDL cholesterol and remnant cholesterol in bustly and specifically with it. This is a reasonable assumption in the triglyceride-rich lipoproteins. That this is likely the case, is in fact case of PNPLA3 I148M and NAFLD, given the large effect of PNPLA3 what the present study suggests. Finally, we agree that more studies I148M on the entire spectrum of NAFLD in numerous cohorts, on the relationship between NAFLD and IHD are needed. including a highly significant association in the subset of individuals Conflict of interest: none declared. with measured hepatic fat content in our study. Therefore, we do not fail to show an association with risk of IHD in 1439 individuals Reference with liver fat content detected by computerized tomography scan, . 1. Lauridsen BK, Stender S, Kristensen TS, Kofoed KF, Kober L, Nordestgaard BG, we fail to show an association between lifelong increased liver fat Tybjærg-Hansen A. Liver fat content, non-alcoholic fatty liver disease, and content (exposure) and risk of IHD (outcome) in 94 708 individuals ischaemic heart disease: Mendelian randomization and meta-analysis of 279013 of whom 10 897 had IHD, despite confirming causal associations with individuals. Eur Heart J 2017;39:385–393. * Corresponding author. Tel: þ45 3545 4159, Fax: þ45 3545 4160, Email: anne.tybjaerg.hansen@regionh.dk Published on behalf of the European Society of Cardiology. All rights reserved. V The Author(s) 2018. For permissions, please email: journals.permissions@oup.com. Downloaded from https://academic.oup.com/eurheartj/advance-article-abstract/doi/10.1093/eurheartj/ehy250/4992676 by Ed 'DeepDyve' Gillespie user on 08 June 2018

Journal

European Heart JournalOxford University Press

Published: May 3, 2018

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