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. 2023 Jun 6;52(3):921-931.
doi: 10.1093/ije/dyac212.

Evaluating the role of non-alcoholic fatty liver disease in cardiovascular diseases and type 2 diabetes: a Mendelian randomization study in Europeans and East Asians

Shiu Lun Au Yeung  1 , Maria Carolina Borges  2   3 , Tommy Hon Ting Wong  1 , Deborah A Lawlor  2   3   4 , C Mary Schooling  1   5
Affiliations

Evaluating the role of non-alcoholic fatty liver disease in cardiovascular diseases and type 2 diabetes: a Mendelian randomization study in Europeans and East Asians

Shiu Lun Au Yeung et al. Int J Epidemiol. .

Abstract

Background: Whether non-alcoholic fatty liver disease (NAFLD) causes cardiovascular disease (CVD) and type 2 diabetes (T2D) is unclear and possible differences between ethnicities have not been thoroughly explored. We used Mendelian randomization (MR) to assess the role of NAFLD in CVD and T2D risk in Europeans and East Asians.

Methods: We conducted a MR study using genetic predictors of alanine aminotransferase (ALT), liability to NAFLD, aspartate transaminase (AST), liver magnetic resonance imaging corrected T1 and proton density fat fraction and combined them with genome-wide association studies (GWAS) summary statistics of CVD, T2D and glycaemic traits (sample size ranging from 14 400 to 977 320). Inverse-variance weighted analysis was used to assess the effect of NAFLD in these outcomes, with sensitivity analyses and replication in FinnGen. We conducted analyses in East Asians using ethnicity-specific genetic predictors of ALT and AST, and the respective outcome GWAS summary statistics.

Results: In Europeans, higher ALT was associated with higher T2D risk (odds ratio: 1.77 per standard deviation, 95% CI 1.5 to 2.08), with similar results for other exposures, across sensitivity analyses and in FinnGen. Although NAFLD proxies were related to higher coronary artery disease (CAD) and stroke risk, sensitivity analyses suggested possible bias by horizontal pleiotropy. In East Asians, higher ALT was possibly associated with higher T2D risk, and ALT and AST were inversely associated with CAD.

Conclusions: NAFLD likely increases the risk of T2D in Europeans and East Asians. Potential differential effects on CAD between Europeans and East Asians require further investigation.

Keywords: Atrial fibrillation; Mendelian randomization; NAFLD; coronary artery disease; heart failure; stroke; type 2 diabetes.

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Conflict of interest statement

D.A.L. receives support from several national and international government and charitable research funders, as well as from Medtronic Ltd and Roche Diagnostics for research unrelated to that presented here. All other authors declare they have no conflict of interest, financial or otherwise.

Figures

Figure 1
Figure 1
The impact of alanine aminotransferase level (SD) and liability to NAFLDa (per log odds) on cardiovascular diseases and type 2 diabetes using Mendelian randomization in predominantly European populations. SD, standard deviation; NAFLD, non-alcoholic fatty liver disease; RAPS, robust adjusted profile score. SDs and odds as provided in the original genome-wide association studies. aDefined as a high alanine aminotransferase level using sex-specific thresholds
Figure 2
Figure 2
The impact of aspartate transaminase level (SD) and MRI-based liver cT1 (SD) on cardiovascular diseases and type 2 diabetes using Mendelian randomization in predominantly European populations. SD, standard deviation (as provided in the original genome-wide association studies); MRI-based liver cT1, magnetic resonance imaging-based liver corrected T1; RAPS, robust adjusted profile score
Figure 3
Figure 3
The impact of alanine aminotransferase level (SD) and liability to NAFLDa (per log odds) on cardiovascular diseases and type 2 diabetes in FinnGen using Mendelian randomization. SD, standard deviation; NAFLD, non-alcoholic fatty liver disease; RAPS, robust adjusted profile score. SDs and odds as provided in the original genome-wide association studies. aDefined as a high alanine aminotransferase level using sex-specific thresholds
Figure 4
Figure 4
The impact of aspartate transaminase level (SD) and MRI-based liver cT1 (SD) on cardiovascular diseases and type 2 diabetes in FinnGen using Mendelian randomization. SD, standard deviation (as provided in the original genome-wide association studies); MRI-based liver cT1, magnetic resonance imaging-based liver corrected T1; RAPS, robust adjusted profile score
Figure 5
Figure 5
The impact of alanine aminotransferase level (per SD of log) and aspartate transaminase (per SD of log) on cardiovascular diseases and type 2 diabetes using Mendelian randomization in East Asians. SD, standard deviation (as provided in the original genome-wide association studies); RAPS, robust adjusted profile score
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