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. 2023 Jan 1;77(1):230-238.
doi: 10.1002/hep.32534. Epub 2022 May 18.

Relationship between NAFLD and coronary artery disease: A Mendelian randomization study

Zhewen Ren  1   2   3 , Pomme I H G Simons  1   2   3 , Anke Wesselius  4   5 , Coen D A Stehouwer  2   3   6 , Martijn C G J Brouwers  1   3
Affiliations

Relationship between NAFLD and coronary artery disease: A Mendelian randomization study

Zhewen Ren et al. Hepatology. .

Abstract

Background and aims: There is an ongoing debate on whether NAFLD is an active contributor or an innocent bystander in the pathogenesis of coronary artery disease (CAD). The aim of the present study was to assess the causal relationship between NAFLD and CAD.

Approach and results: We performed two-sample Mendelian randomization (MR) analyses using summary-level data to assess the association between genetically predicted NAFLD (i.e., chronically elevated serum alanine aminotransferase levels [cALT], imaging-based and biopsy-confirmed NAFLD) and risk of CAD. Analyses were repeated after exclusion of NAFLD susceptibility genes that are associated with impaired VLDL secretion.Inverse-variance weighted MR analyses showed a statistically significant association between genetically predicted cALT and risk of CAD (OR: 1.116, 95% CI: 1.039, 1.199), but not for the other NAFLD-related traits (OR: 1.046, 95% CI: 0.764, 1.433 and OR: 1.014, 95% CI: 0.968, 1.062 for imaging-based and biopsy-confirmed NAFLD, respectively). MR-Egger regression revealed a statistically significant intercept, indicative of directional pleiotropy, for all traits. Repeat analyses after exclusion of genes associated with impaired VLDL secretion showed consistent associations between genetically predicted NAFLD and CAD for all traits (i.e., cALT [OR: 1.203, 95% CI: 1.113, 1.300]), imaging-based (OR: 2.149, 95% CI: 1.276, 3.620) and biopsy-confirmed NAFLD (OR: 1.113, 95% CI: 1.041, 1.189), which persisted when more stringent biopsy-confirmed NAFLD criteria were used (OR: 1.154, 95% CI: 1.043, 1.278) or when more stringent MR methods were applied. MR-Egger regression did not show a statistically significant intercept.

Conclusion: The two-sample MR analyses showed a robust association between genetically predicted NAFLD and CAD after exclusion of genetic variants that are implicated in impaired VLDL secretion.

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Conflict of interest statement

The authors declare there are no conflicts of interest.

Figures

None
Graphical abstract
FIGURE 1
FIGURE 1
Association of genetically predicted chronically elevated serum alanine aminotransferase level (cALT), imaging‐based and biopsy‐confirmed NAFLD (using either general or stringent criteria, see Methods section) with risk of coronary artery disease (CAD), analyzed with four different Mendelian randomization (MR) methods. Effect estimates are presented as increase in odds of CAD per SD increase in imaging, or per unit increase in (log)odds of cALT or biopsy‐confirmed NAFLD. SNP, single nucleotide polymorphism
FIGURE 2
FIGURE 2
Relationship between genetically predicted biopsy‐confirmed NAFLD (with stringent criteria) and CAD, using inverse variance–weighted method (solid line), simple median method (dashed‐dotted line), penalized weighted–median method (dashed line), and contamination mixture method (dotted line)
FIGURE 3
FIGURE 3
Association of genetically predicted cALT, imaging‐based and biopsy‐confirmed NAFLD (using either general or stringent criteria, see methods section) (after exclusion of genes associated with impaired VLDL secretion) with risk of CAD, analyzed with four different MR methods. Effect estimates are presented as increase in odds of CAD per SD increase in imaging, or per unit increase in (log)odds of cALT‐based or biopsy‐confirmed NAFLD
FIGURE 4
FIGURE 4
Relationship between genetically predicted biopsy‐confirmed NAFLD (with stringent criteria, after exclusion of genes associated with impaired VLDL secretion) and CAD, using inverse variance–weighted method (solid line), simple median method (dashed‐dotted line), penalized weighted– median method (dashed line), and contamination mixture method (dotted line)
See this image and copyright information in PMC

Comment in

References

    1. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease—meta‐analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64:73–84. - PubMed
    1. European Association for the Study of the Liver (EASL). EASL‐EASD‐EASO Clinical Practice Guidelines for the management of non‐alcoholic fatty liver disease. J Hepatol. 2016;64:1388–402. - PubMed
    1. Feldstein AE, Charatcharoenwitthaya P, Treeprasertsuk S, Benson JT, Enders FB, Angulo P. The natural history of non‐alcoholic fatty liver disease in children: a follow‐up study for up to 20 years. Gut. 2009;58:1538–44. - PMC - PubMed
    1. Younossi ZM, Stepanova M, Ong J, Trimble G, AlQahtani S, Younossi I, et al. . Nonalcoholic steatohepatitis is the most rapidly increasing indication for liver transplantation in the United States. Clin Gastroenterol Hepatol. 2021;19:580–89.e585. - PubMed
    1. Ong JP, Pitts A, Younossi ZM. Increased overall mortality and liver‐related mortality in non‐alcoholic fatty liver disease. J Hepatol. 2008;49:608–12. - PubMed

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