Shared Genetic Links Between Nonalcoholic Fatty Liver Disease and Coronary Artery Disease

Overview

Journal Glob Heart

Publisher Ubiquity Press

Specialty Cardiology & Vascular Diseases

Date 2024 Dec 2

PMID 39619635

Authors

Hua Di

Shouhao Wang

Chengan Xu

Qiaoqiao Yin

Keyang Xu

Wei Zheng

Affiliations

Soon will be listed here.

Abstract

Background: Epidemiological and clinical studies have shown that there is a co-morbidity between nonalcoholic fatty liver disease (NAFLD) and coronary artery disease (CAD).

Methods: In this study, we utilized linkage disequilibrium score regression (LDSC) to evaluate the genetic correlation between non-alcoholic fatty liver disease (NAFLD) and coronary artery disease (CAD). We identified pleiotropic loci and genes using SNP-Level PLACO analysis. Following this, MAGMA gene set enrichment analysis was conducted to assess the biological significance of these pleiotropic genes. Finally, a two-sample two-way Mendelian randomization (MR) analysis was performed to evaluate causal relationships between NAFLD and CAD.

Results: We found a significant genetic correlation between NAFLD and CAD. Secondly, PLACO multi-effect analysis identified 6 sites (mainly involved in the establishment of chylomicrons, mitochondrial membrane protein localization and herpes simplex virus 1 infection signaling pathway). Then, three pleiotropic genes (APOC1, TOMM40 and PBX4) were identified by MAGMA gene analysis. Finally, a two-sample two-way MR analysis suggested that there was no causal relationship between NAFLD and CAD.

Conclusions: Our results show that there are significant gene overlaps and pleiotropic genes between NAFLD and CAD and point out their common molecular mechanisms. These findings provide evidence for the common etiology between them and also help to better understand the pleiotropic nature between NAFLD and CAD, which may be of guiding significance for future treatment strategies.

References

Than N, Newsome P . A concise review of non-alcoholic fatty liver disease. Atherosclerosis. 2015; 239(1):192-202. DOI: 10.1016/j.atherosclerosis.2015.01.001. View

de Leeuw C, Mooij J, Heskes T, Posthuma D . MAGMA: generalized gene-set analysis of GWAS data. PLoS Comput Biol. 2015; 11(4):e1004219. PMC: 4401657. DOI: 10.1371/journal.pcbi.1004219. View

Lu H, Sun J, Sun L, Shu X, Xu Y, Xie D . Polymorphism of human leptin receptor gene is associated with type 2 diabetic patients complicated with non-alcoholic fatty liver disease in China. J Gastroenterol Hepatol. 2008; 24(2):228-32. DOI: 10.1111/j.1440-1746.2008.05544.x. View

Selvarajan I, Toropainen A, Garske K, Lopez Rodriguez M, Ko A, Miao Z . Integrative analysis of liver-specific non-coding regulatory SNPs associated with the risk of coronary artery disease. Am J Hum Genet. 2021; 108(3):411-430. PMC: 8008493. DOI: 10.1016/j.ajhg.2021.02.006. View

Brouwers M, Simons N, Stehouwer C, Koek G, Schaper N, Isaacs A . Relationship Between Nonalcoholic Fatty Liver Disease Susceptibility Genes and Coronary Artery Disease. Hepatol Commun. 2019; 3(4):587-596. PMC: 6442707. DOI: 10.1002/hep4.1319. View

Yavorska O, Burgess S . MendelianRandomization: an R package for performing Mendelian randomization analyses using summarized data. Int J Epidemiol. 2017; 46(6):1734-1739. PMC: 5510723. DOI: 10.1093/ije/dyx034. View

Subramanian A, Tamayo P, Mootha V, Mukherjee S, Ebert B, Gillette M . Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005; 102(43):15545-50. PMC: 1239896. DOI: 10.1073/pnas.0506580102. View

Auton A, Brooks L, Durbin R, Garrison E, Kang H, Korbel J . A global reference for human genetic variation. Nature. 2015; 526(7571):68-74. PMC: 4750478. DOI: 10.1038/nature15393. View

Li X, Sui J, Lu L, Zhang N, Xu X, Dong Q . Gene polymorphisms associated with non-alcoholic fatty liver disease and coronary artery disease: a concise review. Lipids Health Dis. 2016; 15:53. PMC: 4785616. DOI: 10.1186/s12944-016-0221-8. View

10.

Palmer N, Kahali B, Kuppa A, Chen Y, Du X, Feitosa M . Allele-specific variation at APOE increases nonalcoholic fatty liver disease and obesity but decreases risk of Alzheimer's disease and myocardial infarction. Hum Mol Genet. 2021; 30(15):1443-1456. PMC: 8283205. DOI: 10.1093/hmg/ddab096. View

11.

Torres G, Dose J, Hasenbein T, Nygaard M, Krause-Kyora B, Mengel-From J . Long-Lived Individuals Show a Lower Burden of Variants Predisposing to Age-Related Diseases and a Higher Polygenic Longevity Score. Int J Mol Sci. 2022; 23(18). PMC: 9504529. DOI: 10.3390/ijms231810949. View

12.

Nseir W, Shalata A, Marmor A, Assy N . Mechanisms linking nonalcoholic fatty liver disease with coronary artery disease. Dig Dis Sci. 2011; 56(12):3439-49. DOI: 10.1007/s10620-011-1767-y. View

13.

Burgess S, Thompson S . Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol. 2017; 32(5):377-389. PMC: 5506233. DOI: 10.1007/s10654-017-0255-x. View

14.

Ghodsian N, Abner E, Emdin C, Gobeil E, Taba N, Haas M . Electronic health record-based genome-wide meta-analysis provides insights on the genetic architecture of non-alcoholic fatty liver disease. Cell Rep Med. 2021; 2(11):100437. PMC: 8606899. DOI: 10.1016/j.xcrm.2021.100437. View

15.

Younossi Z, Koenig A, Abdelatif D, Fazel Y, Henry L, Wymer M . Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2015; 64(1):73-84. DOI: 10.1002/hep.28431. View

16.

Lin B, Huang Y, Zhang M, Wang J, Wu Y . Association between apolipoprotein C3 Sst I, T-455C, C-482T and C1100T polymorphisms and risk of coronary heart disease. BMJ Open. 2014; 4(1):e004156. PMC: 3902403. DOI: 10.1136/bmjopen-2013-004156. View

17.

Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V . Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012; 380(9859):2095-128. PMC: 10790329. DOI: 10.1016/S0140-6736(12)61728-0. View

18.

Bulik-Sullivan B, Finucane H, Anttila V, Gusev A, Day F, Loh P . An atlas of genetic correlations across human diseases and traits. Nat Genet. 2015; 47(11):1236-41. PMC: 4797329. DOI: 10.1038/ng.3406. View

19.

Farrell G, Wong V, Chitturi S . NAFLD in Asia--as common and important as in the West. Nat Rev Gastroenterol Hepatol. 2013; 10(5):307-18. DOI: 10.1038/nrgastro.2013.34. View

20.

Alberti K, Eckel R, Grundy S, Zimmet P, Cleeman J, Donato K . Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation;.... Circulation. 2009; 120(16):1640-5. DOI: 10.1161/CIRCULATIONAHA.109.192644. View