Examining the Potential Causal Relationships Among Smoking Behaviors, Blood DNA Methylation Profiles, and the Development of Coronary Heart Disease and Myocardial Infarction

Overview

Journal Clin Epigenetics

Publisher Biomed Central

Specialty Genetics

Date 2024 Nov 29

PMID 39614281

Authors

Wenhua Li

Pan Dong

Yixiao Li

Jiaxin Tang

Siyang Liu

Ling Tu

Xizhen Xu

Affiliations

Soon will be listed here.

Abstract

Background: Smoking has been identified as a standalone risk factor for coronary heart disease (CHD) and myocardial infarction (MI), but the precise underlying mechanisms remain incompletely elucidated.

Results: In this study, we conducted a two-sample Mendelian randomization analysis to examine the impact of smoking behaviors (including smoking initiation, age of smoking initiation, cigarettes per day, and smoking cessation) and smoking-related DNA methylation at CpG sites on CHD and MI based on the UK Biobank dataset. Additionally, we included the FinnGen and Biobank Japan datasets as replications and performed a meta-analysis to combine the results from different data sources. We further validated our results using genetic colocalization analysis. In genomic analysis, we provided compelling evidence on the association between genetically predicted smoking initiation and increased susceptibility to CHD and MI. In epigenetic analysis, we identified 11 smoking-related CpG sites linked to CHD risk and 10 smoking-related CpG sites associated with the risk of MI based on the UK Biobank dataset. Subsequently, some of these CpG sites were further replicated using the FinnGen or BBJ datasets. Ultimately, a meta-analysis was conducted to integrate findings from various data sources (3 for CHD, and 2 for MI), revealing that 7 of 11 CpG sites were linked to CHD risk; whereas, 7 of 10 CpG sites were associated with MI risk. Furthermore, we performed genetic colocalization analysis and found that cg19744173 (FBLN7), cg00395063 (ARHGEF12), and cg16822035 (MCF2L) exhibited robust evidence of colocalization with coronary heart disease; whereas, cg19529732 (DIABLO), cg26405020 (FES), and cg08940075 (CNN3) demonstrated strong colocalization evidence with the risk of myocardial infarction.

Conclusions: Our research offers a novel insight into the impact of smoking on the susceptibility to CHD and MI through the lens of epigenetic DNA methylation.

References

Rosenberg L, Palmer J, Shapiro S . Decline in the risk of myocardial infarction among women who stop smoking. N Engl J Med. 1990; 322(4):213-7. DOI: 10.1056/NEJM199001253220401. View

Heidari L, Ghaderian S, Vakili H, Salmani T . Promoter methylation and functional variants in arachidonate 5-lipoxygenase and forkhead box protein O1 genes associated with coronary artery disease. J Cell Biochem. 2019; 120(8):12360-12368. DOI: 10.1002/jcb.28501. View

Avci E, Sarvari P, Savai R, Seeger W, Pullamsetti S . Epigenetic Mechanisms in Parenchymal Lung Diseases: Bystanders or Therapeutic Targets?. Int J Mol Sci. 2022; 23(1). PMC: 8745712. DOI: 10.3390/ijms23010546. View

Huxley R, Woodward M . Cigarette smoking as a risk factor for coronary heart disease in women compared with men: a systematic review and meta-analysis of prospective cohort studies. Lancet. 2011; 378(9799):1297-305. DOI: 10.1016/S0140-6736(11)60781-2. View

Du P, Gao K, Cao Y, Yang S, Wang Y, Guo R . RFX1 downregulation contributes to TLR4 overexpression in CD14 monocytes via epigenetic mechanisms in coronary artery disease. Clin Epigenetics. 2019; 11(1):44. PMC: 6413463. DOI: 10.1186/s13148-019-0646-9. View

Takefuji M, Kruger M, Sivaraj K, Kaibuchi K, Offermanns S, Wettschureck N . RhoGEF12 controls cardiac remodeling by integrating G protein- and integrin-dependent signaling cascades. J Exp Med. 2013; 210(4):665-73. PMC: 3620351. DOI: 10.1084/jem.20122126. View

van der Net J, Oosterveer D, Versmissen J, Defesche J, Yazdanpanah M, Aouizerat B . Replication study of 10 genetic polymorphisms associated with coronary heart disease in a specific high-risk population with familial hypercholesterolemia. Eur Heart J. 2008; 29(18):2195-201. PMC: 2733738. DOI: 10.1093/eurheartj/ehn303. View

Chen Y, Xu X, Wang L, Li K, Sun Y, Xiao L . Genetic insights into therapeutic targets for aortic aneurysms: A Mendelian randomization study. EBioMedicine. 2022; 83:104199. PMC: 9385553. DOI: 10.1016/j.ebiom.2022.104199. View

Duncan M, Freiberg M, Greevy Jr R, Kundu S, Vasan R, Tindle H . Association of Smoking Cessation With Subsequent Risk of Cardiovascular Disease. JAMA. 2019; 322(7):642-650. PMC: 6704757. DOI: 10.1001/jama.2019.10298. View

10.

Chen Y, Sun Y, Wang L, Xu K, Wang D . Genetic insights into associations of multisite chronic pain with common diseases and biomarkers using data from the UK Biobank. Br J Anaesth. 2023; 132(2):372-382. DOI: 10.1016/j.bja.2023.11.007. View

11.

Liu M, Jiang Y, Wedow R, Li Y, Brazel D, Chen F . Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use. Nat Genet. 2019; 51(2):237-244. PMC: 6358542. DOI: 10.1038/s41588-018-0307-5. View

12.

Burgess S, Butterworth A, Thompson S . Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol. 2013; 37(7):658-65. PMC: 4377079. DOI: 10.1002/gepi.21758. View

13.

Bowden J, Del Greco M F, Minelli C, Davey Smith G, Sheehan N, Thompson J . A framework for the investigation of pleiotropy in two-sample summary data Mendelian randomization. Stat Med. 2017; 36(11):1783-1802. PMC: 5434863. DOI: 10.1002/sim.7221. View

14.

Chai J, Du C, Wu J, Kyin S, Wang X, Shi Y . Structural and biochemical basis of apoptotic activation by Smac/DIABLO. Nature. 2000; 406(6798):855-62. DOI: 10.1038/35022514. View

15.

Hiltunen M, Turunen M, Hakkinen T, Rutanen J, Hedman M, Makinen K . DNA hypomethylation and methyltransferase expression in atherosclerotic lesions. Vasc Med. 2002; 7(1):5-11. DOI: 10.1191/1358863x02vm418oa. View

16.

Critchley J, Capewell S . Mortality risk reduction associated with smoking cessation in patients with coronary heart disease: a systematic review. JAMA. 2003; 290(1):86-97. DOI: 10.1001/jama.290.1.86. View

17.

Notara V, Panagiotakos D, Kouroupi S, Stergiouli I, Kogias Y, Stravopodis P . Smoking determines the 10-year (2004-2014) prognosis in patients with Acute Coronary Syndrome: the GREECS observational study. Tob Induc Dis. 2015; 13:38. PMC: 4658767. DOI: 10.1186/s12971-015-0063-6. View

18.

Hartiala J, Han Y, Jia Q, Hilser J, Huang P, Gukasyan J . Genome-wide analysis identifies novel susceptibility loci for myocardial infarction. Eur Heart J. 2021; 42(9):919-933. PMC: 7936531. DOI: 10.1093/eurheartj/ehaa1040. View

19.

Deaton A, Bird A . CpG islands and the regulation of transcription. Genes Dev. 2011; 25(10):1010-22. PMC: 3093116. DOI: 10.1101/gad.2037511. View

20.

Joehanes R, Just A, Marioni R, Pilling L, Reynolds L, Mandaviya P . Epigenetic Signatures of Cigarette Smoking. Circ Cardiovasc Genet. 2016; 9(5):436-447. PMC: 5267325. DOI: 10.1161/CIRCGENETICS.116.001506. View