Mendelian Randomization and Multiomics Comprehensively Reveal the Causal Relationship and Potential Mechanism Between Atrial Fibrillation and Gastric Cancer

Overview

Journal Front Genet

Date 2025 Feb 18

PMID 39963672

Authors

Zhao Sicheng

Zhang Jingcheng

Zhang Shuo

Lou Jiaheng

Cai Yan

Bai Xing

Jiang Tao

Zhang Guangji

Affiliations

Soon will be listed here.

Abstract

Objective: Gastric cancer is a harmful disease, the comorbidity mechanism and causality relationship between this disease and other diseases are worth studying.

Methods: Using a two-sample Mendelian Randomization method, this study revealed the potential causal effect of atrial fibrillation (AF) on gastric cancer (GC) risk by constructing a genetic instrument containing 136 AF associated SNPs. Subsequently, analysis identifies 62 AF-GC co-associated genes and constructs a protein-protein interaction network of key genes. High-throughput sequencing data were further used to analyze the association between the two and their impact on the survival outcome of gastric cancer.

Results: The results showed that AF was negatively associated with gastric cancer, and further analysis revealed that this relationship was independent of GC risk factors such as chronic gastritis, infection, and alcohol consumption. Enrichment analysis reveals associations of key genes with pathways related to cardiovascular disease, inflammatory gastrointestinal diseases, and tumorigenesis. Through single-cell sequencing data analysis, fibroblast subpopulations associated with the key gene set are identified in GC, showing significant correlations with cancer progression and inflammation regulation pathways. Transcription factor analysis and developmental trajectory analysis reveal the potential role of fibroblasts in GC development. Finally, prognosis analysis and gene mutation analysis using TCGA-STAD data indicate an adverse prognosis associated with the key gene set in GC.

Conclusion: This study provides new insights into the association between AF and GC and offers novel clues for understanding its impact on the pathogenesis and therapeutic strategies of GC.

References

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

Haaland G, Falk R, Straume O, Lorens J . Association of Warfarin Use With Lower Overall Cancer Incidence Among Patients Older Than 50 Years. JAMA Intern Med. 2017; 177(12):1774-1780. PMC: 5820735. DOI: 10.1001/jamainternmed.2017.5512. View

Gulati G, Sikandar S, Wesche D, Manjunath A, Bharadwaj A, Berger M . Single-cell transcriptional diversity is a hallmark of developmental potential. Science. 2020; 367(6476):405-411. PMC: 7694873. DOI: 10.1126/science.aax0249. View

Hao Y, Stuart T, Kowalski M, Choudhary S, Hoffman P, Hartman A . Dictionary learning for integrative, multimodal and scalable single-cell analysis. Nat Biotechnol. 2023; 42(2):293-304. PMC: 10928517. DOI: 10.1038/s41587-023-01767-y. View

Wei S, Sun P, Guo Y, Chen J, Wang J, Song C . Gene Expression in the Hippocampus in a Rat Model of Premenstrual Dysphoric Disorder After Treatment With Baixiangdan Capsules. Front Psychol. 2018; 9:2065. PMC: 6242977. DOI: 10.3389/fpsyg.2018.02065. View

Rich J, Neely J, Paniello R, Voelker C, Nussenbaum B, Wang E . A practical guide to understanding Kaplan-Meier curves. Otolaryngol Head Neck Surg. 2010; 143(3):331-6. PMC: 3932959. DOI: 10.1016/j.otohns.2010.05.007. View

Suo S, Zhu Q, Saadatpour A, Fei L, Guo G, Yuan G . Revealing the Critical Regulators of Cell Identity in the Mouse Cell Atlas. Cell Rep. 2018; 25(6):1436-1445.e3. PMC: 6281296. DOI: 10.1016/j.celrep.2018.10.045. View

Van Cutsem E, Sagaert X, Topal B, Haustermans K, Prenen H . Gastric cancer. Lancet. 2016; 388(10060):2654-2664. DOI: 10.1016/S0140-6736(16)30354-3. View

Bowden J, Davey Smith G, Haycock P, Burgess S . Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator. Genet Epidemiol. 2016; 40(4):304-14. PMC: 4849733. DOI: 10.1002/gepi.21965. View

10.

Budzynski J, Kozinski M, Klopocka M, Kubica J, Kubica J . Clinical significance of Helicobacter pylori infection in patients with acute coronary syndromes: an overview of current evidence. Clin Res Cardiol. 2014; 103(11):855-86. DOI: 10.1007/s00392-014-0720-4. View

11.

Davey Smith G, Ebrahim S . Mendelian randomization: prospects, potentials, and limitations. Int J Epidemiol. 2004; 33(1):30-42. DOI: 10.1093/ije/dyh132. View

12.

Tsubosaka A, Komura D, Kakiuchi M, Katoh H, Onoyama T, Yamamoto A . Stomach encyclopedia: Combined single-cell and spatial transcriptomics reveal cell diversity and homeostatic regulation of human stomach. Cell Rep. 2023; 42(10):113236. DOI: 10.1016/j.celrep.2023.113236. View

13.

Bowden J, Del Greco M F, Minelli C, Zhao Q, Lawlor D, Sheehan N . Improving the accuracy of two-sample summary-data Mendelian randomization: moving beyond the NOME assumption. Int J Epidemiol. 2018; 48(3):728-742. PMC: 6659376. DOI: 10.1093/ije/dyy258. View

14.

Davey Smith G, Ebrahim S . 'Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease?. Int J Epidemiol. 2003; 32(1):1-22. DOI: 10.1093/ije/dyg070. View

15.

Giacobbi N, Mullapudi S, Nabors H, Pyeon D . The Chemokine CXCL14 as a Potential Immunotherapeutic Agent for Cancer Therapy. Viruses. 2024; 16(2). PMC: 10892169. DOI: 10.3390/v16020302. View

16.

Lawlor D . Commentary: Two-sample Mendelian randomization: opportunities and challenges. Int J Epidemiol. 2016; 45(3):908-15. PMC: 5005949. DOI: 10.1093/ije/dyw127. View

17.

Krijthe B, Kunst A, Benjamin E, Lip G, Franco O, Hofman A . Projections on the number of individuals with atrial fibrillation in the European Union, from 2000 to 2060. Eur Heart J. 2013; 34(35):2746-51. PMC: 3858024. DOI: 10.1093/eurheartj/eht280. View

18.

Sung H, Ferlay J, Siegel R, Laversanne M, Soerjomataram I, Jemal A . Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 71(3):209-249. DOI: 10.3322/caac.21660. View

19.

Qiu X, Mao Q, Tang Y, Wang L, Chawla R, Pliner H . Reversed graph embedding resolves complex single-cell trajectories. Nat Methods. 2017; 14(10):979-982. PMC: 5764547. DOI: 10.1038/nmeth.4402. View

20.

Jin S, Li R, Chen M, Yu C, Tang L, Liu Y . Single-cell transcriptomic analysis defines the interplay between tumor cells, viral infection, and the microenvironment in nasopharyngeal carcinoma. Cell Res. 2020; 30(11):950-965. PMC: 7784966. DOI: 10.1038/s41422-020-00402-8. View