Association between antithrombotic agents use and hepatocellular carcinoma risk: a two-sample mendelian randomization analysis.
Antithrombotic agents
Causal relationship
Hepatocellular carcinoma
Mendelian randomization study
Journal
Journal of cancer research and clinical oncology
ISSN: 1432-1335
Titre abrégé: J Cancer Res Clin Oncol
Pays: Germany
ID NLM: 7902060
Informations de publication
Date de publication:
22 Oct 2024
22 Oct 2024
Historique:
received:
20
06
2024
accepted:
18
09
2024
medline:
22
10
2024
pubmed:
22
10
2024
entrez:
22
10
2024
Statut:
epublish
Résumé
Hepatocellular carcinoma (HCC) is the most common primary liver cancer worldwide. Multiple observational studies demonstrated a negative association between the use of antithrombotic agents and the risk of HCC. However, the precise causal relationship between these factors remains uncertain. Therefore, our study used a two-sample Mendelian randomization (MR) analysis to assess the causal link between these two factors. The summary statistics of single nucleotide polymorphisms (SNPs) associated with the use of antithrombotic agents were acquired from a genome-wide association study (GWAS) performed on individuals of European descent. A two-sample MR analysis was performed using the inverse variance weighting (IVW), the weighted median estimate, the MR-Egger regression, and the weighted-mode estimate. Sensitivity analysis of the primary findings was performed using MR-PRESSO, MR-Egger regression, Cochran's Q test, and Leave-one-out analysis. Ten SNPs associated with the use of antithrombotic agents were selected as instrumental variables. The MR analysis performed using the four methods mentioned above revealed a negative causal association between the use of antithrombotic agents and HCC. Univariate MR estimates based on the inverse variance weighting (IVW) method suggested a negative causal association between the use of antithrombotic agents and HCC [odds ratio (OR) 0.444, 95% confidence interval (CI) 0.279 to 0.707, P = 0.001]. The other methods also produced similar results. No heterogeneity and horizontal pleiotropy were found. Our findings suggested an inverse causal association of antithrombotic agents with the risk of HCC.
Sections du résumé
BACKGROUND
BACKGROUND
Hepatocellular carcinoma (HCC) is the most common primary liver cancer worldwide. Multiple observational studies demonstrated a negative association between the use of antithrombotic agents and the risk of HCC. However, the precise causal relationship between these factors remains uncertain. Therefore, our study used a two-sample Mendelian randomization (MR) analysis to assess the causal link between these two factors.
METHOD
METHODS
The summary statistics of single nucleotide polymorphisms (SNPs) associated with the use of antithrombotic agents were acquired from a genome-wide association study (GWAS) performed on individuals of European descent. A two-sample MR analysis was performed using the inverse variance weighting (IVW), the weighted median estimate, the MR-Egger regression, and the weighted-mode estimate. Sensitivity analysis of the primary findings was performed using MR-PRESSO, MR-Egger regression, Cochran's Q test, and Leave-one-out analysis.
RESULTS
RESULTS
Ten SNPs associated with the use of antithrombotic agents were selected as instrumental variables. The MR analysis performed using the four methods mentioned above revealed a negative causal association between the use of antithrombotic agents and HCC. Univariate MR estimates based on the inverse variance weighting (IVW) method suggested a negative causal association between the use of antithrombotic agents and HCC [odds ratio (OR) 0.444, 95% confidence interval (CI) 0.279 to 0.707, P = 0.001]. The other methods also produced similar results. No heterogeneity and horizontal pleiotropy were found.
CONCLUSION
CONCLUSIONS
Our findings suggested an inverse causal association of antithrombotic agents with the risk of HCC.
Identifiants
pubmed: 39436427
doi: 10.1007/s00432-024-05960-7
pii: 10.1007/s00432-024-05960-7
doi:
Substances chimiques
Fibrinolytic Agents
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
470Subventions
Organisme : Jin Yang
ID : 2023YFQ0101
Organisme : Jin Yang
ID : 2023YFQ0101
Organisme : Jin Yang
ID : 2023YFQ0101
Organisme : Jin Yang
ID : 2023YFQ0101
Organisme : Jin Yang
ID : 2023YFQ0101
Organisme : Yaling Li
ID : 2022YFS0625
Organisme : Yaling Li
ID : 2022YFS0625
Organisme : Yaling Li
ID : 2022YFS0625
Organisme : Yaling Li
ID : 2022YFS0625
Organisme : Yaling Li
ID : 2022YFS0625
Organisme : Xiaoli Yang
ID : 2022-SYF-55
Organisme : Xiaoli Yang
ID : 2022-SYF-55
Organisme : Xiaoli Yang
ID : 2022-SYF-55
Organisme : Xiaoli Yang
ID : 2022-SYF-55
Organisme : Xiaoli Yang
ID : 2022-SYF-55
Informations de copyright
© 2024. The Author(s).
Références
Bowden J, Holmes MV (2019) Meta-analysis and mendelian randomization: a review. Res Synth Methods 10(4):486–496. https://doi.org/10.1002/jrsm.1346
doi: 10.1002/jrsm.1346
pubmed: 30861319
pmcid: 6973275
Bowden J, Davey Smith G, Burgess S (2015) Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol 44(2):512–525. https://doi.org/10.1093/ije/dyv080
doi: 10.1093/ije/dyv080
pubmed: 26050253
pmcid: 4469799
Burgess S, Thompson SG (2017) Interpreting findings from mendelian randomization using the MR-Egger method [published correction appears in. Eur J Epidemiol 2017;:] Eur J Epidemiol 32(5):377–389. https://doi.org/10.1007/s10654-017-0255-x
doi: 10.1007/s10654-017-0255-x
pubmed: 28527048
Burgess S, Butterworth A, Malarstig A, Thompson SG (2012) Use of mendelian randomisation to assess potential benefit of clinical intervention. BMJ 345:e7325. https://doi.org/10.1136/bmj.e7325
Burgess S, Butterworth A, Thompson SG (2013) Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol 37(7):658–665. https://doi.org/10.1002/gepi.21758
doi: 10.1002/gepi.21758
pubmed: 24114802
pmcid: 4377079
Burgess S, Daniel RM, Butterworth AS, Thompson SG, EPIC-InterAct Consortium (2015) Network mendelian randomization: using genetic variants as instrumental variables to investigate mediation in causal pathways. Int J Epidemiol 44(2):484–495. https://doi.org/10.1093/ije/dyu176
doi: 10.1093/ije/dyu176
pubmed: 25150977
Burgess S, Davey Smith G, Davies NM et al (2023) Guidelines for performing mendelian randomization investigations: update for summer 2023. Wellcome Open Res 4:186. https://doi.org/10.12688/wellcomeopenres.15555.3
doi: 10.12688/wellcomeopenres.15555.3
pubmed: 32760811
pmcid: 7384151
Chiu HF, Ho SC, Chen CC, Yang CY (2011) Statin use and the risk of liver cancer: a population-based case–control study. Am J Gastroenterol 106(5):894–898. https://doi.org/10.1038/ajg.2010.475
doi: 10.1038/ajg.2010.475
pubmed: 21157439
Cho Y, Haycock PC, Sanderson E et al (2020) Exploiting horizontal pleiotropy to search for causal pathways within a mendelian randomization framework. Nat Commun 11(1):1010 Published 2020 Feb 21. https://doi.org/10.1038/s41467-020-14452-4
doi: 10.1038/s41467-020-14452-4
pubmed: 32081875
pmcid: 7035387
Cui Z, Feng H, He B, He J, Tian Y (2021) Relationship between serum amino acid levels and bone Mineral density: a mendelian randomization study. Front Endocrinol (Lausanne) 12:763538 Published 2021 Nov 9. https://doi.org/10.3389/fendo.2021.763538
doi: 10.3389/fendo.2021.763538
pubmed: 34858335
Davies NM, Holmes MV, Davey Smith G (2018) Reading mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ 362(k601). https://doi.org/10.1136/bmj.k601 . Published 2018 Jul 12
DiNicolantonio JJ, O’Keefe JH, Lavie CJ (2012) Benefits and risks of aspirin use. JAMA 308(11):1088–1090. https://doi.org/10.1001/2012.jama.10717
doi: 10.1001/2012.jama.10717
pubmed: 22990257
Drew DA, Chan AT (2021) Aspirin in the Prevention of Colorectal Neoplasia. Annu Rev Med 72:415–430. https://doi.org/10.1146/annurev-med-060319-120913
doi: 10.1146/annurev-med-060319-120913
pubmed: 33035431
Fitzmaurice C, Abate D et al (2021) Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-Years for 29 Cancer Groups, 1990 to 2017: A Systematic Analysis for the Global Burden of Disease Study [published correction appears in JAMA Oncol. 2020;6(3):444] [published correction appears in JAMA Oncol. 2020;6(5):789] [published correction appears in JAMA Oncol. 2021;7(3):466]. JAMA Oncol. 2019;5(12):1749–1768. https://doi.org/10.1001/jamaoncol.2019.2996
Heimbach JK, Kulik LM, Finn RS et al (2018) AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology 67(1):358–380. https://doi.org/10.1002/hep.29086
doi: 10.1002/hep.29086
pubmed: 28130846
Hemani G, Zheng J, Elsworth B et al (2018) The MR-Base platform supports systematic causal inference across the human phenome. Elife 7:e34408. https://doi.org/10.7554/eLife.34408 . Published 2018 May 30
doi: 10.7554/eLife.34408
pubmed: 29846171
pmcid: 5976434
Huang Z, Fang W, Liu W et al (2018) Aspirin induces beclin-1-dependent autophagy of human hepatocellular carcinoma cell. Eur J Pharmacol 823:58–64. https://doi.org/10.1016/j.ejphar.2018.01.031
doi: 10.1016/j.ejphar.2018.01.031
pubmed: 29408091
Hwang IC, Chang J, Kim K, Park SM (2018) Aspirin use and risk of Hepatocellular Carcinoma in a National Cohort Study of Korean adults. Sci Rep 8(1):4968. https://doi.org/10.1038/s41598-018-23343-0
doi: 10.1038/s41598-018-23343-0
pubmed: 29563592
pmcid: 5862896
Iannacone M, Sitia G, Isogawa M et al (2005) Platelets mediate cytotoxic T lymphocyte-induced liver damage. Nat Med 11(11):1167–1169. https://doi.org/10.1038/nm1317
doi: 10.1038/nm1317
pubmed: 16258538
pmcid: 2908083
Kamat MA, Blackshaw JA, Young R et al (2019) PhenoScanner V2: an expanded tool for searching human genotype-phenotype associations. Bioinformatics 35(22):4851–4853. https://doi.org/10.1093/bioinformatics/btz469
doi: 10.1093/bioinformatics/btz469
pubmed: 31233103
pmcid: 6853652
Kim G, Jang SY, Han E et al (2017) Effect of statin on hepatocellular carcinoma in patients with type 2 diabetes: A nationwide nested case-control study. Int J Cancer. 2017;140(4):798–806. https://doi.org/10.1002/ijc.30506
Kumar M, Zhao X, Wang XW (2011) Molecular carcinogenesis of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: one step closer to personalized medicine? Cell Biosci 1(1):5. https://doi.org/10.1186/2045-3701-1-5 . Published 2011 Jan 24
doi: 10.1186/2045-3701-1-5
pubmed: 21711594
pmcid: 3116244
Kurilshikov A, Medina-Gomez C, Bacigalupe R et al (2021) Large-scale association analyses identify host factors influencing human gut microbiome composition. Nat Genet 53(2):156–165. https://doi.org/10.1038/s41588-020-00763-1
doi: 10.1038/s41588-020-00763-1
pubmed: 33462485
pmcid: 8515199
Lee TY, Hsu YC, Tseng HC et al (2019) Association of Daily Aspirin Therapy with Risk of Hepatocellular Carcinoma in patients with chronic Hepatitis B. JAMA Intern Med 179(5):633–640. https://doi.org/10.1001/jamainternmed.2018.8342
doi: 10.1001/jamainternmed.2018.8342
pubmed: 30882847
pmcid: 6503573
Liao YH, Hsu RJ, Wang TH et al (2020) Aspirin decreases hepatocellular carcinoma risk in hepatitis C virus carriers: a nationwide cohort study. BMC Gastroenterol 20(1):6. https://doi.org/10.1186/s12876-020-1158-y . Published 2020 Jan 9
doi: 10.1186/s12876-020-1158-y
pubmed: 31918672
pmcid: 6953130
Maini MK, Schurich A (2012) Platelets harness the immune response to drive liver cancer. Proc Natl Acad Sci U S A 109(32):12840–12841. https://doi.org/10.1073/pnas.1210296109
doi: 10.1073/pnas.1210296109
pubmed: 22826219
pmcid: 3420167
Marrero JA, Kulik LM, Sirlin CB et al (2018) Diagnosis, staging, and management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the study of Liver diseases. Hepatology 68(2):723–750. https://doi.org/10.1002/hep.29913
doi: 10.1002/hep.29913
pubmed: 29624699
McGlynn KA, Petrick JL, El-Serag HB (2021) Epidemiology of Hepatocellular Carcinoma. Hepatol 73 Suppl 1(Suppl 1):4–13. https://doi.org/10.1002/hep.31288
doi: 10.1002/hep.31288
Pang Q, Jin H, Qu K et al (2017) The effects of nonsteroidal anti-inflammatory drugs in the incident and recurrent risk of hepatocellular carcinoma: a meta-analysis. Onco Targets Ther 10:4645–4656 Published 2017 Sep 20. https://doi.org/10.2147/OTT.S143154
doi: 10.2147/OTT.S143154
pubmed: 29033583
pmcid: 5614766
Pavlovic N, Rani B, Gerwins P, Heindryckx F (2019) Platelets as key factors in Hepatocellular Carcinoma. Cancers (Basel) 11(7):1022. https://doi.org/10.3390/cancers11071022 . Published 2019 Jul 20
doi: 10.3390/cancers11071022
pubmed: 31330817
Petrick JL, Sahasrabuddhe VV, Chan AT, Alavanja MC, Beane-Freeman LE, Buring JE, Chen J, Chong DQ, Freedman ND, Fuchs CS, Gaziano JM, Giovannucci E, Graubard BI, Hollenbeck AR, Hou L, Jacobs EJ, King LY, Koshiol J, Lee IM, Linet MS, McGlynn KA (2015) NSAID Use and Risk of Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma: the Liver Cancer Pooling Project. Cancer prevention research (Philadelphia, Pa. 8(12):1156–1162. https://doi.org/10.1158/1940-6207.CAPR-15-0126
Sahasrabuddhe VV, Gunja MZ, Graubard BI et al (2012) Nonsteroidal anti-inflammatory drug use, chronic liver disease, and hepatocellular carcinoma. J Natl Cancer Inst 104(23):1808–1814. https://doi.org/10.1093/jnci/djs452
doi: 10.1093/jnci/djs452
pubmed: 23197492
pmcid: 3514167
Sanna S, van Zuydam NR, Mahajan A et al (2019) Causal relationships among the gut microbiome, short-chain fatty acids and metabolic diseases. Nat Genet 51(4):600–605. https://doi.org/10.1038/s41588-019-0350-x
doi: 10.1038/s41588-019-0350-x
pubmed: 30778224
pmcid: 6441384
Shetty VV, Kellarai A (2022) Comprehensive Review of Hepatocellular Carcinoma in India: current challenges and future directions. JCO Glob Oncol 8:e2200118. https://doi.org/10.1200/GO.22.00118
doi: 10.1200/GO.22.00118
pubmed: 36198133
pmcid: 9812497
Shi T, Fujita K, Gong J et al (2020) Aspirin inhibits hepatocellular carcinoma cell proliferation in vitro and in vivo via inducing cell cycle arrest and apoptosis. Oncol Rep 44(2):457–468. https://doi.org/10.3892/or.2020.7630
doi: 10.3892/or.2020.7630
pubmed: 32627038
pmcid: 7336451
Shin S, Lee SH, Lee M et al (2020) Aspirin and the risk of hepatocellular carcinoma development in patients with alcoholic cirrhosis. Med (Baltim) 99(9):e19008. https://doi.org/10.1097/MD.0000000000019008
doi: 10.1097/MD.0000000000019008
Siegel RL, Miller KD, Fuchs HE, Jemal A (2021) Cancer Statistics, CA Cancer J Clin. 2021;71(1):7–33. https://doi.org/10.3322/caac.21654
Simon TG, Ma Y, Ludvigsson JF, Chong DQ, Giovannucci EL, Fuchs CS, Meyerhardt JA, Corey KE, Chung RT, Zhang X, Chan AT (2018) Association between Aspirin Use and Risk of Hepatocellular Carcinoma. JAMA Oncol 4(12):1683–1690. https://doi.org/10.1001/jamaoncol.2018.4154
doi: 10.1001/jamaoncol.2018.4154
pubmed: 30286235
pmcid: 6440745
Singal AG, Lampertico P, Nahon P (2020) Epidemiology and surveillance for hepatocellular carcinoma: new trends. J Hepatol 72(2):250–261. https://doi.org/10.1016/j.jhep.2019.08.025
doi: 10.1016/j.jhep.2019.08.025
pubmed: 31954490
pmcid: 6986771
Slob EAW, Burgess S (2020) A comparison of robust mendelian randomization methods using summary data. Genet Epidemiol 44(4):313–329. https://doi.org/10.1002/gepi.22295
doi: 10.1002/gepi.22295
pubmed: 32249995
pmcid: 7317850
Smith GD, Ebrahim S (2004) Mendelian randomization: prospects, potentials, and limitations. Int J Epidemiol 33(1):30–42. https://doi.org/10.1093/ije/dyh132
doi: 10.1093/ije/dyh132
pubmed: 15075143
Tsan YT, Lee CH, Wang JD, Chen PC (2012) Statins and the risk of hepatocellular carcinoma in patients with hepatitis B virus infection [published correction appears in J Clin Oncol. 2013;31(24):3049]. J Clin Oncol. 30(6):623–630. https://doi.org/10.1200/JCO.2011.36.0917
Villanueva A (2019) Hepatocellular Carcinoma. N Engl J Med 380(15):1450–1462. https://doi.org/10.1056/NEJMra1713263
doi: 10.1056/NEJMra1713263
pubmed: 30970190
Vogel A, Meyer T, Sapisochin G, Salem R, Saborowski A (2022) Hepatocellular carcinoma. Lancet 400(10360):1345–1362. https://doi.org/10.1016/S0140-6736(22)01200-4
doi: 10.1016/S0140-6736(22)01200-4
pubmed: 36084663
Walker VM, Davies NM, Hemani G et al (2019) Using the MR-Base platform to investigate risk factors and drug targets for thousands of phenotypes. Wellcome Open Res 4:113 Published 2019 Nov 7. https://doi.org/10.12688/wellcomeopenres.15334.2
doi: 10.12688/wellcomeopenres.15334.2
pubmed: 31448343
pmcid: 6694718
Wang T, Fu X, Jin T et al (2019) Aspirin targets P4HA2 through inhibiting NF-κB and LMCD1-AS1/let-7 g to inhibit tumour growth and collagen deposition in hepatocellular carcinoma. EBioMedicine 45:168–180. https://doi.org/10.1016/j.ebiom.2019.06.048
doi: 10.1016/j.ebiom.2019.06.048
pubmed: 31278071
pmcid: 6642319
Wu Y, Byrne EM, Zheng Z et al (2019) Genome-wide association study of medication-use and associated disease in the UK Biobank. Nat Commun 10(1):1891 Published 2019 Apr 23. https://doi.org/10.1038/s41467-019-09572-5
doi: 10.1038/s41467-019-09572-5
pubmed: 31015401
pmcid: 6478889
Zeng RW, Yong JN, Tan DJH et al (2023) Meta-analysis: chemoprevention of hepatocellular carcinoma with statins, aspirin and metformin. Aliment Pharmacol Ther 57(6):600–609. https://doi.org/10.1111/apt.17371
doi: 10.1111/apt.17371
pubmed: 36625733
pmcid: 10792521