Current issue
Archive
Manuscripts accepted
About the Journal
Editorial office
Editorial board
Section Editors
Abstracting and indexing
Subscription
Contact
Ethical standards and procedures
Most read articles
Instructions for authors
Article Processing Charge (APC)
Regulations of paying article processing charge (APC)
ONCOLOGY / CLINICAL RESEARCH
Dissecting the potential impact of appendectomy on colorectal cancer through metabolites and inflammatory proteins: a Mendelian randomization study
1
The First Affiliated Hospital of Guangxi Medical University, China
2
Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer, China
These authors had equal contribution to this work
Submission date: 2024-09-17
Final revision date: 2025-05-25
Acceptance date: 2025-07-17
Online publication date: 2025-09-06
Corresponding author
Minglin Lin
The First Affiliated Hospital of Guangxi Medical University Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer China
The First Affiliated Hospital of Guangxi Medical University Guangxi Key Laboratory of Enhanced Recovery after Surgery for Gastrointestinal Cancer China
Article (PDF)
Supplementary files
References (53)
Dissecting the potential_Supplementary Figure S1.pdf
Dissecting the potential_Supplementary Figure S2.pdf
Dissecting the potential_Supplementary Figure S3.pdf
Dissecting the potential_Supplementary Table SI.pdf
Dissecting the potential_Supplementary Table SII.pdf
Dissecting the potential_Supplementary Table SIII.pdf
Dissecting the potential_Supplementary Table SIV.pdf
Dissecting the potential_Supplementary Table SV.pdf
Dissecting the potential_Supplementary Table SVI.pdf
Dissecting the potential_Supplementary Table SVII.pdf
KEYWORDS
TOPICS
ABSTRACT
Introduction:
Traditional longitudinal epidemiological investigations have demonstrated an association between appendectomy and the cumulative incidence of colorectal cancer (CRC). However, there is a paucity of evidence for a causal relationship between appendectomy and CRC from alternative methodologies.
Material and methods:
We extracted summary statistics for CRC, appendectomy, 1,400 metabolites, and 91 inflammatory proteins from the largest European ancestry genome-wide association studies (GWAS) and the FinnGen study. Using two-sample bidirectional Mendelian randomization (MR), we explored the potential causal relationship between genetic liability to appendectomy and CRC. Moreover, we employed a two-step MR approach to identify metabolites and inflammatory proteins that may mediate the effects of genetic liability to appendectomy on CRC risk and analyzed their potential mediator variables. Furthermore, we used the significant single nucleotide polymorphisms (SNPs) associated with the risk of CRC due to appendectomy, searched for the nearest genes in the FinnGen, and explored the relationship between these genes and CRC prognosis by analyzing transcriptomic data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO).
Results:
Two-sample MR analysis revealed evidence supporting a potential causal effect of genetic liability to appendectomy on an increased risk of CRC. Two-step MR analysis identified carnitine and interleukin-13 (IL-13) as key mediators potentially involved in the positive causal relationship between genetic liability to appendectomy and CRC. Survival analysis showed that upregulation of HLX and OSR1 expression is positively correlated with poor prognosis in CRC patients.
Conclusions:
This MR investigation provides evidence supporting a potential causal relationship between genetic liability to appendectomy and CRC, with carnitine and IL-13 potentially acting as partial mediators of this effect.
Traditional longitudinal epidemiological investigations have demonstrated an association between appendectomy and the cumulative incidence of colorectal cancer (CRC). However, there is a paucity of evidence for a causal relationship between appendectomy and CRC from alternative methodologies.
Material and methods:
We extracted summary statistics for CRC, appendectomy, 1,400 metabolites, and 91 inflammatory proteins from the largest European ancestry genome-wide association studies (GWAS) and the FinnGen study. Using two-sample bidirectional Mendelian randomization (MR), we explored the potential causal relationship between genetic liability to appendectomy and CRC. Moreover, we employed a two-step MR approach to identify metabolites and inflammatory proteins that may mediate the effects of genetic liability to appendectomy on CRC risk and analyzed their potential mediator variables. Furthermore, we used the significant single nucleotide polymorphisms (SNPs) associated with the risk of CRC due to appendectomy, searched for the nearest genes in the FinnGen, and explored the relationship between these genes and CRC prognosis by analyzing transcriptomic data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO).
Results:
Two-sample MR analysis revealed evidence supporting a potential causal effect of genetic liability to appendectomy on an increased risk of CRC. Two-step MR analysis identified carnitine and interleukin-13 (IL-13) as key mediators potentially involved in the positive causal relationship between genetic liability to appendectomy and CRC. Survival analysis showed that upregulation of HLX and OSR1 expression is positively correlated with poor prognosis in CRC patients.
Conclusions:
This MR investigation provides evidence supporting a potential causal relationship between genetic liability to appendectomy and CRC, with carnitine and IL-13 potentially acting as partial mediators of this effect.
REFERENCES (53)
1.
Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71: 209-49.
2.
Zhang Q, Zhou Y, Song L, et al. China special issue on gastrointestinal tumors-Improved survival after multidisciplinary team decision for patients with advanced gastrointestinal cancer: a multicenter, noninterventional, controlled study. Int J Cancer 2023; 153: 1885-93.
3.
Bożyk A, Krawczyk P, Reszka K, et al. Correlation between KRAS, NRAS and BRAF mutations and tumor localizations in patients with primary and metastatic colorectal cancer. Arch Med Sci 2022; 18: 1221-30.
4.
Shi F, Liu G, Lin Y, et al. Altered gut microbiome composition by appendectomy contributes to colorectal cancer. Oncogene 2023; 42: 530-40.
5.
Agrawal M, Allin KH, Mehandru S, Faith J, Jess T, Colombel JF. The appendix and ulcerative colitis – an unsolved connection. Nature Rev Gastroenterol Hepatol 2023; 20: 615-24.
6.
Vitetta L, Chen J, Clarke S. The vermiform appendix: an immunological organ sustaining a microbiome inoculum. Clin Sci 2019; 133: 1-8.
7.
Ishimoto Y, Tomiyama-Miyaji C, Watanabe H, et al. Age-dependent variation in the proportion and number of intestinal lymphocyte subsets, especially natural killer T cells, double-positive CD4+ CD8+ cells and B220+ T cells, in mice. Immunology 2004; 113: 371-7.
8.
Collard MK, Tourneur-Marsille J, Uzzan M, et al. The appendix orchestrates T-cell mediated immunosurveillance in colitis-associated cancer. Cell Mol Gastroenterol Hepatol 2023; 15: 665-87.
9.
Dai C, Jiang M, Huang YH. Appendectomy and future risk of microscopic colitis: correlation or causation? Clin Gastroenterol Hepatol 2023; 21: 1376-7.
10.
Harnoy Y, Bouhnik Y, Gault N, et al. Effect of appendicectomy on colonic inflammation and neoplasia in experimental ulcerative colitis. J Br Surg 2016; 103: 1530-8.
11.
Lee KH, Lee S, Park JH, et al. Risk of hematologic malignant neoplasms from abdominopelvic computed tomographic radiation in patients who underwent appendectomy. JAMA Surg 2021; 156: 343-51.
12.
Yang CY, Wu MC, Lin MC, Wei JCC. Risk of irritable bowel syndrome in patients who underwent appendectomy: a nationwide population-based cohort study. EClinicalMedicine 2020; 23. https://doi.org/10.1016/j.ecli....
13.
Emdin CA, Khera AV, Kathiresan S. Mendelian randomization. JAMA 2017; 318: 1925-6.
14.
Glymour MM, Tchetgen Tchetgen EJ, Robins JM. Credible Mendelian randomization studies: approaches for evaluating the instrumental variable assumptions. Am J Epidemiol 2012; 175: 332-9.
15.
Bouras E, Karhunen V, Gill D, et al. Circulating inflammatory cytokines and risk of five cancers: a Mendelian randomization analysis. BMC Med 2022; 20: 3.
16.
Liu X, Tong X, Zou Y, et al. Mendelian randomization analyses support causal relationships between blood metabolites and the gut microbiome. Nat Genet 2022; 54: 52-61.
17.
Sanna S, van Zuydam NR, Mahajan A, et al. Causal relationships among the gut microbiome, short-chain fatty acids and metabolic diseases. Nat Genet 2019; 51: 600-5.
18.
Huyghe JR, Bien SA, Harrison TA, et al. Discovery of common and rare genetic risk variants for colorectal cancer. Nat Genet 2019; 51: 76-87.
19.
Chen Y, Lu T, Pettersson-Kymmer U, et al. Genomic atlas of the plasma metabolome prioritizes metabolites implicated in human diseases. Nat Genet 2023; 55: 44-53.
20.
Zhao JH, Stacey D, Eriksson N, et al. Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets. Nat Immunol 2023; 24: 1540-51.
21.
Marisa L, de Reyniès A, Duval A, et al. Gene expression classification of colon cancer into molecular subtypes: characterization, validation, and prognostic value. PLoS Med 2013; 10: e1001453.
22.
Yang J, Yan B, Zhao B, et al. Assessing the causal effects of human serum metabolites on 5 major psychiatric disorders. Schizophr Bull 2020; 46: 804-13.
23.
Folkersen L, Gustafsson S, Wang Q, et al. Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals. Nat Metabol 2020; 2: 1135-48.
24.
Choi KW, Chen CY, Stein MB, et al. Assessment of bidirectional relationships between physical activity and depression among adults: a 2-sample Mendelian randomization study. JAMA Psychiatry 2019; 76: 399-408.
25.
Chen L, Yang H, Li H, He C, Yang L, Lv G. Insights into modifiable risk factors of cholelithiasis: a Mendelian randomization study. Hepatology 2022; 75: 785-96.
26.
Pierce BL, Burgess S. Efficient design for Mendelian randomization studies: subsample and 2-sample instrumental variable estimators. Am J Epidemiol 2013; 178: 1177-84.
27.
Boehm FJ, Zhou X. Statistical methods for Mendelian randomization in genome-wide association studies: a review. Comp Struct Biotechnol J 2022; 20: 2338-51.
28.
Liu Y, Si M, Qian Y, et al. Bidirectional Mendelian randomization analysis investigating the genetic association between primary breast cancer and colorectal cancer. Front Immunol 2024; 14: 1260941.
29.
Hu X, Zhao J, Lin Z, et al. Mendelian randomization for causal inference accounting for pleiotropy and sample structure using genome-wide summary statistics. Proc Natl Acad Sci 2022; 119: e2106858119.
30.
Bowden J, Holmes MV. Meta-analysis and Mendelian randomization: a review. Res Synth Meth 2019; 10: 486-96.
31.
Morrison J, Knoblauch N, Marcus J H, Stephens M, He X. Mendelian randomization accounting for correlated and uncorrelated pleiotropic effects using genome-wide summary statistics. Nat Genet 2020; 52: 740-7.
32.
Verbanck M, Chen CY, Neale B, Do R. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet 2018; 50: 693-8.
33.
Feng Y, Liu X, Tan H. Causal association of peripheral immune cell counts and atrial fibrillation: a Mendelian randomization study. Front Cardiovasc Med 2023; 9: 1042938.
34.
Bowden J, Del Greco MF, Minelli C, Davey Smith G, Sheehan NA, Thompson JR. Assessing the suitability of summary data for two-sample Mendelian randomization analyses using MR-Egger regression: the role of the I 2 statistic. Int J Epidemiol 2016; 45: 1961-74.
35.
Carter AR, Sanderson E, Hammerton G, et al. Mendelian randomisation for mediation analysis: current methods and challenges for implementation. Eur J Epidemiol 2021; 36: 465-78.
36.
Jalava K, Sallinen V, Lampela H, et al. Role of preoperative in-hospital delay on appendiceal perforation while awaiting appendicectomy (PERFECT): a Nordic, pragmatic, open-label, multicentre, non-inferiority, randomised controlled trial. Lancet 2023; 402: 1552-61.
37.
Masahata K, Umemoto E, Kayama H, et al. Generation of colonic IgA-secreting cells in the caecal patch. Nat Commun 2014; 5: 3704.
38.
Mörbe UM, Jørgensen PB, Fenton TM, et al. Human gut-associated lymphoid tissues (GALT); diversity, structure, and function. Mucosal Immunol 2021; 14: 793-802.
39.
Cai S, Fan Y, Zhang B, et al. Appendectomy is associated with alteration of human gut bacterial and fungal communities. Front Microbiol 2021; 12: 724980.
40.
Kooij I, Sahami S, Meijer S, Buskens C, Te Velde A. The immunology of the vermiform appendix: a review of the literature. Clin Exp Immunol 2016; 186: 1-9.
41.
Sekula P, Fabiola Del Greco M, Pattaro C, Köttgen A. Mendelian randomization as an approach to assess causality using observational data. J Am Soc Nephrol 2016; 27: 3253-65.
42.
Luo J, Thomassen JQ, Bellenguez C, et al. Genetic associations between modifiable risk factors and Alzheimer disease. JAMA Network Open 2023; 6: e2313734.
43.
Dahabra L, Tallat M, Abouyassine A, Deeb L. S134 Does appendectomy alter the risk of colorectal cancer? a large population-based study in the United States. Am J Gastroenterol 2021; 116: S58-9.
44.
Lee S, Jang EJ, Jo J, Park SJ, Ryu HG. Long-term impacts of appendectomy associated with increased incidence of inflammatory bowel disease, infection, and colorectal cancer. Int J Colorectal Dis 2021; 36: 1643-52.
45.
Shi F, Liu G, Lin Y, Guo C l, Han J, She J. IDDF2021-ABS-0054 Appendectomy increases the risk of colorectal cancer through causing gut microbiota dysbiosis in a large population-based study. Gut 2021; 70: A17-9.
46.
Stellingwerf ME, de Koning MA, Pinkney T, Bemelman WA, D’Haens GR, Buskens CJ. The risk of colectomy and colorectal cancer after appendectomy in patients with ulcerative colitis: a systematic review and meta-analysis. J Crohn’s Colitis 2019; 13: 309-18.
47.
Wu SC, Chen WTL, Muo CH, Ke TW, Fang CW, Sung FC. Association between appendectomy and subsequent colorectal cancer development: an Asian population study. PLoS One 2015; 10: e0118411.
48.
Balan Y, Packirisamy RM, Mohanraj PS. High dietary salt intake activates inflammatory cascades via Th17 immune cells: impact on health and diseases. Arch Med Sci 2022; 18: 459-65.
49.
Aggeletopoulou I, Tsounis E P, Triantos C. Molecular mechanisms underlying IL-33-mediated inflammation in inflammatory bowel disease. Int J Mol Sci 2023; 24: 623.
50.
Murdaca G, Gangemi S, Greco M. The IL-33/IL-31 axis in allergic and immune-mediated diseases. Int J Mol Sci 2023; 24: 9227.
51.
Murdaca G, Tagliafico L, Page E, Paladin F, Gangemi S. Gender differences in the interplay between vitamin D and microbiota in allergic and autoimmune diseases. Biomedicines 2024; 12: 1023.
52.
Fu Q, Liao H, Li Z, Chen X, Zhang X, Di J. Preventive effects of 13 different drugs on colorectal cancer: a network meta-analysis. Arch Med Sci 2023; 19: 1428-45.
53.
Murdaca G, Greco M, Borro M, Gangemi S. Hygiene hypothesis and autoimmune diseases: a narrative review of clinical evidences and mechanisms. Autoimmun Rev 2021; 20: 102845.
Share
RELATED ARTICLE
| eISSN: | 1896-9151 |
| ISSN: | 1734-1922 |
We process personal data collected when visiting the website. The function of obtaining information about users and their behavior is carried out by voluntarily entered information in forms and saving cookies in end devices. Data, including cookies, are used to provide services, improve the user experience and to analyze the traffic in accordance with the Privacy policy. Data are also collected and processed by Google Analytics tool (more).
You can change cookies settings in your browser. Restricted use of cookies in the browser configuration may affect some functionalities of the website.
You can change cookies settings in your browser. Restricted use of cookies in the browser configuration may affect some functionalities of the website.
