Mendelian Randomization Reveals the Anatomical Site Differences and Reverse Causality in the Association Between Diverticular Disease and Colorectal Cancer

Mendelian Randomization Reveals the Anatomical Site Differences and Reverse Causality in the Association Between Diverticular Disease and Colorectal Cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Mendelian Randomization Reveals the Anatomical Site Differences and Reverse Causality in the Association Between Diverticular Disease and Colorectal Cancer Biaohui Zheng, Dongbo Chen, Hao Zeng, Shuangming Lin This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4930792/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose Colorectal cancer (CRC) is a leading global health concern due to its high incidence and mortality rates. Diverticular disease (DD), characterized by the formation of pouches in the colon wall, is prevalent in Western populations, and shares several risk factors with CRC. However, the causal relationship between DD and CRC, including its precancerous lesion, remains to be elucidated. Methods This study employed Mendelian randomization (MR) approach using genomic data from European cohort to investigate the potential causal link between DD and the risk of colorectal adenoma, CRC, and its anatomical subtypes (proximal colon cancer, distal colon cancer, and rectal cancer). Single nucleotide polymorphisms significantly associated with these conditions were utilized as instrumental variables in MR analysis to assess causality. Results The forward MR analysis indicated no significant causal effect of DD on the risk of colorectal adenoma (OR 0.87, 95% CI 0.74–1.03, p = 0.103), CRC (OR 0.94, 95% CI 0.87–1.02, p = 0.117), or its anatomical subtypes. In contrast, the reverse MR analysis showed that distal colon cancer may increase the risk of DD (OR 1.02, 95% CI 1-1.04, p = 0.026), while proximal colon cancer and rectal Cancer did not show this association. Conclusion The study findings do not support DD as a risk factor for CRC or its precancerous lesion (colorectal adenoma). However, a possible association between distal colon cancer and an increased risk of DD was found, providing new insights into the prevention and treatment of both diseases. Diverticular Disease Colorectal Cancer Colorectal Adenoma Precancerous Lesion Mendelian Randomization Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Colorectal cancer (CRC) represents the third most common malignant tumor worldwide, exhibiting a high incidence and mortality rate for decades. The latest statistics indicate that in 2020, the number of new CRC cases worldwide reached an alarming 1.93 million, resulting in 935,200 deaths 1 . Furthermore, the global incidence of colorectal adenoma, a critical precancerous lesion to CRC, is also increasing. In 2020, the overall incidence reached 23.9% 2 . The high morbidity and mortality rates associated with CRC and its precancerous lesion continue to exert a considerable socio-economic burden, despite the rapid advancements in global medical technology. Diverticular disease (DD), a disease that is typified by the formation of cystic bulges in the colonic wall, is particularly prevalent in Western countries 3 . According to authoritative statistics, the prevalence of DD has reached 30% in the 50-year-old age group and has increased to over 70% in the 80-year-old and above age group 4 . The high prevalence of DD undoubtedly places a substantial financial burden on the healthcare system. In the United States, for instance, the financial burden of comprehensive treatment for DD is estimated to be as high as $2.6 billion per year, underscoring its considerable impact on public health 5 . It is noteworthy that DD and CRC share a number of risk factors, including, but not limited to, low-fiber dietary habits, high red meat intake, sedentary lifestyle, obesity status, and maladaptive behaviors such as smoking 67 . Despite the clinical manifestations differences between the two diseases, their anatomical proximity and the presence of several epidemiological clues have prompted an in-depth exploration of a potential link between them 8 . Nevertheless, a consensus on the findings of this association has yet to be reached, which may be attributed to discrepancies in design methodology, sample size, and the control of confounding factors across different studies 9 1011 . To explore more deeply the potential causal relationship between DD and colorectal cancer/adenoma, we introduced the cutting-edge statistical method of bidirectional two-sample Mendelian randomization (MR). This method draws on genetic variants from genome-wide association studies (GWAS) as instrumental variables (IV), aiming to reveal causal associations between exposures and outcomes 12 . This innovative approach can not only analyze the effect of DD on CRC and colorectal adenoma, explores the role of CRC and colorectal adenoma on DD in reverse, providing new research perspectives and tools for a deeper understanding of this complex biological relationship. Materials and methods Study design This study aims to explore the possible causal relationship between DD and colorectal cancer/adenoma by using a bidirectional two-sample MR method. Specifically, forward MR analysis focused on the potential impact of DD on the development of colorectal adenoma and CRC, whereas reverse MR explored whether colorectal adenoma and CRC promote DD. Within this framework, we selected single nucleotide polymorphism (SNP) strongly associated with DD, colorectal adenoma, and CRC as IVs to infer causal effects between them. To ensure the validity of the IVs, this study strictly followed the three core assumptions of MR analysis (Figure 1): 1. The "correlation" assumption, where IVs are strongly associated with exposure factors (DD, colorectal adenoma and CRC); 2. The "independence" assumption, IVs are not associated with confounders;3. The "exclusivity" assumption, where IVs are not associated with the outcome (another disease). Datasets The GWAS data for DD used in this study were derived from the latest DF11 version of the FinnGen database, is a large-scale genomics initiative that has analyzed over 500,000 Finnish biobank samples and correlated genetic variation with health data to understand disease mechanisms and predispositions. The project is a collaboration between research organisations and biobanks within Finland and international industry partners 13 . For colorectal adenoma GWAS data, we use the GWAS Explorer, is a publicly available webtool developed and hosted by the Division of Cancer Epidemiology and Genetics, National Cancer Institute, part of the National Institutes of Health, which aggregates association data for 90 traits and more than 78 million genomic markers, with a special focus on cancer and its associated phenotypes 14 . For CRC GWAS data, we selected "ebi-a-GCST90018808" from the IEU Open GWAS project, which included a total of 470,002 samples, including 6,581 experimental and 463,421 control subjects. In addition, to further refine the stratified analysis of CRC, GWAS data for proximal colon cancer (cecum, ascending colon, hepatic flexure, transverse colon, or splenic flexure), distal colon cancer (descending colon or sigmoid colon), and rectal cancer were also obtained from GWAS Explorer. It is noteworthy that all subjects in the aforementioned studies had a background of European ancestry. (Table 1). Selection of IVs To ensure the accuracy and reliability of inferring a causal relationship between DD and colorectal adenoma/cancer, we carefully screened SNPs that were significantly associated with exposure factors as IVs. During the screening process, we initially set a stringent threshold condition: 1. Threshold p-value < 5×10 -8 ; 2. Compliance with linkage disequilibrium (LD) with R 2 10,000; 3. F-statistic＞10.However, due to the limited number of SNPs meeting the above criteria, we moderately relaxed the p-value criterion for colorectal adenoma, proximal colon cancers, distal colon cancers, and rectal cancers to p-value <5×10 -6 . On this basis, we leveraged the "MR-PRESSO" tool to detect and eliminate potential outliers among the SNPs. This approach ensured the identification and rejection of anomalous observations. Finally, we further excluded SNPs that may be significantly associated with potential confounding factors (such as body mass index, high-fat diet, and smoking) (https://ldlink.nih.gov/?tab=home) through the LDlink platform to ensure the purity and effectiveness of the IVs. MR analysis In assessing the causal relationship between DD and colorectal adenoma/cancer, we used several MR analysis methods, including Inverse variance weighted (IVW), MR-Egger, Weighted median, Simple mode, Weighted mode, and Leave-one-out sensitivity analysis. Among them, IVW as the main analytical method in this study, is based on the assumption premise that all IVs are valid variables, and the combined causal estimates are derived by combining the Wald ratios of all IVs 15 . If the resulting p-value <0.05, we consider that there is a potential causal relationship between the two. Furthermore, the MR-Egger method was employed to ascertain the existence of horizontal pleiotropy. When the intercept of an MR-Egger regression is not zero, it may indicate the potential for horizontal pleiotropy, which could challenge the fundamental assumptions of the MR analyses. Leave-one-out sensitivity analysis was conducted to assess the dependence of the results on a IV and the stability of the results. This was achieved by eliminating each SNP one by one and re-performing the MR analysis. We also assessed the heterogeneity among IVs using IVW and MR-Egger's Q statistic; p-valu e <0.05 for the heterogeneity test indicates significant heterogeneity among IVs. All analyses were performed using "TwoSampleMR", "MRPRESSO", "ggplot2" and "foreach" in R 4.3.2. "foreach" software packages in R 4.3.2. Results Selection of IVs In accordance with the established criteria, a total of 49, 14, 18, 7, 8, and 6 SNPs were identified as IVs for the following diseases: DD, colorectal adenoma, CRC, proximal colon cancer, distal colon cancer, and rectal cancer, respectively. The specific screening results are presented in the Supplementary Tables 1-6. Causal assessment of DD on colorectal adenoma and CRC in forward MR analysis Figure 2 demonstrates the IVW results of the forward MR analysis. The analysis showed that no significant causal relationship was observed between DD on colorectal adenoma (OR 0.87, 95% CI 0.74-1.03, p =0.103) and CRC (OR 0.94, 95% CI 0.87-1.02, p =0.117). A further stratified analysis of CRC yielded similar results, with no observed causal effect on proximal colon cancer (OR, 95% CI 0.74-1.29, p =0.844), distal colon cancer (OR 0.86, 95% CI 0.58-1.28, p =0.455), or rectal cancer (OR 0.86, 95% CI 0.43-1.11, p =0.128). In addition, the results of the other MR methods were consistent with IVW, and detailed results are shown in Supplementary Table 7. Meanwhile, we have provided a visual representation of the MR results through scatter plots (Figure 3). Causal assessment of colorectal adenoma and CRC on DD in inverse MR analysis Figure 4 demonstrates the IVW results of the reverse MR analysis. Preliminary analysis showed that neither colorectal adenoma (OR 1.04, 95% CI 1-1.09, p =0.059) nor CRC (OR 1.04, 95% CI 0.99-1.09, p =0.160) exhibited a significant causal effect on DD. However, after further stratification of CRC, positive results were obtained. Although proximal colon cancer (OR 0.99, 95% CI 0.96-1.02, p =0.578) and rectal cancer (OR 1.00, 95% CI 0.99-1.02, p =0.715) similarly had no effect on DD, distal colon cancer (OR 1.02, 95% CI 1-1.04, p =0.026) showed a trend towards increased risk of DD. The scatter plot of distal colon cancer also confirmed the consistency of other MR methods with the IVW direction (Figure 5). For the results of other MR methods in the reverse MR analysis, refer to Supplementary Table 8. Heterogeneity and Pleiotropy Furthermore, a heterogeneity test was conducted on all IVs, and the results demonstrated that no significant heterogeneity ( P > 0.05) (Table 2). Concurrently, the test for horizontal pleiotropy likewise did not identify any significant pleiotropy among the IVs ( P >0.05). Ultimately, we employed the leave-one-out sensitivity analysis, forest plot, and funnel plot to comprehensively visualize all IVs and MR results (Supplementary Figure 1-6). Discussion The findings of this study indicate that there is no significant correlation between DD and the risk of developing colorectal adenoma and CRC. Conversely, the study observed that distal colon cancer increased the risk of DD, while this phenomenon did not occur in proximal colon cancer and rectal cancer. This finding is of great significance for further analysis of the potential association between DD and CRC and its precancerous lesion. It is expected to provide key guidance and inspiration for future research and clinical diagnosis and treatment strategies. The occurrence of colorectal tumors is the result of a complex interplay between genetic and environmental factors, as well as multiple pathophysiological mechanisms. These factors include physical activity, dietary habits, obesity, smoking habits, inflammatory response, and the composition of the gut microbiota 16171819 . It is noteworthy that several studies have indicated that DD and CRC may have a shared underlying pathogenesis. For example, an increase in dietary fiber intake can reduce the risk of CRC by lowering the pH of the stool through fermentation, which can inhibit the production of bacterial carcinogens produced by bile acid metabolism 20 . Similarly, inadequate dietary fiber intake can result in constipation, which can elevate the pressure within the intestinal lumen and facilitate the formation of diverticula 21 . Furthermore, obesity not only directly increases the risk of CRC but also the increased intra-abdominal pressure caused by the accumulation of visceral fat is considered an important contributing factor to the development of DD 2223 . In view of the above findings, extensive and in-depth studies have been conducted to investigate whether the manifestation of the association between them is confounded by confounding factors as well as the same pathogenic factors, or it is indeed a causal relationship. Previous retrospective studies have suggested that DD may have a potential impact on the risk of colorectal adenoma 2425 . For example, one study involving 2,223 patients showed that the prevalence of colorectal adenoma was higher in patients with DD than in normal patients 9 . However, it is worth noting that these studies have limitations in terms of sample selection, as most of the patients included in the study had already shown some symptoms before undergoing colonoscopy, which inevitably introduces selection bias. To overcome this limitation, Peery conducted a prospective study that not only included asymptomatic patients, but also took into account a variety of potential confounding factors, such as age, gender, and dietary habits 10 . In the end, the study found no association between DD and an increased risk of colorectal adenoma. This conclusion was also supported by a large cross-sectional study conducted in the Netherlands, which included 4,241 patients and further verified that DD does not increase the risk of adenoma through age-stratified analysis 26 . Furthermore, Lee summarized the results of several studies in a meta-analysis and came to the same conclusion 27 . In summary, based on this high-quality evidence and our own findings, we can conclude that there is no causal link between DD and colorectal adenoma. The association between DD and CRC risk has been extensively studied. Although a few studies have suggested a link, the vast majority of studies have shown that DD does not directly increase the risk of CRC 8 . A large retrospective study in Taiwan involving 41,359 patients clearly did not find a direct link between DD and subsequent CRC risk 28 . This view is further supported by a meta-analysis of multiple studies, which combined the results of four cross-sectional studies, two case-control studies and one cohort study and came to a similar conclusion 29 . Our MR analysis not only reached the same conclusion, verified through a stratified analysis that DD is not significantly associated with CRC in different anatomical locations. However, there are relatively limited studies on the possible reverse effect between them. Our study revealed a differential effect of different colon cancer sites on DD, which may be due to the unique anatomical and tumor-physiological characteristics of each colon region 30 . Specifically, the proximal colon is less likely to cause obstruction due to its large lumen and the common polypoid tumor morphology. The distal colon is more likely to cause intestinal obstruction due to its smaller lumen and the tumor morphology of annular infiltrative growth. The accompanying increase in intestinal lumen pressure and local inflammatory response may change the mechanical properties of the colon wall, destroy its structural integrity, and promote the formation of diverticula 31 . In addition, the gut microbiota composition is different in different parts of the colon. These microbiotas produce short-chain fatty acids (such as acetate, propionate and butyrate), through fermentation of dietary fiber. These substances play an important role in maintaining intestinal health 3233 . It is worth noting that the concentration of butyrate in the distal colon is lower than that in the proximal colon, which may make the impact of distal colon cancer on DD more significant 34 . In summary, although our study has preliminarily revealed the complex relationship between distal colon cancer and DD, the exact causal relationship between them and the underlying biological mechanisms still needs to be further elucidated through more in-depth prospective studies. This study has significant advantages. Firstly, it used a bidirectional two-sample MR design, which effectively reduces the potential impact of confounding factors and reverse causality in traditional epidemiological studies. Secondly, with the advantage of a large sample size, this study has sufficient statistical power. Thirdly, this study further revealed the differences in the effects of tumors in different parts of the colon on DD by performing a stratified analysis of colorectal cancer. Finally, by focusing on European descent, the study effectively reduced the impact of ethnic differences on the results. Certainly, we must also face the limitations of this study. Firstly, due to the lack of key information on age, gender, lifestyle habits, and comorbidities in the data set, the study was unable to conduct more in-depth stratified analysis of the data and may face unknown confounding factors. Secondly, the results of this study may not be applicable to other ethnic groups and geographic regions, and their applicability needs to be further verified in a wider population. Therefore, based on the limitations of this study, future studies should aim to expand the sample size to include more ethnic groups and geographic regions. At the same time, more genetic variants and potential environmental factors should be considered in depth to achieve a more comprehensive assessment of the relationship between DD and CRC and its precancerous lesion. Conclusion The results of this study do not support DD as a direct risk factor for CRC and its precancerous lesion (colorectal adenoma). On the contrary, our findings indicate that the impact of CRC on DD varies by anatomical location. Specifically, distal colon cancer was associated with an increased risk of DD, whereas proximal colon cancer and rectal cancer did not show a similar correlation. This reminds us that DD should not be overemphasized as a prevention focus for CRC. Instead, it may be necessary to consider the possibility of DD in the treatment of distal colon cancer, and then develop different treatment plans and differentiated management of patients. Declarations Funding The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. Competing Interests The authors have no relevant financial or non-financial interests to disclose. Author Contributions Biaohui Zheng: Data curation (equal); formal analysis (equal); investigation (equal); project administration (equal); writing – original draft (lead). Dongbo Chen: Data curation (equal); formal analysis (equal); project administration (equal). Hao Zeng: Data curation (equal). Shuangming Lin: Data curation (equal); writing – review and editing (equal). Data Availability The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. Ethics approval This study is a secondary analysis of public data, and the study of data sources has been approved by the appropriate ethics committee. Consent to participate Not applicable. Consent to publish Not applicable. References Sung, H., Ferlay, J., Siegel, R. L., Laversanne, M., Soerjomataram, I., Jemal, A., & Bray, F. (2021). Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: a cancer journal for clinicians, 71(3), 209–249. Wong, M. C. S., Huang, J., Huang, J. L. W., Pang, T. W. Y., Choi, P., Wang, J., Chiang, J. I., & Jiang, J. Y. (2020). 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The role of short-chain fatty acids in health and disease. Advances in immunology, 121, 91–119. https://doi.org/10.1016/B978-0-12-800100-4.00003-9 Tables Table 1 and 2 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1.xlsx Table2.xlsx SupplementaryFigure16.pdf SupplementaryTable18.xlsx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4930792","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":354641155,"identity":"c1274093-dbd5-4be2-9ce5-3746ea68aab5","order_by":0,"name":"Biaohui Zheng","email":"","orcid":"","institution":"Longyan First Hospital","correspondingAuthor":false,"prefix":"","firstName":"Biaohui","middleName":"","lastName":"Zheng","suffix":""},{"id":354641156,"identity":"bea2e508-9117-4be7-8c3c-b1d722eb99ab","order_by":1,"name":"Dongbo Chen","email":"","orcid":"","institution":"Longyan First Hospital","correspondingAuthor":false,"prefix":"","firstName":"Dongbo","middleName":"","lastName":"Chen","suffix":""},{"id":354641157,"identity":"cdf80479-538b-465a-88c9-c763250fc0bb","order_by":2,"name":"Hao Zeng","email":"","orcid":"","institution":"Longyan First Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hao","middleName":"","lastName":"Zeng","suffix":""},{"id":354641158,"identity":"cb6a0db2-8408-4086-8669-5177cc218432","order_by":3,"name":"Shuangming Lin","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4klEQVRIiWNgGAWjYDCCAwyMBxIYauT42RsfGEBFCGphAGo5ZizZc9iABC0MDMyJBjeSDeAieAHf8eYHBx7uYEswuPmYoehmG4Mc340Exs8FeLRInjlmcCDxjEye5O1kBuPcNgZjyRsJzNIz8GgxuJHDcCCxja2Y73b+AZCWxA03EtiYeQhrYU5suHkYbEs98Vom3GAGa0kwIKQF4pc2UCAD/ZJzTsJw5pmHzdL4tABD7OHDn22gqDzMZpxTZiPPdzz54Gd8WpABGzBiJIA0YwORGoDx+YBopaNgFIyCUTCiAACR0FO39hE+/wAAAABJRU5ErkJggg==","orcid":"","institution":"Longyan First Hospital","correspondingAuthor":true,"prefix":"","firstName":"Shuangming","middleName":"","lastName":"Lin","suffix":""}],"badges":[],"createdAt":"2024-08-17 17:25:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4930792/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4930792/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":65111629,"identity":"2cca0c91-8e3c-4ad5-8601-341496077124","added_by":"auto","created_at":"2024-09-23 18:14:09","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":186412,"visible":true,"origin":"","legend":"\u003cp\u003eSchematic design of Mendelian randomization. Mendelian randomization requires valid genetic instrumental variables satisfying three assumptions.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4930792/v1/80ed30ec4c5d01dbb96b6aad.jpg"},{"id":65111908,"identity":"e7852b86-a117-4b71-8d56-5d4fe2eff3aa","added_by":"auto","created_at":"2024-09-23 18:22:09","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":90071,"visible":true,"origin":"","legend":"\u003cp\u003eThe IVW results of the forward MR analysis. OR: Odds ratios; CI: Confidence interval.\u003c/p\u003e","description":"","filename":"OnlineFigure2.png","url":"https://assets-eu.researchsquare.com/files/rs-4930792/v1/6ab4c5d660e47cc86a4ec3f7.png"},{"id":65111633,"identity":"69cdbd21-7d7f-413f-9738-f825ae78540f","added_by":"auto","created_at":"2024-09-23 18:14:09","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":276512,"visible":true,"origin":"","legend":"\u003cp\u003eScatter plot of diverticular disease on the causality of colorectal adenoma and cancer. (a) Colorectal Adenoma;(b) CRC;(c) Proximal Colon Cancer;(d) Distal Colon Cancer (e) Rectal Cancer.\u003c/p\u003e","description":"","filename":"OnlineFigure3.png","url":"https://assets-eu.researchsquare.com/files/rs-4930792/v1/fb00e12ab6f164a1d5928f9f.png"},{"id":65111631,"identity":"a38a9320-bdda-476a-b111-e13a9908169c","added_by":"auto","created_at":"2024-09-23 18:14:09","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":88509,"visible":true,"origin":"","legend":"\u003cp\u003eThe IVW results of the reverse MR analysis. OR: Odds ratios; CI: Confidence interval.\u003c/p\u003e","description":"","filename":"OnlineFigure4.png","url":"https://assets-eu.researchsquare.com/files/rs-4930792/v1/2368d06a03088380b81959a2.png"},{"id":65111910,"identity":"8f6d840c-15a3-4714-9628-9bab3f28ab31","added_by":"auto","created_at":"2024-09-23 18:22:10","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":272335,"visible":true,"origin":"","legend":"\u003cp\u003eScatter plot of colorectal adenoma and cancer on the causality of diverticular disease. (a) Colorectal Adenoma;(b) CRC;(c) Proximal Colon Cancer;(d) Distal Colon Cancer;(e) Rectal Cancer.\u003c/p\u003e","description":"","filename":"OnlineFigure5.png","url":"https://assets-eu.researchsquare.com/files/rs-4930792/v1/4799b523d259bef5e6456312.png"},{"id":65925147,"identity":"8903fa93-3e07-4bf0-9e3c-fb0b980353c3","added_by":"auto","created_at":"2024-10-04 12:47:16","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1750648,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4930792/v1/428e1608-d80a-4891-a0a0-d62741359ca1.pdf"},{"id":65111628,"identity":"f0b5acb9-16e1-46bd-ad87-c73097d45a93","added_by":"auto","created_at":"2024-09-23 18:14:09","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":11097,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4930792/v1/f16aa3dc8d5d61b0de5a4508.xlsx"},{"id":65111909,"identity":"eef462c6-4e41-414a-81ae-fb721136eee9","added_by":"auto","created_at":"2024-09-23 18:22:09","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":11907,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4930792/v1/b3d298c0f05c767c71fb0d88.xlsx"},{"id":65111634,"identity":"b9dd6158-fa5d-4bb9-88b7-30dd7acafc00","added_by":"auto","created_at":"2024-09-23 18:14:09","extension":"pdf","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":2172487,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigure16.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4930792/v1/0f644809584290d3ce1c6bc8.pdf"},{"id":65111635,"identity":"0b4f1420-1a16-4adf-abfc-ff082dd1758d","added_by":"auto","created_at":"2024-09-23 18:14:09","extension":"xlsx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":31110,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable18.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4930792/v1/51c425a3668cd36c4a7aaaca.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Mendelian Randomization Reveals the Anatomical Site Differences and Reverse Causality in the Association Between Diverticular Disease and Colorectal Cancer","fulltext":[{"header":"Introduction","content":"\u003cp\u003eColorectal cancer (CRC) represents the third most common malignant tumor worldwide, exhibiting a high incidence and mortality rate for decades. The latest statistics indicate that in 2020, the number of new CRC cases worldwide reached an alarming 1.93 million, resulting in 935,200 deaths\u003csup\u003e1\u003c/sup\u003e. Furthermore, the global incidence of colorectal adenoma, a critical precancerous lesion to CRC, is also increasing. In 2020, the overall incidence reached 23.9%\u003csup\u003e2\u003c/sup\u003e. The high morbidity and mortality rates associated with CRC and its precancerous lesion continue to exert a considerable socio-economic burden, despite the rapid advancements in global medical technology.\u003c/p\u003e\n\u003cp\u003eDiverticular disease (DD), a disease that is typified by the formation of cystic bulges in the colonic wall, is particularly prevalent in Western countries\u003csup\u003e3\u003c/sup\u003e. According to authoritative statistics, the prevalence of DD has reached 30% in the 50-year-old age group and has increased to over 70% in the 80-year-old and above age group\u003csup\u003e4\u003c/sup\u003e. The high prevalence of DD undoubtedly places a substantial financial burden on the healthcare system. In the United States, for instance, the financial burden of comprehensive treatment for DD is estimated to be as high as $2.6 billion per year, underscoring its considerable impact on public health\u003csup\u003e5\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eIt is noteworthy that DD and CRC share a number of risk factors, including, but not limited to, low-fiber dietary habits, high red meat intake, sedentary lifestyle, obesity status, and maladaptive behaviors such as smoking\u003csup\u003e67\u003c/sup\u003e. Despite the clinical manifestations differences between the two diseases, their anatomical proximity and the presence of several epidemiological clues have prompted an in-depth exploration of a potential link between them\u003csup\u003e8\u003c/sup\u003e. Nevertheless, a consensus on the findings of this association has yet to be reached, which may be attributed to discrepancies in design methodology, sample size, and the control of confounding factors across different studies\u003csup\u003e9\u003c/sup\u003e\u003csup\u003e1011\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eTo explore more deeply the potential causal relationship between DD and colorectal cancer/adenoma, we introduced the cutting-edge statistical method of bidirectional two-sample Mendelian randomization (MR). This method draws on genetic variants from genome-wide association studies (GWAS) as instrumental variables (IV), aiming to reveal causal associations between exposures and outcomes\u003csup\u003e12\u003c/sup\u003e. This innovative approach can not only analyze the effect of DD on CRC and colorectal adenoma, explores the role of CRC and colorectal adenoma on DD in reverse, providing new research perspectives and tools for a deeper understanding of this complex biological relationship.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003e\u003cstrong\u003eStudy design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study aims to explore the possible causal relationship between DD and colorectal cancer/adenoma by using a bidirectional two-sample MR method. Specifically, forward MR analysis focused on the potential impact of DD on the development of colorectal adenoma and CRC, whereas reverse MR explored whether colorectal adenoma and CRC promote DD. Within this framework, we selected single nucleotide polymorphism (SNP) strongly associated with DD, colorectal adenoma, and CRC as IVs to infer causal effects between them. To ensure the validity of the IVs, this study strictly followed the three core assumptions of MR analysis (Figure 1): 1. The \u0026quot;correlation\u0026quot; assumption, where IVs are strongly associated with exposure factors (DD, colorectal adenoma and CRC); 2. The \u0026quot;independence\u0026quot; assumption, IVs are not associated with confounders;3. The \u0026quot;exclusivity\u0026quot; assumption, where IVs are not associated with the outcome (another disease).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDatasets\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe GWAS data for DD used in this study were derived from the latest DF11 version of the FinnGen database, is a large-scale genomics initiative that has analyzed over 500,000 Finnish biobank samples and correlated genetic variation with health data to understand disease mechanisms and predispositions. The project is a collaboration between research organisations and biobanks within Finland and international industry partners\u003csup\u003e13\u003c/sup\u003e. For colorectal adenoma GWAS data, we use the GWAS Explorer, is a publicly available webtool developed and hosted by the Division of Cancer Epidemiology and Genetics, National Cancer Institute, part of the National Institutes of Health, which aggregates association data for 90 traits and more than 78 million genomic markers, with a special focus on cancer and its associated phenotypes\u003csup\u003e14\u003c/sup\u003e. For CRC GWAS data, we selected \u0026quot;ebi-a-GCST90018808\u0026quot; from the IEU Open GWAS project, which included a total of 470,002 samples, including 6,581 experimental and 463,421 control subjects. In addition, to further refine the stratified analysis of CRC, GWAS data for proximal colon cancer (cecum, ascending colon, hepatic flexure, transverse colon, or splenic flexure), distal colon cancer (descending colon or sigmoid colon), and rectal cancer were also obtained from GWAS Explorer. It is noteworthy that all subjects in the aforementioned studies had a background of European ancestry. (Table 1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSelection of IVs\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo ensure the accuracy and reliability of inferring a causal relationship between DD and colorectal adenoma/cancer, we carefully screened SNPs that were significantly associated with exposure factors as IVs. During the screening process, we initially set a stringent threshold condition: 1. Threshold \u003cem\u003ep-value\u0026nbsp;\u003c/em\u003e\u0026lt; 5\u0026times;10\u003csup\u003e-8\u0026nbsp;\u003c/sup\u003e; 2. Compliance with linkage disequilibrium (LD) with R\u003csup\u003e2\u003c/sup\u003e \u0026lt; 0.001 and LD \u0026gt; 10,000; 3. F-statistic＞10.However, due to the limited number of SNPs meeting the above criteria, we moderately relaxed the \u003cem\u003ep-value\u003c/em\u003e criterion for colorectal adenoma, proximal colon cancers, distal colon cancers, and rectal cancers to \u003cem\u003ep-value\u003c/em\u003e\u0026lt;5\u0026times;10\u003csup\u003e-6\u003c/sup\u003e. On this basis, we leveraged the \u0026quot;MR-PRESSO\u0026quot; tool to detect and eliminate potential outliers among the SNPs. This approach ensured the identification and rejection of anomalous observations. Finally, we further excluded SNPs that may be significantly associated with potential confounding factors (such as body mass index, high-fat diet, and smoking) (https://ldlink.nih.gov/?tab=home) through the LDlink platform to ensure the purity and effectiveness of the IVs.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMR analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn assessing the causal relationship between DD and colorectal adenoma/cancer, we used several MR analysis methods, including Inverse variance weighted (IVW), MR-Egger, Weighted median, Simple mode, Weighted mode, and Leave-one-out sensitivity analysis. Among them, IVW as the main analytical method in this study, is based on the assumption premise that all IVs are valid variables, and the combined causal estimates are derived by combining the Wald ratios of all IVs\u003csup\u003e15\u003c/sup\u003e. If the resulting \u003cem\u003ep-value\u003c/em\u003e\u0026lt;0.05, we consider that there is a potential causal relationship between the two. Furthermore, the MR-Egger method was employed to ascertain the existence of horizontal pleiotropy. When the intercept of an MR-Egger regression is not zero, it may indicate the potential for horizontal pleiotropy, which could challenge the fundamental assumptions of the MR analyses. Leave-one-out sensitivity analysis was conducted to assess the dependence of the results on a IV and the stability of the results. This was achieved by eliminating each SNP one by one and re-performing the MR analysis. We also assessed the heterogeneity among IVs using IVW and MR-Egger\u0026apos;s Q statistic; \u003cem\u003ep-valu\u003c/em\u003ee \u0026lt;0.05 for the heterogeneity test indicates significant heterogeneity among IVs. All analyses were performed using \u0026quot;TwoSampleMR\u0026quot;, \u0026quot;MRPRESSO\u0026quot;, \u0026quot;ggplot2\u0026quot; and \u0026quot;foreach\u0026quot; in R 4.3.2. \u0026quot;foreach\u0026quot; software packages in R 4.3.2.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eSelection of IVs\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn accordance with the established criteria, a total of 49, 14, 18, 7, 8, and 6 SNPs were identified as IVs for the following diseases: DD, colorectal adenoma, CRC, proximal colon cancer, distal colon cancer, and rectal cancer, respectively. The specific screening results are presented in the Supplementary Tables 1-6.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCausal assessment of DD on colorectal adenoma and CRC in forward MR analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFigure 2 demonstrates the IVW results of the forward MR analysis. The analysis showed that no significant causal relationship was observed between DD on colorectal adenoma (OR 0.87, 95% CI 0.74-1.03, \u003cem\u003ep\u003c/em\u003e=0.103) and CRC (OR 0.94, 95% CI 0.87-1.02, \u003cem\u003ep\u003c/em\u003e=0.117). A further stratified analysis of CRC yielded similar results, with no observed causal effect on proximal colon cancer (OR, 95% CI 0.74-1.29, \u003cem\u003ep\u003c/em\u003e=0.844), distal colon cancer (OR 0.86, 95% CI 0.58-1.28, \u003cem\u003ep\u003c/em\u003e=0.455), or rectal cancer (OR 0.86, 95% CI 0.43-1.11, \u003cem\u003ep\u003c/em\u003e=0.128). In addition, the results of the other MR methods were consistent with IVW, and detailed results are shown in Supplementary Table 7. Meanwhile, we have provided a visual representation of the MR results through scatter plots (Figure 3).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCausal assessment of colorectal adenoma and CRC on DD in inverse MR analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFigure 4 demonstrates the IVW results of the reverse MR analysis. Preliminary analysis showed that neither colorectal adenoma (OR 1.04, 95% CI 1-1.09, \u003cem\u003ep\u003c/em\u003e=0.059) nor CRC (OR 1.04, 95% CI 0.99-1.09, \u003cem\u003ep\u003c/em\u003e=0.160) exhibited a significant causal effect on DD. However, after further stratification of CRC, positive results were obtained. Although proximal colon cancer (OR 0.99, 95% CI 0.96-1.02, \u003cem\u003ep\u003c/em\u003e=0.578) and rectal cancer (OR 1.00, 95% CI 0.99-1.02, \u003cem\u003ep\u003c/em\u003e=0.715) similarly had no effect on DD, distal colon cancer (OR 1.02, 95% CI 1-1.04, \u003cem\u003ep\u003c/em\u003e=0.026) showed a trend towards increased risk of DD. The scatter plot of distal colon cancer also confirmed the consistency of other MR methods with the IVW direction (Figure 5). For the results of other MR methods in the reverse MR analysis, refer to Supplementary Table 8.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHeterogeneity and Pleiotropy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFurthermore, a heterogeneity test was conducted on all IVs, and the results demonstrated that no significant heterogeneity (\u003cem\u003eP\u0026nbsp;\u003c/em\u003e\u0026gt; 0.05) (Table 2). Concurrently, the test for horizontal pleiotropy likewise did not identify any significant pleiotropy among the IVs (\u003cem\u003eP\u0026nbsp;\u003c/em\u003e\u0026gt;0.05). Ultimately, we employed the leave-one-out sensitivity analysis, forest plot, and funnel plot to comprehensively visualize all IVs and MR results (Supplementary Figure 1-6).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe findings of this study indicate that there is no significant correlation between DD and the risk of developing colorectal adenoma and CRC. Conversely, the study observed that distal colon cancer increased the risk of DD, while this phenomenon did not occur in proximal colon cancer and rectal cancer. This finding is of great significance for further analysis of the potential association between DD and CRC and its precancerous lesion. It is expected to provide key guidance and inspiration for future research and clinical diagnosis and treatment strategies.\u003c/p\u003e\n\u003cp\u003eThe occurrence of colorectal tumors is the result of a complex interplay between genetic and environmental factors, as well as multiple pathophysiological mechanisms. These factors include physical activity, dietary habits, obesity, smoking habits, inflammatory response, and the composition of the gut microbiota\u003csup\u003e16171819\u003c/sup\u003e. It is noteworthy that several studies have indicated that DD and CRC may have a shared underlying pathogenesis. For example, an increase in dietary fiber intake can reduce the risk of CRC by lowering the pH of the stool through fermentation, which can inhibit the production of bacterial carcinogens produced by bile acid metabolism\u003csup\u003e20\u003c/sup\u003e. Similarly, inadequate dietary fiber intake can result in constipation, which can elevate the pressure within the intestinal lumen and facilitate the formation of diverticula\u003csup\u003e21\u003c/sup\u003e. Furthermore, obesity not only directly increases the risk of CRC but also the increased intra-abdominal pressure caused by the accumulation of visceral fat is considered an important contributing factor to the development of DD\u003csup\u003e2223\u003c/sup\u003e. In view of the above findings, extensive and in-depth studies have been conducted to investigate whether the manifestation of the association between them is confounded by confounding factors as well as the same pathogenic factors, or it is indeed a causal relationship.\u003c/p\u003e\n\u003cp\u003ePrevious retrospective studies have suggested that DD may have a potential impact on the risk of colorectal adenoma\u003csup\u003e2425\u003c/sup\u003e. For example, one study involving 2,223 patients showed that the prevalence of colorectal adenoma was higher in patients with DD than in normal patients\u003csup\u003e9\u003c/sup\u003e. However, it is worth noting that these studies have limitations in terms of sample selection, as most of the patients included in the study had already shown some symptoms before undergoing colonoscopy, which inevitably introduces selection bias. To overcome this limitation, Peery conducted a prospective study that not only included asymptomatic patients, but also took into account a variety of potential confounding factors, such as age, gender, and dietary habits\u003csup\u003e10\u003c/sup\u003e. In the end, the study found no association between DD and an increased risk of colorectal adenoma. This conclusion was also supported by a large cross-sectional study conducted in the Netherlands, which included 4,241 patients and further verified that DD does not increase the risk of adenoma through age-stratified analysis\u003csup\u003e26\u003c/sup\u003e. Furthermore, Lee summarized the results of several studies in a meta-analysis and came to the same conclusion\u003csup\u003e27\u003c/sup\u003e. In summary, based on this high-quality evidence and our own findings, we can conclude that there is no causal link between DD and colorectal adenoma.\u003c/p\u003e\n\u003cp\u003eThe association between DD and CRC risk has been extensively studied. Although a few studies have suggested a link, the vast majority of studies have shown that DD does not directly increase the risk of CRC\u003csup\u003e8\u003c/sup\u003e. A large retrospective study in Taiwan involving 41,359 patients clearly did not find a direct link between DD and subsequent CRC risk\u003csup\u003e28\u003c/sup\u003e. This view is further supported by a meta-analysis of multiple studies, which combined the results of four cross-sectional studies, two case-control studies and one cohort study and came to a similar conclusion\u003csup\u003e29\u003c/sup\u003e. Our MR analysis not only reached the same conclusion, verified through a stratified analysis that DD is not significantly associated with CRC in different anatomical locations. However, there are relatively limited studies on the possible reverse effect between them. Our study revealed a differential effect of different colon cancer sites on DD, which may be due to the unique anatomical and tumor-physiological characteristics of each colon region\u003csup\u003e30\u003c/sup\u003e. Specifically, the proximal colon is less likely to cause obstruction due to its large lumen and the common polypoid tumor morphology. The distal colon is more likely to cause intestinal obstruction due to its smaller lumen and the tumor morphology of annular infiltrative growth. The accompanying increase in intestinal lumen pressure and local inflammatory response may change the mechanical properties of the colon wall, destroy its structural integrity, and promote the formation of diverticula\u003csup\u003e31\u003c/sup\u003e. In addition, the gut microbiota composition is different in different parts of the colon. These microbiotas produce short-chain fatty acids (such as acetate, propionate and butyrate), through fermentation of dietary fiber. These substances play an important role in maintaining intestinal health\u003csup\u003e3233\u003c/sup\u003e. It is worth noting that the concentration of butyrate in the distal colon is lower than that in the proximal colon, which may make the impact of distal colon cancer on DD more significant\u003csup\u003e34\u003c/sup\u003e. In summary, although our study has preliminarily revealed the complex relationship between distal colon cancer and DD, the exact causal relationship between them and the underlying biological mechanisms still needs to be further elucidated through more in-depth prospective studies.\u003c/p\u003e\n\u003cp\u003eThis study has significant advantages. Firstly, it used a bidirectional two-sample MR design, which effectively reduces the potential impact of confounding factors and reverse causality in traditional epidemiological studies. Secondly, with the advantage of a large sample size, this study has sufficient statistical power. Thirdly, this study further revealed the differences in the effects of tumors in different parts of the colon on DD by performing a stratified analysis of colorectal cancer. Finally, by focusing on European descent, the study effectively reduced the impact of ethnic differences on the results.\u003c/p\u003e\n\u003cp\u003eCertainly, we must also face the limitations of this study. Firstly, due to the lack of key information on age, gender, lifestyle habits, and comorbidities in the data set, the study was unable to conduct more in-depth stratified analysis of the data and may face unknown confounding factors. Secondly, the results of this study may not be applicable to other ethnic groups and geographic regions, and their applicability needs to be further verified in a wider population. Therefore, based on the limitations of this study, future studies should aim to expand the sample size to include more ethnic groups and geographic regions. At the same time, more genetic variants and potential environmental factors should be considered in depth to achieve a more comprehensive assessment of the relationship between DD and CRC and its precancerous lesion.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe results of this study do not support DD as a direct risk factor for CRC and its precancerous lesion (colorectal adenoma). On the contrary, our findings indicate that the impact of CRC on DD varies by anatomical location. Specifically, distal colon cancer was associated with an increased risk of DD, whereas proximal colon cancer and rectal cancer did not show a similar correlation. This reminds us that DD should not be overemphasized as a prevention focus for CRC. Instead, it may be necessary to consider the possibility of DD in the treatment of distal colon cancer, and then develop different treatment plans and differentiated management of patients.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that no funds, grants, or other support were received during the preparation of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBiaohui Zheng: Data curation (equal); formal analysis (equal); investigation (equal); project administration (equal); writing\u0026nbsp;\u0026ndash;\u0026nbsp;original draft (lead). Dongbo Chen: Data curation (equal); formal analysis (equal); project administration (equal). Hao Zeng: Data curation (equal). Shuangming Lin: Data curation (equal); writing\u0026nbsp;\u0026ndash;\u0026nbsp;review and editing (equal).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is a secondary analysis of public data, and the study of data sources has been approved by the appropriate ethics committee.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to publish\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003e Sung, H., Ferlay, J., Siegel, R. 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Advances in immunology, 121, 91\u0026ndash;119. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/B978-0-12-800100-4.00003-9\u003c/span\u003e\u003cspan address=\"10.1016/B978-0-12-800100-4.00003-9\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Diverticular Disease, Colorectal Cancer, Colorectal Adenoma, Precancerous Lesion, Mendelian Randomization","lastPublishedDoi":"10.21203/rs.3.rs-4930792/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4930792/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eColorectal cancer (CRC) is a leading global health concern due to its high incidence and mortality rates. Diverticular disease (DD), characterized by the formation of pouches in the colon wall, is prevalent in Western populations, and shares several risk factors with CRC. However, the causal relationship between DD and CRC, including its precancerous lesion, remains to be elucidated.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis study employed Mendelian randomization (MR) approach using genomic data from European cohort to investigate the potential causal link between DD and the risk of colorectal adenoma, CRC, and its anatomical subtypes (proximal colon cancer, distal colon cancer, and rectal cancer). Single nucleotide polymorphisms significantly associated with these conditions were utilized as instrumental variables in MR analysis to assess causality.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe forward MR analysis indicated no significant causal effect of DD on the risk of colorectal adenoma (OR 0.87, 95% CI 0.74\u0026ndash;1.03, p\u0026thinsp;=\u0026thinsp;0.103), CRC (OR 0.94, 95% CI 0.87\u0026ndash;1.02, p\u0026thinsp;=\u0026thinsp;0.117), or its anatomical subtypes. In contrast, the reverse MR analysis showed that distal colon cancer may increase the risk of DD (OR 1.02, 95% CI 1-1.04, p\u0026thinsp;=\u0026thinsp;0.026), while proximal colon cancer and rectal Cancer did not show this association.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThe study findings do not support DD as a risk factor for CRC or its precancerous lesion (colorectal adenoma). However, a possible association between distal colon cancer and an increased risk of DD was found, providing new insights into the prevention and treatment of both diseases.\u003c/p\u003e","manuscriptTitle":"Mendelian Randomization Reveals the Anatomical Site Differences and Reverse Causality in the Association Between Diverticular Disease and Colorectal Cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-09-23 18:14:04","doi":"10.21203/rs.3.rs-4930792/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8a4b46dd-be25-49a5-b27b-9724afc2f409","owner":[],"postedDate":"September 23rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-10-04T12:39:03+00:00","versionOfRecord":[],"versionCreatedAt":"2024-09-23 18:14:04","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4930792","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4930792","identity":"rs-4930792","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}