Exploring the Causal Effect of Dietary Factors on Hemorrhoids: A Two-Sample Mendelian Randomization Study

doi:10.21203/rs.3.rs-4710781/v1

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Exploring the Causal Effect of Dietary Factors on Hemorrhoids: A Two-Sample Mendelian Randomization Study

https://doi.org/10.21203/rs.3.rs-4710781/v1

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Background

Previous research has found that dietary factors are closely associated with the risk of hemorrhoids. Modifying dietary structure and offering evidence-based dietary guidance are crucial for preventing and managing hemorrhoids disease. Our study aims to investigate the causal effects of 17 dietary factors on the risk of hemorrhoids using a two-sample mendelian randomization (MR) approach.

Method

Genetic variants and instrumental variables for dietary factors (exposure datasets) were obtained from UK Biobank (UKB), and hemorrhoids (outcome datasets) related single-nucleotide polymorphisms (SNPs) were extracted from the European Bioinformatics Institute (EBI). Eligible SNPs were selected for subsequent MR analysis and the Inverse Variance Weighted (IVW) method served as the primary analytical approach. Finally, we conducted sensitivity analyses and heterogeneity tests on the MR results

Result

Our findings indicated that vegetables (OR: 0.591, 95% CI: 0.428–0.817, p = 0.010) and fruits (OR: 0.764, 95% CI: 0.639–0.915, p = 0.005) intake has a protective effect, while alcohol intake (OR: 1.588, 95% CI: 1.246–2.024, p < 0.001), processed meat (OR: 1.307, 95% CI: 1.077–1.585, p = 0.007), oily fish (OR: 1.119, 95% CI: 1.014–1.235, p = 0.025), and cereal (OR: 1.209, 95% CI: 1.036–1.411, p = 0.016) intake have been identified as risk factors for hemorrhoids. Indeed, the causal relationships between above dietary factors and hemorrhoids were robust under the MR pleiotropy residual sum and outlier (MR-PRESSO) test and heterogeneity test.

Conclusions

This study offers scientific dietary guidance for patients and aims to decrease the incidence of hemorrhoids by elucidating the specific effects of dietary factors.

Health sciences/Risk factors

Health sciences/Diseases/Gastrointestinal diseases

Health sciences/Health care/Public health

dietary factors

hemorrhoids

mendelian randomization

risk

causal effect

Hemorrhoidal disease, the most common anorectal disorders, is pathological hypertrophy cushions of specialized submucosal tissue located in the annal canal¹. Hemorrhoids have a prevalence up to 40% in the population and are more likely to being observed in women than man (24% vs 16%)^{2, 3}. According to epidemiological research, one in three Americans has hemorrhoids on screening colonoscopy. Approximately 20% of the US population has undergone surgery for hemorrhoids. In office and emergency departments, hemorrhoid visits accounted for nearly 1.8 million annually. These visits were more frequent than those for gastritis, dyspepsia, cholelithiasis, irritable bowel syndrome or inflammatory bowel disease and appendicitis⁴. Additionally, millions of over-the-counter treatments for hemorrhoids are purchased each year. The clinical symptoms of hemorrhoids present with anal pain, rectal bleeding, itching and hemorrhoids tissue prolapse^{5, 6}. According to the position of hemorrhoids and dentate line, hemorrhoids can be divided into internal, external or mixed⁷. Even though hemorrhoids have extremely high incidence, seriously affecting patients’ quality of life and bringing serious economic burden, they have received little research attention surprisingly.

Up to now, the etiology of hemorrhoids has been a subject of ongoing debate. According to D. P. Burkitt and Morgagni, the incidence of hemorrhoids is associated with socioeconomic status. And the etiology of hemorrhoids can be attributed to walking upright, psychological stress, low-fiber diet and constipation^8–10. However, J F Johanson think that the occurrence of hemorrhoids is associated with diarrhea rather than constipation¹¹. Additionally, it has been discovered that the posture during defecation is also a contributing factor to the development of hemorrhoids. When adopting a squatting position for defecation, the alignment of the anus and rectum becomes straightened, thereby facilitating easier bowel movements. Some scholars contend that adopting a squatting position during defecation may potentially reduce the duration of bowel movements as a preventive measure against hemorrhoids^{12, 13}. Consequently, they advocate limiting the time spent on defecation to three to five minutes per day¹⁴. In general, anything such as prolonged bowel movements, constipation or diarrhea, pregnancy, and age are believed to contribute to the development of hemorrhoids by exerting pressure on the veins in the lower body¹⁵. In conclusion, the pathogenesis and etiology of hemorrhoids remains still not clear. Conducting more comprehensive and high-quality research on the etiology and pathogenesis of hemorrhoids would greatly benefit clinicians by enhancing their understanding of this condition, thereby facilitating improved prevention and treatment strategies for hemorrhoids.

Dietary factors have a complex and significant association with hemorrhoids. Alcohol and spicy foods may increase the risk of developing hemorrhoids, while a diet rich in fiber, fresh fruits, and vegetables appears to have a protective effect^{16, 17}. From a dietary perspective, improving people's dietary structure to prevent the occurrence of hemorrhoids has considerable clinical significance.

However, the previous traditional studies on the relationship between dietary factors and hemorrhoids face several limitations. First, they often struggle with confounding factors such as lifestyle, genetic background, and socioeconomic status, which can affect the accuracy of the results. Second, these studies are usually observational and cannot establish a causal relationship between dietary factors and hemorrhoids. Third, many of these studies are cross-sectional or involve short-term follow-ups, making it difficult to capture the long-term effects of dietary habits on hemorrhoids. Finally, the complexity of dietary patterns, with multiple foods and nutrients interacting, makes it challenging to isolate the impact of individual dietary factors. These limitations contribute to the uncertainty and constraints in interpreting the findings of traditional research in this area.

The genetic epidemiological approach of Mendelian randomization (MR) is used for rigorous and scientific causal inference. In MR studies, genetic variations are commonly employed as instrumental variables (IVs), typically represented by single nucleotide polymorphisms (SNPs) ¹⁸. During meiosis, the distribution of genetic variation is stochastic and occurs prior to disease occurrence and potential confounding factors, enabling MR studies to avoid confounding biases and reverse causation¹⁹.

In this study, we utilize a two-sample MR approach for the first time to investigate the causal relationships between various dietary factors (alcohol, tea, coffee, vegetables, fruits, dry fruits, beef, lamb, poultry, fish, processed meats, cereal, etc.) and hemorrhoids. By employing the MR method, we mitigate the impact of multiple confounding factors, providing direct causal evidence on the relationship between different food intakes and the occurrence of hemorrhoids.

2.1 Study Design

The study examines the causal impact of 17 dietary factors on hemorrhoids through two-sample MR analysis. The study design is illustrated in Fig. 1. For MR analysis, three prerequisites must be met: (1) instrumental variables (usually SNPs) must be strongly associated with the exposure factor (alcohol intake, tea intake, vegetables intake, fruits intake etc.); (2) SNPs must not be correlated with any potential confounding factors; (3) SNPs must only be associated with the risk of outcome (hemorrhoids) through the exposure factor (dietary factors). Genetic data were sourced from public genome-wide association study (GWAS) data. The study adhered to the Strengthening the Reporting of Observational Studies in Epidemiology-Mendelian randomization (STROBE-MR) guidelines (Supplementary Table 18)²⁰. All data we used were obtained from published studies that had received participant content and ethical approval. We confirmed that all methods were performed in accordance with the relevant guidelines and regulations.

2.2 Data sources

The analysis was carried out using published statistics from publicly available genome-wide association studies (GWAS) data. The GWAS database collected extensive and comprehensive genetic information from participants, encompassing genome-wide genotyping, genetic variation, and a diverse array of health-related outcomes²¹. The exposure datasets were obtained from the UK Biobank (UKB), a large-scale biomedical database containing de-identified genetic, lifestyle, and health information from half a million UK participants, and the Integrative Epidemiology Unit (IEU), which offers a comprehensive collection of publicly accessible GWAS summary statistics for a wide range of traits, facilitating genetic epidemiology and Mendelian randomization studies. The outcome datasets, which included participants diagnosed with hemorrhoids, were sourced from the European Bioinformatics Institute (EBI), a leading resource in molecular biology information. The reasons for choosing these two databases are as follows: 1, both databases include participants of European descent, ensuring genetic consistency within the study population; 2, the two different databases ensure that there is no overlap between the exposure group and the outcome group; 3, the two databases have a large number of participants, providing a substantial number of SNPs, which enhances the reliability of the results. To rigorously examine the effects of different foods on the incidence of hemorrhoids, we selected 17 exposure datasets and 1 outcome dataset, as detailed in Table 1. Given the publicly available nature of the GWAS data and their prior approval by the relevant ethical review boards, no additional ethical clearance was required for the analysis conducted in this study.

2.3 Selection and Validation of SNPs

Independent SNPs associated with dietary factors and hemorrhoids were identified according to three criteria. First, since SNPs must be strongly associated with exposure factors, only SNPs that had reached a genome-wide significance level (p < 5 × 10^− 8) were selected. Second, in order to avoid the effects of potential bias, SNPs with F-statistics > 10 were selected, where F can be calculated by following formula: F = R² / (1 − R²) × (N − k − 1) / k. In this formula, N was the sample size and k was the number of SNPs. Third, genetic variants in close genomic proximity tend to be co-inherited, a phenomenon known as linkage disequilibrium. The closer the SNPs are in terms of linkage disequilibrium, the more likely they are to have similar functions. To avoid the impact of linkage disequilibrium, SNPs with R² > 0.001 and width of linkage disequilibrium > 1 Mb. R² can be calculated by the formula: R² = 2 × β² × EAF × (1 − EAF), where β was the estimated effect size of SNPs and EAF indicated effect allele frequency.

2.4 MR methods

First, we conducted five two-sample MR analysis methods, including inverse-variance weight (IVW), MR-Egger, weighted median, simple mode and weighted mode to evaluate the causal links between dietary factors and hemorrhoids. We used the IVM method as the main analysis to evaluate the effect estimates, which can combine the ratio estimates of all selected SNPs based on a fixed-effects model. Second, we used the MR-PRESSO method to exclude potential SNPs with pleiotropy and confounding factors, further validating the MR analysis results and causal relationships.

2.5 Sensitivity analysis

The horizontal pleiotropy must be evaluated, which is the basic prerequisite for the results of MR (the exclusion restriction assumption). And the intercept term from MR-Egger regression was used. The intercept p > 0.05 shows that there is no pleiotropy. Sensitivity analysis was performed to verify and adjust the validity and stability of the results, which included heterogeneity test (Cochrane’s Q statistics, funnel plots, forest plots), and leave-one-out test. Finally, MR pleiotropy residual sum and outlier (MR-PRESSO) was performed to evaluate and calibrate horizontal pleiotropic outliers of IVW model. The MR-PRESSO global test was completed and p > 0.05 was considered no horizontal pleiotropic outliers. The results were reserved for three decimal places to present the accuracy. All statistical analysis were performed using the “TwoSampleMR” packages in R 4.2.1. The results were visualized by “ggplot2” packages in R and GraphPad Prism 8.

3.1 Selected IVs of MR

Each IV was deemed valid with an F-statistic > 10 and p < 5 × 10^− 8. The flow chart illustrating the process of SNP selection is depicted in Fig. 1. The information on the 17 dietary factors (exposure datasets) and hemorrhoids (outcome datasets) is presented in Table 1. In detail, a total of 11 alcohol intake versus 10 years previously (Supplementary table 1) and 25 alcohol intake frequency (Supplementary table 2) related SNPs, 33 tea intake (Supplementary table 3), 39 fresh fruit intake (Supplementary table 4), 34 coffee intake (Supplementary table 5), 10 cooked vegetable intake (Supplementary table 6), 30 dried fruit intake (Supplementary table 7), 16 processed meat intake (Supplementary table 8), 12 beef intake (Supplementary table 9), 21 lamb intake (Supplementary table 10), 6 poultry intake (Supplementary table 11), 38 oily fish intake (Supplementary table 12), 10 non-oily fish intake (Supplementary table 13), 8 pork intake (Supplementary table 14), 24 bread intake (Supplementary table 15), 51 cheese intake (Supplementary table 16), 28 cereal intake (Supplementary table 17) SNPs were identified, respectively.

3.2 Results of MR

In the primary MR analysis employing the IVM method, alcohol intake demonstrated a positively association with hemorrhoid incidence (Table 2, Fig. 2A). In detail, individuals who frequently consume alcohol have a 1.08 times higher probability of developing hemorrhoids compared to the general population (OR: 1.080, 95%: 1.011–1.155, p = 0.023). Additionally, the risk of developing hemorrhoids has increased by 1.588 times compared to 10 years ago (OR: 1.588, 95%: 1.246–2.024, p < 0.001). The intake of coffee (OR: 0.739, 95% CI: 0.622–0.903, p = 0.002), fruits (OR: 0.990, 95% CI: 0.981–0.998, p = 0.020), and vegetables (OR: 0.584, 95% CI: 0.410–0.831, p = 0.003) was found to reduce the incidence of hemorrhoids. However, the intake of processed meat (OR: 1.307, 95% CI: 1.077–1.585, p = 0.007), oily fish (OR: 1.119, 95% CI: 1.014–1.235, p = 0.025), and cereal (OR: 1.209, 95% CI: 1.036–1.411, p = 0.016) was associated with an increased incidence of hemorrhoids.

Additionally, validation results using the MR-PRESSO method indicate that, alcohol intake vs 10 years previously (OR: 1.446, 95% CI: 1.100–1.900, p = 0.023), alcohol intake frequency (OR: 1.068, 95% CI: 1.006–1.133, p = 0.040), processed meat intake (OR: 1.304, 95% CI: 1.091–1.558, p = 0.010), oily fish intake (OR: 1.147, 95% CI: 1.044–1.261, p = 0.008), and cereal intake (OR: 1.182, 95% CI: 1.036–1.348, p = 0.017) have a promoting and causal effect on the incidence of hemorrhoids. In addition, the intake of vegetables (OR: 0.591, 95% CI: 0.428–0.817, p = 0.010) and fruits (OR: 0.764, 95% CI: 0.639–0.915, p = 0.005) shows a protective effect against the development of hemorrhoids. However, after validation, coffee intake (p > 0.05) was found to have no statistically significant association. Generally, the results of the MR-PRESSO analysis were greatly consistent with the results of the IVW model.

3.4 Sensitivity Analysis

We completed the pleiotropy test for the MR analysis results by the MR-Egger intercepts and MR-PRESSO methods. As shown in Table 2, the MR-Egger intercept method indicates that only beef intake shows potential pleiotropy (p < 0.05). However, the MR-PRESSO Global test suggests that this pleiotropy is not statistically significant (p > 0.05). And the other dietary factors, upon testing, did not exhibit evidence of pleiotropy. According to the heterogeneity test (Table 2), both the MR-Egger and IVW methods indicated no significant heterogeneity in the MR results. Additionally, scatter plots, forest plots, and funnel plots for the analysis are displayed in Supplementary Figs. 1, 2, and 3, respectively. The leave-one-out analysis demonstrated that no individual SNP significantly influenced the overall causal estimate (Supplementary Figs. 4).

Hemorrhoids are a common anorectal disease, significantly impacting patients' quality of life. In recent years, diet has been widely recognized as a crucial factor in hemorrhoid occurrence. In this study, we employed MR to investigate the causal effects of dietary factors on the incidence of hemorrhoids. This is the first time MR methodology has been utilized to comprehensively and systematically analyze the impact of 17 dietary factors on hemorrhoids. Our findings reveal significant associations and causal links between various dietary habits and the risk of developing hemorrhoids. Specifically, we identified that alcohol intake, processed meat intake, oily fish intake, and cereal intake are positively associated with the incidence of hemorrhoids, suggesting a potential risk factor. Conversely, the intake of vegetables and fruits protective effects against the development of hemorrhoids. Previous research has shown a link between dietary factors and hemorrhoids²². Adjusting diet to prevent and alleviate hemorrhoids is an effective non-pharmacological and non-surgical method. This is especially important for high-risk groups such as pregnant women, obese individuals, patients with constipation and so on²³. To ensure the robustness of our results, we conducted several sensitivity analyses including the MR-Egger intercept test and MR-PRESSO method to evaluate pleiotropy and heterogeneity. And the results were shown to be robust and reliable. The scatter plots, forest plots, funnel plots and the leave-one-out analysis, consistently supported our findings. This demonstrates the validity and strength of the observed associations. Overall, this study can provide a detailed dietary guide for individuals with hemorrhoids and those at high risk.

In this study, the intake of vegetables and fruits was found to be a protective factor against hemorrhoids, effectively reducing the incidence of hemorrhoids, consistent with previous research findings. According to previous studies, vegetables and fruits are rich in dietary fiber, which can help improve constipation and prevent the occurrence of hemorrhoids²⁴. Additionally, increasing dietary fiber intake can help obese patients lose weight, and obesity is one of the risk factors for hemorrhoids²⁵. Additionally, increasing the intake of fiber-rich foods such as vegetables and fruits can improve gut microbiota, enhance gastrointestinal motility, and reduce defecation time, thereby preventing the occurrence of hemorrhoids²⁶.

We found a causal relationship between alcohol intake and the occurrence of hemorrhoids. Alcohol promotes vasodilation, increasing blood flow in the anal-rectal areas, which can cause vascular congestion and dilation, damaging endothelial cells and thereby exacerbating hemorrhoid symptoms or triggering their occurrence^{27, 28}. Additionally, alcohol possesses diuretic properties, resulting in fluid loss and dehydration^{29, 30}. Dehydration can lead to the formation of dry and hard stools, increasing the difficulty of defecation and causing constipation, thereby elevating the risk of hemorrhoids. Additionally, alcohol intake can disrupt intestinal structure and affect overall gut function. Ethanol can damage the intestinal mucosa, disrupt the gut microbiota, compromise the intestinal immune barrier, impair nutrient absorption, and increase bowel movement frequency, leading to diarrhea³¹. Frequent diarrhea can increase the pressure on the anal and rectal areas, exacerbating hemorrhoids³². Long-term heavy drinking can harm the liver, potentially leading to alcoholic cirrhosis, which elevates portal vein pressure and subsequently increases vascular pressure in the anal dentate line area, thereby triggering hemorrhoids.

Processed meat and oily fish intake may lead to constipation due to their lack of essential dietary fiber. The high-fat content in these foods can slow down the digestive process and affect intestinal motility, ultimately causing difficulty in bowel movements and the occurrence of hemorrhoids. Additionally, a high-fat diet might impact the gut microbiota and microenvironment, inducing weakened gastrointestinal motility and constipation³³. Processed meat products contain high levels of salt and preservatives, which might lead to fluid retention in the body, irritate the gastrointestinal mucosa, and increase the incidence of constipation and diarrhea. It is generally believed that whole grains are rich in dietary fiber, which promotes stool formation and intestinal motility, prevents constipation, reduces pressure during defecation, and lowers the risk of hemorrhoids. However, cereal lose a significant amount of dietary fiber and some nutrients during processing, which can lead to insufficient fiber intake, ultimately causing constipation and hemorrhoids. Furthermore, a higher intake of refined grains can elevate the risk of type 2 diabetes and obesity, both of which are established risk factors for perianal diseases^{25, 34}. Overall, an unbalanced diet can result in inadequate dietary fiber intake, negatively impacting gut health and increasing the risk of hemorrhoids.

In this study, although we found that coffee intake is a protective factor against hemorrhoids using the two-sample Mendelian randomization method, this result was not validated by MR-PRESSO analysis. We speculate that the reasons might be as follows: 1, MR-PRESSO has high requirements for detecting bias and effect robustness, the insufficient sample size and number of SNPs in the included datasets may result in inadequate statistical power, failing to detect the actual causal relationship; 2, Despite excluding some potential confounding SNPs, there may still be residual confounding factors affecting the final results. In summary, although the preliminary results suggest that coffee intake may have a protective effect against hemorrhoids, further research and validation are needed. Caffeine is a natural stimulant. Previous high-quality studies have found that drinking coffee can promote distal colon motility and facilitate bowel movements³⁵. Additionally, coffee is rich in polyphenols, which have antioxidant and anti-inflammatory properties³⁶. These compounds can help reduce intestinal inflammation and oxidative stress, thereby protecting the vascular health of the anal and rectal areas and reducing the incidence of hemorrhoids. Furthermore, caffeine can increase the basal metabolic rate and enhance calorie expenditure, aiding in weight management. Obesity is a risk factor for hemorrhoids, so controlling weight may also help lower the likelihood of developing hemorrhoids.

This study has several limitations. First, not all MR analysis methods can yield valid causal relationships. Since all IVs passed heterogeneity and pleiotropy tests, we chose the results of the IVW method, which has the highest test efficiency, as the primary reference. Second, the dataset used in this study only includes patients of European population, which limits the generalizability of the results to other demographic groups (such as patients of African or Asian ancestry). Future research needs to verify these findings in other populations and ethnicities. Furthermore, the two-sample MR analysis method may not adjust for all potential confounding factors, especially the interactions between different dietary factors. Therefore, our results may be influenced by these unadjusted confounders. Although studies have shown that multivariable MR analysis can effectively avoid this issue, we still opted for the two-sample MR method. The main reason is that while multivariable MR analysis can adjust for the effects of multiple exposures simultaneously, it may cause severe multicollinearity issues when dealing with several highly correlated dietary factors. Multicollinearity can lead to unstable analysis results and affect the accuracy of causal relationships^{37, 38}. Additionally, due to the complexity of the data and the possible interactions between different exposures, the interpretation of multivariable MR analysis results is more complex.

In conclusion, this study provides evidence supporting the causal relationship between dietary factors and hemorrhoids. Consumption of vegetables and fruits has a protective effect, while consumption of alcohol, processed meat, oily fish, and cereal has been identified as risk factors for hemorrhoids. These findings emphasize the importance of adjusting dietary habits in the prevention and treatment of hemorrhoids. By clarifying the specific effects of dietary factors on hemorrhoids, this study provides scientific dietary guidance for hemorrhoid patients, thereby improving their quality of life.

mendelian randomization

UKB

United Kingdom Biobank

SNPs

single nucleotide polymorphisms

IVW

inverse variance weight

odd ratio

confidence interval

MR-PRESSO

mendelian randomization pleiotropy residual sum and outlier

IVs

instrumental variables

Data Availability Statement

Code and extracted data are available on request for Zhao ZX. All the data analyzed can be found in already published studies, and no new original data were generated or analyzed in this study.

Funding

This work was supported by the Health Commission of Fuyang City, Anhui, China (No. FY2021-18 to Zhao ZX), Health Commission of Anhui Province (NO. AHWJ2023BAa20164 to Zhao ZX).

Institutional Review Board Statement

This study used summary data published by multiple GWAS.

Informed Consent Statement

Patient informed consents were obtained by corresponding studies.

Conflicts of Interest

The authors declare no conflict of interest.

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Tables 1-3 are available in the Supplementary Files section.

There is NO conflict of interest to disclose.

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26 Jul, 2024
First submitted to journal
25 Jul, 2024
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10 Jul, 2024

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Exploring the Causal Effect of Dietary Factors on Hemorrhoids: A Two-Sample Mendelian Randomization Study

Status:

Version 1

Abstract

Background

Method

Result

Conclusions

Figures

1. Introduction

2. Materials and Methods

2.1 Study Design

2.2 Data sources

2.3 Selection and Validation of SNPs

2.4 MR methods

2.5 Sensitivity analysis

3. Result

3.1 Selected IVs of MR

3.2 Results of MR

3.4 Sensitivity Analysis

4. Discussion

5. Conclusions

Abbreviations

Declarations

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 1