Causality between cholecystectomy, blood lipids, and major adverse cardiac and cerebrovascular events: a Mendelian randomization analysis

doi:10.21203/rs.3.rs-3291505/v1

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Causality between cholecystectomy, blood lipids, and major adverse cardiac and cerebrovascular events: a Mendelian randomization analysis

https://doi.org/10.21203/rs.3.rs-3291505/v1

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Background

Several studies have provided evidence of changes in lipids and major adverse cardiac and cerebrovascular events (MACCE) after cholecystectomy. However, the results of these studies are controversial. Here, we performed Mendelian randomization (MR) to predict the effects of cholecystectomy on blood lipid levels and MACCE with less confounding.

Methods

Summary data on cholecystectomy, lipid levels, and MACCE were obtained from publicly available genetic databases and analyzed using two sets of genetic instruments. MR analyses were conducted using the inverse-variance weighted (IVW; primary method for causal inference in two-sample MR analysis) method. We performed multivariate MR (MVMR) to screen and prioritize the most likely causal lipids and analyzed the mediated effects of these lipids.

Results

Six types of MACCE, including angina, chronic ischemic heart disease, coronary heart disease, heart failure, myocardial infarction, and ischemic stroke, were found to have a negative association with cholecystectomy. Furthermore, we identified a decreased apolipoprotein B/apolipoprotein A1 (ApoB/ApoA1) ratio with subsequent coronary heart disease with a mediated proportion of 52.9% (95% CI: 21.5–97.5%, P = 0.000), chronic ischemic heart disease with a mediated proportion of 42.6% (95% CI: 23.1–91.6%, P = 0.000), and a reduced risk of myocardial infarction with a mediated proportion of 39.4% (95% CI: 24.8–95.5%, P = 0.000).

Conclusions

The findings present genetic evidence supporting the link between cholecystectomy, blood lipids, and MACCE, which may offer valuable insights into the mechanisms involved in the improvement of blood lipids and the prevention of MACCE following cholecystectomy.

Mendelian randomization

cholecystectomy

MACCE

blood lipids

causality

The incidence of gallstones in adults is approximately 10–20%[1]. Cholesterol stones are predominant, accounting for three-quarters of all types of gallstones[2]. Cholecystectomy, the gold standard surgical treatment for gallstones, is the most common surgical procedure worldwide[3]. The gallbladder is an important organ in the human digestive system, involved in functions such as bile storage, concentration, and secretion[4]. However, there are concerns about the occurrence of postoperative complications after gallbladder removal, which is one of the reasons why some in the medical community still advocate for the non-surgical treatment of gallbladder diseases[5]. Furthermore, as the gallbladder plays a role in lipid metabolism, there is still a debate on whether cholecystectomy has a positive or negative effect on lipid metabolism. A study involving 5,672 patients in China who underwent cholecystectomy found that they experienced postoperative weight gain and poor control of fasting blood glucose levels, indicating metabolic issues[6]. Another study discovered that cholecystectomy could disrupt fat metabolism in the liver, leading to metabolic syndrome[7]. In a Finnish study, it was found that very-low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL)-apolipoprotein B levels were increased during long-term follow-up after cholecystectomy, and these elevated lipid levels may increase the risk of hypertension and cardiovascular diseases[8]. Some researchers believe that after gallbladder removal, the enterohepatic circulation rate increases, increasing the secretion of bile acids (BAs) and cholesterol in the bile and enhancing fat absorption[9]. Some of these effects may be related to the deconjugation and dehydroxylation of BAs by gut microbiota[10, 11].

However, there are also studies that show different outcomes. One study found that after cholecystectomy, there was a decrease in average low-density lipoprotein (LDL) levels and average total cholesterol (TC) levels[12]. Another clinical study observed that within 3 days and 6 months after cholecystectomy, there was a significant reduction in plasma concentrations of TC, triglycerides, and LDL cholesterol. However, during the study period, the concentration of high-density lipoprotein (HDL) cholesterol did not show a significant increase or decrease[13]. It is well known that dyslipidemia, characterized by elevated cholesterol levels, elevated triglyceride levels, and reduced HDL levels, is closely associated with major adverse cardiac and cerebrovascular events (MACCE).

The existing evidence raises the question of whether the controversy surrounding the effect of cholecystectomy on lipid metabolism also extends to its effect on MACCE. In a nationwide population-based study, it was found that cholecystectomy could reduce the overall risk of stroke and could be considered as one of the preventive measures for stroke[14]. Another study reported the protective effect of cholecystectomy against the development of acute myocardial infarction and suggested that it may be attributed to the reduction of oxidative stress levels after cholecystectomy[15]. However, there is no conclusive evidence suggesting that patients undergoing cholecystectomy would have cardiovascular risk reduction benefits, including for both myocardial infarction and stroke. Moreover, a higher risk of cardiovascular diseases after gallbladder removal has been observed in males[16].

The controversial nature of the topic has prompted us to use a novel research approach to investigate the relationship between cholecystectomy, lipid profiles, and MACCE. In particular, conducting large-scale, multicenter epidemiological studies on cholecystectomy and MACCE is challenging due to high costs and ethical limitations. In comparison with traditional epidemiological studies, Mendelian randomization (MR) analysis is less susceptible to environmental confounding factors, providing more reliable insights into causal relationships and revealing the associations between risk factors and disease outcomes[17].

As shown in the Graphical Abstract, we employed a two-sample and mediation MR design to investigate the causal association between cholecystectomy and MACCE, as well as the potential role of blood lipids as mediators. The results of this study indicated that cholecystectomy may reduce the risk of MACCE, and it identified the apolipoprotein B/apolipoprotein A1 (ApoB/ApoA1) ratio as the most significant lipid factor involved in this relationship.

2.1. Effects of cholecystectomy on MACCE

In this study, we used the inverse-variance weighted (IVW) method and weighted median to ascertain the impact of cholecystectomy on MACCE. For univariable MR analysis, Cochran’s Q test was used to assess the heterogeneity between MACCE and cholecystectomy. Notably, significant Q-statistics and corresponding P values were obtained, indicating potential heterogeneity. To account for this heterogeneity, the weighted median was selected as the primary method.

Next, we assessed the impact of cholecystectomy on selected representative MACCE traits, including angina, chronic ischemic heart disease, coronary heart disease, heart arrhythmia, heart failure, myocardial infarction, and ischemic stroke (Fig. 1). The weighted-median method revealed that the remaining six MACCE traits negatively correlated with cholecystectomy (OR: 0.946, 95% CI: 0.916–0.977, and P = 0.001 for angina; OR: 0.976, 95% CI: 0.957–0.996, and P = 0.021 for chronic ischemic heart disease; OR: 0.208, 95% CI: 0.054–0.799, and P = 0.022 for coronary heart disease; OR: 0.233, 95% CI: 0.094–0.533, and P = 0.049 for ischemic stroke; OR: 0.999, 95% CI: 0.977–1.023, and P = 0.001 for myocardial infarction; OR: 0.167, 95% CI: 0.058–0.478, and P = 0.001 for heart failure; Fig. 2). The effect of cholecystectomy on myocardial ischemia (OR: 0.978, 95% CI: 0.963–0.993, and P = 0.005) and heart failure (OR: 0.298, 95% CI: 0.108–0.821, and P = 0.000) were also confirmed using IVW analysis. However, there was no significant correlation between cholecystectomy and heart arrhythmia (Supplementary material 1).

2.2. Causal association between cholecystectomy and blood lipids

Because of heterogeneity, univariable MR analysis of the relationship between cholecystectomy and seven blood lipids was done using the weighted median (Fig. 3). The results revealed an effect of cholecystectomy on apoB (OR: 1.186, 95% CI: 0.843–1.670, P = 0.000), ApoB/ApoA1 ratio (OR: 0.186, 95% CI: 0.127–0.273, P = 0.000), small VLDL cholesterol (OR: 0.211, 95% CI: 0.144–0.310, P = 0.000), and LDL cholesterol (OR: = 0.198, 95% CI: 0.136–0.287, P = 0.000). However, there was no significant association between genetically determined cholecystectomy and apoA1, total triglycerides, and HDL cholesterol (Supplementary Material 1).

2.3. Effects of blood lipids on MACCE

Univariable Mendelian randomization analysis of the relationship between lipid profiles and MACCE after cholecystectomy revealed that angina, chronic ischemic heart disease, coronary heart disease, and myocardial infarction correlated with four lipid traits: apoB, ApoB/ApoA1 ratio, small VLDL cholesterol, and small VLDL cholesterol. However, only small VLDL cholesterol was found to be associated with ischemic stroke and heart failure. Multivariable Mendelian randomization analysis of the impact of these lipid traits on angina, chronic ischemic heart disease, coronary heart disease, and myocardial infarction, revealed that the ApoB/ApoA1 ratio was the most likely mediator of the negative regulation between cholecystectomy and angina, chronic ischemic heart disease, coronary heart disease, and myocardial infarction (Fig. 4)

The results demonstrated robust genetic correlation between the ApoB/ApoA1 ratio and chronic ischemic heart disease (OR: 1.004, 95% CI: 1.001–1.008, P = 0.018), coronary heart disease (OR: 2.394, 95% CI: 1.481–3.868, P = 0.000), and myocardial infarction (OR: 1.316, 95% CI: 1.011–1.712, P = 0.041) (Supplementary Material 1).

2.4. The mediating effect of blood lipids between cholecystectomy and MACCE

Multivariate MR (MVMR) analysis of how cholecystectomy affects MACCE via lipids (Fig. 1), revealed that cholecystectomy-induced reduction in the ApoB/ApoA1 ratio correlated with subsequent coronary heart disease (mediated proportion: 52.9%, 95% CI: 21.5–97.5%, P = 0.000), chronic ischemic heart disease (mediated proportion: 42.6%, 95% CI: 23.1–91.6%, P = 0.000), and reduced risk of myocardial infarction (mediated proportion: 39.4%, 95% CI: 24.8–95.5%, P = 0.000).

Cholecystectomy is recommended for the definitive management of various gallbladder diseases, such as cholecystitis, biliary colic, and gallstones[12]. Although this surgical method effectively treats gallbladder diseases, there are some doubts about the effects of cholecystectomy, with the primary concern of whether it increases the risk of other diseases[5], especially MACCE. Patients with gallstones often have comorbidities such as dyslipidemia and metabolic syndrome[8, 15]; thus, the risk of cardiovascular and cerebrovascular complications is considered by hepatobiliary surgeons when managing gallbladder issues. As mentioned in the introduction section, there is an ongoing debate on the positive or negative effect of cholecystectomy on MACCE. The controversy may arise from several factors, including higher levels of fasting blood glucose, TC, and triglycerides in patients undergoing cholecystectomy, which could create an unfavorable internal environment.

MR employs genetic variation as an instrumental variable[18]. In comparison with traditional epidemiological studies, MR analysis is less affected by environmental confounding factors. Additionally, individual genetic factors are determined during the embryonic period and are not influenced by postnatal disease outcomes, which provides more reliable causal insights into risk factors and disease outcomes[19]. Our results initially showed that cholecystectomy could reduce the risk of angina, chronic ischemic heart disease, coronary heart disease, heart failure, myocardial infarction, and ischemic stroke, except for heart arrhythmia (Fig. 1). The greater role of cholecystectomy in improving patients with preoperative dyslipidemia compared with those with normal lipid levels has been demonstrated previously[20]. Furthermore, research has shown that after cholecystectomy, the small intestine regulates the dynamics of BAs in enterohepatic circulation, thereby promoting the dissolution of cholesterol in the bile[21]. Cholecystectomy can alter bile excretion and BA circulation, leading to an increase in BAs in the intestines[22]. BAs have the ability to activate farnesoid X receptor and Takeda G protein-coupled receptor 5 on hepatocytes and brown adipocytes, thereby improving metabolic disorders[23]. Some studies directly indicated that cholecystectomy may be effective for patients with concurrent heart and coronary artery diseases[24]. In a cohort study conducted in Taiwan, cholecystectomy was associated with a reduced risk of overall stroke, ischemic stroke, and hemorrhagic stroke, and it was considered as one of the measures for patients with gallstones, especially those with stroke risk factors[14].

MR analysis further confirms the relationship between cholecystectomy and representative blood lipids, indicating that cholecystectomy acts as a protective factor by reducing the levels of apoB, ApoB/ApoA1, LDL cholesterol, and small VLDL cholesterol (Fig. 2). In atherosclerosis, lipids (mainly cholesterol) are deposited within the vascular wall, forming structures known as atherosclerotic plaques. Plaque formation leads to the thickening, hardening, and narrowing of the blood vessel wall, ultimately resulting in adverse ischemic outcomes in the corresponding organs, including myocardial infarction and ischemic stroke[25–27]. ApoB, a major pathogenic lipid factor in coronary artery disease, not only represents the concentration of LDL cholesterol but also reflects the number of LDL particles. It is an excellent predictor of atherosclerosis and cardiovascular diseases[28]. In a Swedish cohort study, an elevated ApoB/ApoA1 ratio suggested an increased risk of myocardial infarction and stroke, and it could serve as an early predictor 20 years before the onset of major adverse cardiovascular events[29]. VLDL in obese individuals is associated with a significantly increased risk of myocardial infarction[30]. The harmful effects of dyslipidemia on cardiovascular diseases are well-established, and our results preliminarily indicated that cholecystectomy could not only reduce the risk of MACCE but also act as a protective factor in regulating blood lipid levels. This led us to question whether cholecystectomy influences the risk of MACCE through the mediating effects of blood lipids.

We performed additional analysis to investigate the causal relationship between cholecystectomy, MACCE, and blood lipids. However, no causal relationship was observed between cholecystectomy and apoA1, total triglycerides, and HDL cholesterol. Therefore, we included apoB, ApoB/ApoA1 ratio, LDL cholesterol, and small VLDL cholesterol and performed multivariable MR analysis on different MACCE outcomes, including angina, chronic ischemic heart disease, coronary heart disease, heart failure, myocardial infarction, and ischemic stroke (Fig. 4). We identified the ApoB/ApoA1 ratio as a factor that could mediate the causal effects of cholecystectomy on chronic ischemic heart disease, coronary heart disease, and myocardial infarction. Chronic ischemic heart disease, coronary heart disease, and myocardial infarction share some similarities as they are all related to the formation of atherosclerotic plaques in the coronary arteries and inadequate blood supply to the heart[31]. The ApoB/ApoA1 ratio serves as a measure of the balance between bad (LDL) and good (HDL) lipoproteins in the blood. ApoA1 is the major protein component of HDL and is associated with the prevention of coronary artery disease[32]. On the other hand, ApoB is the major protein component of LDL and other atherogenic lipoproteins and can independently predict cardiovascular and all-cause mortality in the general population[33]. The ApoB/ApoA1 ratio has been shown to be more effective than HDL cholesterol in assessing the severity of coronary artery damage[34]. In a study involving over 20,000 individuals, researchers measured fasting blood lipids and carotid intima-media thickness and found that the ApoB/ApoA1 ratio may be a more accurate indicator than other cholesterol markers for assessing the risk of heart disease[35]. Another study also presented similar findings, highlighting the effectiveness of the ApoB/ApoA1 ratio in assessing the severity of coronary artery damage compared with that of HDL cholesterol[34].

Through MR analysis, we have unraveled the complex and multifaceted relationship between cholecystectomy, blood lipids, and MACCE. The advantage of MR analysis is that it is not limited by the sample size or economic costs. The relatively large sample size of the Genome-wide association study (GWAS) used in our study ensured statistical power. Additionally, the inherent strengths of MR analysis helped mitigate the influence of factors such as dietary habits and gallstone disease, which are difficult to exclude in observational studies, thus avoiding potential biases. We can confirm that cholecystectomy could reduce the risk of MACCE, which, to some extent, indicates the necessity of surgical treatment for gallbladder diseases. Cholecystectomy could not only address the primary pathology but also reduce the harm caused by dyslipidemia. Importantly, our study explored the controversial issues related to cholecystectomy from a genetic perspective. We elucidated the causal relationship between cholecystectomy and MACCE and identified the involvement of pathogenic lipid factors.

It is crucial to acknowledge the limitations inherent to our study. First, MR effect estimates were calculated based on the effect of genetic variants on causal factors, reflecting lifelong genetic exposure. However, in the assessment of the effect of cholecystectomy on short-term MACCE risk after surgery, MR effect estimates may have certain limitations. Second, further MR investigations should be conducted using larger GWAS datasets of psoriasis outcomes, more extensive observational studies, and populations beyond those of white European descent. Additionally, the original study lacked specific data, which prevented the analysis of the association between cholecystectomy and MACCE in subgroups based on age, sex, and other factors.

Conclusions

Our MR results demonstrated the potential causal relationship between cholecystectomy, blood lipids, and MACCE. Specifically, cholecystectomy could reduce the risk of angina, chronic ischemic heart disease, coronary heart disease, heart failure, myocardial infarction, and ischemic stroke. Furthermore, we found that the ApoB/ApoA1 ratio could mediate the effects of cholecystectomy on the risk of chronic ischemic heart disease, coronary heart disease, and myocardial infarction. These findings present genetic evidence for the relationship between cholecystectomy, blood lipids, and MACCE, which may provide valuable insights into the mechanisms involved in the improvement of post-cholecystectomy blood lipids and the prevention of coronary artery disease and stroke.

4.1. Research design

We first performed univariable Mendelian randomization analyses of the effect of cholecystectomy on MACCE, lipid, and lipid-MACCE using the ‘Wampler’ package. Next, we took the intersection of the screened lipids that were significantly affected by cholecystectomy as well as those that were significantly affected by MACCE and further analysed and ranked their effect on MACCE using multivariable MVMR. Finally, MVMR analysis was used to determine the pathway through which cholecystectomy triggers lipid-mediated MACCE.

4.2. Data sources and access

Data on exposure, lipids, and outcomes were obtained from a GWAS study (https://gwas.mrcieu.ac.uk/dataset/). Data on exposure factors and cholecystectomy were obtained from the Medical Research Council integrative epidemiology unit (MRC-IEU), University of Bristol. The MRC-IEU data were from an analysis of the UK Biobank and involved 18,319 patients who had undergone cholecystectomy and 444,614 patients of European origin who had not undergone cholecystectomy.

Data on lipid single nucleotide polymorphism, cholesterol in HDL, cholesterol in LDL, cholesterol in VLDL, total triglycerides, apoB, apoA1, and the ApoB/ApoA1 ratio, were obtained from the Nightingale Health 2020 study, which measured metabolic biomarkers in the UK Biobank.

Data on angina, chronic ischemic heart disease, and heart arrhythmia were obtained from MRC-IEU. Data on coronary heart disease and myocardial infarction were obtained from a genome-wide meta-analysis of coronary heart disease[36]. Heart failure data came from the Finnish research database. Data on ischemic stroke were obtained from a multi-ancestry genome-wide association study on stroke[37].

4.3. Selection of instrumental variables (IVs)

A series of quality assurance measures were taken to determine the most appropriate IVs and to ensure the robustness and precision of our conclusions about the causal relationship between exposure, lipids, and MACCE.

Single nucleotide polymorphisms (SNPs) that were significantly associated with the traits, such as the IVs, were selected. A genome-wide significance threshold of P < 5×10^− 8 was initially used to identify the SNPs but because this cutoff was too stringent, it excluded most SNPs. Thus, to include more SNPs, the threshold was lowered to P < 1.0×10^− 5. To avoid bias during MR analysis, selected IVs should not exhibit linkage disequilibrium (LD). Hence, a stringent LD threshold of R² < 0.001 and a clumping distance of 10,000 kb were applied using the “Wampler” package. To ensure consistency and to mitigate potential bias during MR analysis the effects of SNPs on the exposure should align with the same allele as the effects on the outcome. Thus, palindromic SNPs, including those with A/T or G/C alleles, were excluded to avoid distorting strand orientation or allele coding. As part of the harmonization, the alleles were aligned to the human genome reference sequence, and any ambiguous or duplicated SNPs eliminated. After extracting the relevant data associated with each SNP, such as effect allele and effect size (including the beta value, standard deviation, and P value), the variance (R²) and F-statistics analyses were used to determine the strength of the instruments using the following formula: R² = 2 × MAF × (1 − MAF) × β², F = − R²(n − k − 1) / k (1 − R²). Where MAF is the minor allele frequency of the SNPs used as IVs, n is the sample size, and k is the number of IVs used[38, 39]. The F-statistics for the traits exceeded 10, indicating a low likelihood of encountering weak instrument bias.

4.4. Univariable and multivariable Mendelian randomization analyses

We used univariable MR analysis to determine if there were causal relationships between the traits. Because we did not encounter traits with a single instrumental variable, we used the following commonly used MR methods: the IVW test[40], the weighted mode[41], MR-Egger regression[42], and the weighted median estimator (WME) for features with multiple IVs[43]. To determine heterogeneity between the instruments, as well as their validity, we assessed heterogeneity using Cochran’s Q statistic and a two-sample MR package, with a Q value greater than the number of instruments minus one indicating the presence of heterogeneity and suggesting that the instrument may not be valid. A Cochran’s Q statistic P value of < 0.05 indicates the presence of heterogeneity[44, 45]. In the absence of heterogeneity and pleiotropy, IVW analysis was preferred. In cases with heterogeneity without pleiotropy, weighted median analysis was preferred. In cases with pleiotropy without heterogeneity, MR-Egger analysis was used.

Given the strong correlation among lipid traits, we used MVMR to identify and prioritize the most likely causal lipids. For MVMR analysis, we used inverse variance weighting and applied the MR-Egger test for sensitivity analysis[46].

4.5. Decomposing mediated effects

Multivariate MR analysis enables the use of primary exposure- and secondary exposure-associated genetic variations (mediators) as analysis tools, and it can be used to decompose the overall causal effect of an exposure on outcome into mediator-driven, indirect effects. The direct effect of exposure on outcomes was not mediated through other causal pathways or other mediators. Univariate MR analysis was used to estimate the total causal effect of exposure on outcomes. Multivariate MR analysis was used to estimate the direct effect of exposure on outcomes while adjusting for mediating variables[47].

The overall effect of exposure on outcomes can be broken down into indirect (mediated) and direct (non-mediated) effects[47]. The proportion of the overall effect mediated by lipids was determined by dividing the indirect effect by the overall effect using the formula β1 × β2/β3, where β1 represents the effect of cholecystectomy on lipids, β2 represents the effect of lipids on MACCE, and β3 represents the effect of cholecystectomy on MACCE. The difference-in-differences method (β3-β’) was used to determine the indirect effect of combining multiple mediator variables, where direct effect (β’) refers to the effect of cholecystectomy on MACCE, based on the MVMR model.

For all individual and joint mediators, we calculated the proportion of mediators by dividing the indirect effect by the overall effect and used the delta method to estimate confidence intervals.

4.6. Sensitivity analysis

First, we used the MR-PRESSO method to identify outliers and then reanalysed the data by excluding these outliers. To determine whether variants mediated the association between exposure and the outcome variable, exclusion sensitivity analyses were done by removing one SNP at a time. Next, if the intercept term was statistically significant, MR-Egger regression tests were used to assess horizontal multiplicity in the MR analysis. Finally, Cochran’s Q statistic was used to evaluate heterogeneity. P = 0.05 was applied as the significance threshold. All statistical analyses were done on R version 4.2.0 using the ‘Wampler’, ‘MendelianRandomization’, and ‘MRPRESSO’ packages.

Ethical Statement

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Funding

This study was supported by the Project of Administration of Traditional Chinese Medicine of Guangdong Province of China (Grant No. 20242004).

Authors' contributions

Fang Liu, Ti Yang and Peifeng Ke conducted the statistical analysis and wrote the paper. Xiancheng Zeng, Yifeng He and Juan Duan contributed to the conception and design of the study and provided critical revisions to the manuscript. Fang Liu, Ti Yang, Peifeng Ke, Yufan Chen, Jiafan Guo and Mo Cao performed the research, analyzed the experimental results, and contributed to the writing of the manuscript. Prior to submission, all authors reviewed the language and accuracy of the article and agreed to its publication in written form. As one of the administrators of the Project of Administration of Traditional Chinese Medicine of Guangdong Province of China (Grant No. 20242004), Juan Duan utilized the research funding from this project to support the study.

Acknowledgements

We express our gratitude to the individuals and institutions that have developed openly accessible databases and resources. We also thank the authors involved in this project for their dedication and effort in completing this article.

Availability of data and materials

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Graphical Abstract. Causal relationship between cholecystectomy, blood lipids, and MACCE

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Causality between cholecystectomy, blood lipids, and major adverse cardiac and cerebrovascular events: a Mendelian randomization analysis

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Abstract

Background

Methods

Results

Conclusions

Figures

1. Introduction

2. Results

2.1. Effects of cholecystectomy on MACCE

2.2. Causal association between cholecystectomy and blood lipids

2.3. Effects of blood lipids on MACCE

2.4. The mediating effect of blood lipids between cholecystectomy and MACCE

3. Discussion

4. Materials and Methods

4.1. Research design

4.2. Data sources and access

4.3. Selection of instrumental variables (IVs)

4.4. Univariable and multivariable Mendelian randomization analyses

4.5. Decomposing mediated effects

4.6. Sensitivity analysis

Declarations

Ethical Statement

Consent for publication

Competing interests

Funding

Authors' contributions

Acknowledgements

Availability of data and materials

References

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