Assessing the Influence of Air Pollution on cholelithiasis Formation and Blood Lipid Levels: A Two-Sample Mendelian Randomization Study

doi:10.21203/rs.3.rs-4811191/v1

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Assessing the Influence of Air Pollution on cholelithiasis Formation and Blood Lipid Levels: A Two-Sample Mendelian Randomization Study

https://doi.org/10.21203/rs.3.rs-4811191/v1

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Purpose: This study used a two-sample Mendelian randomization (MR) method to explore the potential causal relationship between air quality, cholelithiasis and its related risk factor, blood lipids.

Patients and methods: This study used Mendelian randomization in European and East Asian groups, utilizing publicly available GWAS data. The main method was inverse variance weighting (IVW), with additional quality checks including weighted median, MR-Egger, simple, and weighted models. Cochran's Q test assessed heterogeneity. MR-Egger regression and MRPRESSO checked for gene pleiotropy, with sensitivity tests using leave-one-out analysis.

Results: No statistically significant association was observed between air pollution and cholelithiasis in both European and East Asian populations for all pollutants analyzed, including PM2.5 (European: p = 0.745, East Asian: p = 0.209), PM2.5–10 (European: p = 0.737), PM10 (European: p = 0.258, East Asian: p = 0.977), NO₂ (European: p = 0.986, East Asian: p = 0.893), and NOx (European: p = 0.902, East Asian: p = 0.843). However, significant correlations between air pollution and blood lipids were identified. In European populations, PM2.5 was significantly correlated with triglycerides (Beta: 0.428; OR: 1.534; 95% CI: 1.058-2.225; p = 0.024). In East Asian populations, PM2.5 showed a significant association with LDL cholesterol (Beta: 0.050; OR: 1.051; 95% CI: 1.006-1.098; p = 0.026). Importantly, no evidence of heterogeneity or pleiotropy was detected in these associations, bolstering the credibility of our findings.

Conclusion: Our study found no clear causal link between air pollution and cholelithiasis. However, we observed significant correlations between PM2.5 and triglycerides in Europeans, and between PM2.5 and LDL cholesterol in East Asians. These results suggest that PM2.5 might affect triglyceride and LDL cholesterol metabolism differently in various populations, potentially raising the risk of cholelithiasis indirectly.

air pollution

cholelithiasis

particulate matter

nitrogen oxides

nitrogen dioxides

Blood lipids

Cholelithiasis represents a prevalent health concern, with notable variations in its prevalence across different populations. Ultrasound studies have revealed an average prevalence of cholelithiasis ranging from 10–15% in European adults to 3–5% in African populations [1]. Notably, in China, the prevalence of cholelithiasis is escalating, with rates ranging from 5–11% [2]. Alarmingly, a considerable proportion of individuals with cholelithiasis remain asymptomatic. Specifically, 76.7% of men and 72% of women are unaware of their condition, and 87.0% of men and 84.9% of women exhibit no symptoms [3, 4]. However, despite its often asymptomatic nature, complications necessitating surgery arise in approximately 1–2% of patients annually [5]. In the United States, cholelithiasis is the leading inpatient diagnosis among gastrointestinal disorders [6]. GERD incurs the highest annual direct costs at $9.3 billion, followed by cholelithiasis at $5.8 billion [7]. With the global incidence of cholelithiasis on the rise, elucidating its etiology assumes paramount importance.

The development of cholelithiasis involves multiple factors, with critical roles played by bile acid and lipoprotein metabolism in its formation. [8]. Epidemiological evidence has elucidated the association between obesity, metabolic syndrome (characterized by hypercholesterolemia, hypertriglyceridemia, LDL cholesterol, and HDL cholesterol), and the development of cholelithiasis, with cholelithiasis often regarded as complications of metabolic dysregulation. Specifically, elevated triglyceride levels are implicated in cholelithiasis pathogenesis through disturbances in lipid homeostasis, influencing bile composition and predisposing to cholesterol crystallization [9–11]. In a similar manner, elevated LDL cholesterol levels interfere with cholesterol metabolism, causing the liver to secrete excess cholesterol into bile. This process increases cholesterol saturation, promotes crystal formation, and ultimately leads to the development of cholelithiasis. Animal models have provided further insights, demonstrating the potential preventive role of lipid regulation in cholelithiasis [12, 13]. It is significant that cholelithiasis and dyslipidemia have several overlapping risk factors, such as obesity, high-fat diets, and sedentary lifestyles [14–16]. Simultaneously, recent studies suggest a connection between prolonged exposure to atmospheric particulate matter (PM) and dyslipidemia, illustrating that PM exposure can alter lipid profiles and increase the risk of dyslipidemia. [17–19].

In today's industrialized societies, air pollution presents a major issue, posing serious threats to human health. Harmful substances such as PM2.5, PM10, NO2, and NOx are commonly found in the atmosphere and have a notable impact on respiratory health. Numerous studies have also highlighted their wider health effects [20, 21]. Research by Jeroen de Bont and colleagues found a significant link between long-term air pollution exposure and increased risks of cardiovascular death and diseases, including stroke, hypertension, and ischemic heart disease. Fine and coarse particles (PM2.5 and PM10), as well as nitrogen oxides, are identified as major contributors to these health issues [22]. Furthermore, Drew A. Glencross et al. delineated the pro-inflammatory immune response incited by ambient air pollutants, characterized by oxidative stress, Toll-like receptor (TLR) activation, and dysregulated intracellular signaling pathways, culminating in inflammation and tissue damage [23]. Notably, investigations probing the association between cholelithiasis and air pollution have suggested a potential link, particularly implicating chronic exposure to ambient particulate matter in heightened cholelithiasis risk among Chinese adults, with dyslipidemia potentially mediating this relationship [24]. Mengyao Wang et al. found that exposure to PM2.5 causes a decrease in the expression of the Farnesoid X receptor (FXR), a crucial nuclear receptor activated by bile acid, playing a vital role in lipid metabolism. FXR modulation by PM2.5 may precipitate hepatocellular steatosis, elucidating a mechanistic pathway underlying PM2.5-induced hepatic pathology [25–27]. Nonetheless, the precise association between cholelithiasis and environmental factors, particularly air pollution, remains enigmatic, warranting further investigation in the present study.

Airborne pollutants infiltrate the human body through diverse routes, instigating inflammatory reactions and oxidative stress, thereby potentially inducing cellular injury and metabolic derangements [28]. This research aims to investigate the impact of air pollution on cholelithiasis and its related risk factors, with a specific emphasis on lipids. Breathing in fine particulate matter endangers respiratory health and can enter the bloodstream, affecting both the development of cholelithiasis and lipid metabolism [29]. This expanded viewpoint sheds light on the interaction between environmental factors and the development of cholelithiasis.

To investigate the potential connection between air pollution and cholelithiasis, publicly accessible GWAS data were used. This research incorporated exposure factors like particulate matter (PM) and nitrogen compounds. The outcome variables were cholelithiasis and associated lipid parameters, allowing for the assessment of causal links between air pollution and cholelithiasis. Additionally, comprehensive analyses were performed on European and East Asian cohorts to investigate geographic differences in the association between air pollution and cholelithiasis. This varied method enables the inclusion of different geographical and demographic factors, as well as possible genetic and environmental impacts. These stratified analyses provide detailed insights and enhance the understanding of how air pollution impacts cholelithiasis. As a result, the findings from this study hold global significance, offering crucial insights that can inform future scientific investigations. Furthermore, these outcomes offer a vital foundation for creating and improving public health policies aimed at addressing the impact of air pollution on gallstone disease. This research not only broadens our knowledge but also supports policymakers in formulating effective strategies to protect public health.

2.1. Design

This study is based on three key assumptions: (1) the instrumental variables are associated with air pollution (exposure), (2) they do not affect cholelithiasis or its related risk factor, blood lipids (outcome), through confounding variables, and (3) their impact on the outcome happens exclusively through air pollution [30]. Air pollution, including various forms of particulate matter and nitrogen compounds, is the primary exposure factor, with relevant SNPs used as instrumental variables. The study focuses on cholelithiasis and its related lipid parameters as outcome variables. Figure 1 provides a schematic representation. A two-sample Mendelian randomization analysis was performed to thoroughly evaluate the possible causal link between air pollution and cholelithiasis. Figure 2 illustrates the MR design.

2.2. Data sources

For this analysis, pollutants in the air, including small particles and nitrogen-based substances, were used as exposure variables. Data on air quality were retrieved from the UK Biobank [31, 32], with related metrics assessed through land-use regression (LUR) models [33]. Information on cholelithiasis and associated lipid metrics, obtained from the IEU Open GWAS project, served as the outcome variables. Table 1 provides a comprehensive summary of these data sources. Mendelian randomization was employed in this investigation, utilizing publicly available databases. Given the non-invasive nature of the methodology and absence of sensitive personal data collection, no additional ethical review was warranted.

2.3. Instrumental Variable Selection

As illustrated in Fig. 2, a genome-wide significance threshold of p < 5 × 10^− 8 was utilized for the exposure, in line with hypothesis (1). Among the factors considered, only PM2.5, PM10, NO₂, and NOx from European data sets had sufficient SNPs.

Previous studies have shown that using linear regression with a screening threshold of p < 5 × 10 − 6 for each genetic variant diminishes the likelihood of weak instrument bias in Mendelian randomization studies [34, 35], We modified the genome-wide significance level to p < 5 × 10^− 6 for the remaining exposures to find sufficient SNPs as instrumental variables (IVs) linked with this degree of significance. PM2.5-10 ( East Asia ) was excluded due to insufficient SNP yield, even after reducing the gene-wide significance threshold.

To exclude SNPs in linkage disequilibrium (LD), r² < 0.001 and kb > 10,000 were set at the time of IV extraction. Palindromic SNPs were subsequently excluded to ensure consistency in allele effects between exposure and outcome. We then computed the R² [36] and the F-statistic [37] for each SNP. The R² represents the overall degree of explanation of all genetic variants for the target exposure, and the F-statistic assesses the strength of the instrumental variable. The F-statistic of each of our selected SNPs is greater than 10, indicating that the selected genetic tools are strong predictors of exposure [38]. Detailed SNP information, R2, and F-statistic values are presented in Supplementary Tables 1–11.

2.4. Genetic Instrumental Variable Analysis

The causal relationship between air pollution, cholelithiasis, and lipids was assessed utilizing the IVW method, initially proposed by Stephen Burgess et al. in 2013 and now widely adopted as the primary analytical approach in Mendelian randomization studies [39, 40]. This method computes the exposure-outcome causal effect for each genetic variant via Wald's method, followed by aggregating these effects using the inverse variance as weights to derive the overall effect estimate. Furthermore, to enhance result reliability and accuracy, we employed weighted median, MR-Egger, simple, and weighted models to validate the causal association between exposure and outcome variables [41].

2.5. Sensitivity analysis

Sensitivity analyses were executed using both the leave-one-out method and the outlier detection approach (MR-PRESSO). The outlier method identifies and addresses potential significant outliers that may introduce heterogeneity and distort the analyses. The leave-one-out method examines individual SNP effects on causality. Each SNP underwent sensitivity analyses to identify and exclude variables with potential significant impacts on the results. The MR-Egger intercept test was utilized to evaluate multiplicity, with the threshold for significance established at P < 0.05, signifying the existence of multiplicity. Heterogeneity was evaluated through IVW and MR-Egger tests, with significance set at P < 0.05 indicating heterogeneity in the study. In cases of study heterogeneity, MR analysis was performed using the random-effects IVW method.

2.6. Statistical analysis

The implementation of Mendelian randomization was performed using the 'TwoSampleMR', 'MendelianRandomisation', and 'gwasglue' libraries within the R statistical framework, version 4.2.3.

3.1. Air pollution and cholelithiasis

MR studies were conducted to assess the causal impact of air pollution components on cholelithiasis within both European and East Asian populations. After excluding instrumental variables with chain imbalance, the number of SNPs per pollutant ranged from 5 to 23 for Europeans (Table 2) and from 3 to 6 for East Asians (Table 3). Using various analytical methods, no significant evidence of a causal link between air pollution and cholelithiasis was found in either population. Specifically, the p-values obtained using the IVW method were as follows: PM2.5 (Europe: p = 0.745, East Asia: p = 0.209), PM2.5-10 (Europe: p = 0.737), PM10 (Europe: p = 0.258, East Asia: p = 0.977), NO₂ (Europe: p = 0.986, East Asia: p = 0.893), and NO_x (Europe: p = 0.902, East Asia: p = 0.843). Additionally, no significant heterogeneity or horizontal pleiotropy was detected (Tables 2 and 3). The scatterplots of causal estimates are shown in Figs. 3 and 4, while leave-one-out analyses (Figs. 5 and 6) indicated minimal impact on the overall causal effect estimates upon SNP exclusion.

3.2. Air pollution and blood lipids

MR results (Tables 4–5) and scatter plots and forest plots (Supplementary Figs. 1–16) are shown.

To further investigate the association between air pollution and cholelithiasis, lipids, recognized as a pertinent risk factor for the condition, were chosen as the study outcome and subjected to re-analysis in the MR study.

In European populations, no causal relationship was found between the following air pollution components and blood lipids: PM2.5 (total cholesterol levels: p = 0.491, LDL: p = 0.975, HDL: p = 0.136), PM2.5-10 (total cholesterol levels: p = 0.735, LDL: p = 0.417, HDL: p = 0.754), PM10 (total cholesterol levels: p = 0.619, LDL: p = 0.991, HDL: p = 0.979), NO₂ (total cholesterol levels: p = 0.745, LDL: p = 0.392, HDL: p = 0.241), and NOx (total cholesterol levels: p = 0.924, LDL: p = 0.772, HDL: p = 0.426). Similarly, in East Asian populations, evidence of a causal relationship between the following air pollution components and blood lipids was not found in replicated Mendelian randomization studies: PM2.5 (triglycerides: p = 0.282, total cholesterol levels: p = 0.053, HDL: p = 0.647), PM10 (triglycerides: p = 0.841, total cholesterol levels: p = 0.346, HDL: p = 0.187), NO₂ (triglycerides: p = 0.406, total cholesterol levels: p = 0.853, HDL: p = 0.352), and NOx (triglycerides: p = 0.774, total cholesterol levels: p = 0.318, HDL: p = 0.575).

However, in European populations, we identified six SNPs (rs77205736, rs6749467, rs1372504, rs12203592, rs77255816, rs1537371) strongly associated with PM2.5 as instrumental variables. Using the IVW method, we observed a significant association between PM2.5 and triglycerides (Beta: 0.428; OR: 1.534; 95%CI: 1.058–2.225; p = 0.024). Likewise, in the East Asian populations, we identified three SNPs strongly associated with PM2.5 (rs11067476, rs7630570, rs80151214) as instrumental variables and detected significant associations between PM2.5 and HDL cholesterol using the IVW method (Beta: 0.050; OR: 1.051; 95%CI: 1.006–1.098; p = 0.026). These results provide important clues to further our understanding of the complex relationship between air pollution and specific lipid fractions.

Despite increasing evidence linking environmental factors to various health conditions, epidemiological evidence connecting air pollution to cholelithiasis remains limited, and the precise role of particulate matter in causing cholelithiasis is still unclear. In a study examining the effects of extended metal pollution exposure on human health through the analysis of gallstones[42], it was found that airborne particulate pollutants, particularly in regions with frequent mining activities, can enter the bloodstream through inhalation and deposit in the gallbladder, gradually accumulating to form gallstones. This finding suggests a plausible mechanism by which particulate matter exposure could increase the risk of cholelithiasis. The rationale behind this link is that the body eliminates some of these inhaled pollutants through bile excretion [43], resulting in their accumulation in the gallbladder over time.

To our knowledge, only a handful of studies have investigated the association between cholelithiasis and air pollution. The first epidemiological study on this topic was conducted by Chan Nie et al. using a cross-sectional study using initial data from the Chinese Multi-Ethnic Cohort [24]. The study comprised 72,893 participants aged 30–79 years, hailing from five southwestern provinces of China and representing seven distinct ethnic groups. The participants' prolonged average exposure to particulate matter was evaluated using validated spatio-temporal models. The association between ambient particulate matter and cholelithiasis risk was evaluated through unconditional logistic regression. Furthermore, mediation analyses were performed to determine if dyslipidemia influenced the link between particulate matter and cholelithiasis. Higher levels of ambient particulate matter were positively associated with an increased risk of cholelithiasis. The odds ratios (ORs) (95% CI) per 10 µg/m³ increase in particulate matter were 1.17 (1.06, 1.28) for PM1, 1.10 (1.05, 1.15) for PM2.5, and 1.07 (1.04, 1.10) for PM10. Mediation analyses indicated that dyslipidemia significantly influenced the relationship between particulate matter and cholelithiasis, with mediation ratios of 5.37%, 9.13%, and 7.66% for PM1, PM2.5, and PM10, respectively. The study suggests that extended exposure to ambient particulate matter may increase the risk of cholelithiasis among Chinese adults, with dyslipidemia possibly mediating this association. Subsequent investigations indicate that this correlation could be notably pronounced in various subpopulations, such as men, alcohol consumers, and centrally obese individuals.

Contrary to the findings of Chan Nie et al., our Mendelian randomization study did not reveal direct genetic evidence linking air pollution to cholelithiasis. However, when examining the causal link between air pollution and lipid levels, a notable association was found between PM2.5 exposure and triglyceride levels in a European population. Additionally, a significant causal link was identified between PM2.5 exposure and LDL cholesterol levels in East Asian populations.

It's worth noting that Chan Nie et al. employed a cohort study with a cross-sectional design, which does not establish causality between exposure and outcome but rather indicates an association. Limitations of their study include reliance on self-report and physical examination of participants, dependence on survey data, and limited detail on covariate controls' adequacy. Adjustments for factors like age, sex, ethnicity, and degree of urbanization might not have been comprehensive enough to eliminate the influence of other potential variables. In contrast, our study represents the first exploration of the causal relationship between air pollution and cholelithiasis using MR methods.

Mendelian randomisation studies present several advantages, including random assignment, enabling causal inference, controlling for confounding variables, conducting long-term follow-up, and implementing double-blind designs. Random assignment clarifies causality, mitigates confounding effects, and enhances experimental control. Long-term follow-up enables the observation of effects' persistence and temporal changes, while double-blind designs minimize subjective bias.

While our analyses did not reveal direct causal relationships, further investigation into the connection between air pollution and blood lipid levels may uncover potential mediating mechanisms. Earlier research has demonstrated a notable association between blood lipid irregularities and the risk of cholelithiasis. Zhang et al.[44] conducted a multi-center study and found that elevated triglycerides and LDL cholesterol levels increase the risk of cholesterol supersaturation in bile, leading to gallstone formation. Similarly, Wang et al.[45] performed a population-based analysis in a large Chinese cohort, identifying high levels of triglycerides and LDL cholesterol as significant risk factors for gallbladder stones. These results emphasize the significance of lipid management in lowering the occurrence of gallbladder stones, proposing lipids as potential mediators in the formation of cholelithiasis.

In our research, although we sought to clarify the causal relationship between air pollution and cholelithiasis, our results did not show a direct connection. However, upon refocusing the inquiry on the causal association between air pollution and blood lipids, a novel insight emerged: particulate matter might influence the metabolic pathways of triglycerides or LDL cholesterol in specific demographics. This is consistent with earlier epidemiological research, which has similarly identified a link between air pollution exposure and adverse changes in lipid profiles. [46–49]。In a Chinese multi-ethnic cohort study encompassing 67,305 participants [50], the relationship between ambient air pollution and blood lipids was investigated using a satellite-based spatio-temporal model to estimate the average concentrations of various air pollution particles over three years. Ultimately, extended exposure to air pollutants was discovered to correlate with lipid levels and the risk of dyslipidemia. Certain experimental models have suggested that higher exposure to PM2.5 may result in increased levels of triglycerides, total cholesterol, and LDL cholesterol. [51–53]。

By conducting an in-depth analysis of the causal relationship between air pollution and lipid profiles, our objective was to pinpoint potential biological mechanisms clarifying the effects of air pollution on cholelithiasis. The variations observed in the associations between European and East Asian populations in our findings are likely caused by genetic and environmental differences among these groups. Additionally, differences in environmental conditions and air pollution levels between regions might also explain these disparities. Variations in atmospheric makeup, climate conditions, and emission sources between European and Asian areas can lead to significant differences in air pollution exposure among populations in these regions.

This highlights the complex interactions between environmental, genetic, and biological factors, requiring more extensive research to clarify how air pollution affects cholelithiasis. Moreover, disparities in data collection methods and criteria across regions may impede study comparability. In the East Asian cohort, the study results were predicated on a genome-wide significance threshold of 5 × 10^− 8 due to an insufficient number of SNPs reaching this threshold. Furthermore, the comparatively small sample sizes in the GWAS dataset for each pollutant can present difficulties for the study's representativeness and generalizability. To gain a more complete understanding of this matter, future studies should include data from various regions and populations to provide a thorough perspective.

In conclusion, this paper explored the correlations between air pollution, cholelithiasis, and lipid profiles, which may offer a more nuanced comprehension of the collective impact of environmental factors on health. Medical professionals should consider environmental factors, like air pollution levels, in their risk evaluations for lipid metabolism disorders and cholelithiasis. It is recommended to regularly monitor blood lipid levels in people exposed to elevated levels of PM2.5. Preventive actions, such as lifestyle changes and limiting outdoor activities during high pollution times, should be advised for patients, particularly those in heavily polluted regions. An integrated, multi-disciplinary approach involving family physicians, cardiologists, and public health experts is essential for effectively tackling the impact of air pollution on lipid metabolism and the associated risk of cholelithiasis development.

Mendelian Randomization

GWAS

Genome-Wide Association Study

IVW

Inverse Variance Weighting

SNP

Single Nucleotide Polymorphism

Particulate Matter

linkage disequilibrium

Instrumental Variable

Ethics approval and consent to participate

Not applicable.

Competing interests

The authors have declared that there are no conflicts of interest related to this work.

Consent for publication

Not applicable.

Funding

This research was supported by the Hubei Provincial Natural Science Foundation of China (grant no. 2023AFB160) and the Scientific Research Project of Tongji Hospital (grant no. 2023B05).

Authors' contributions

Zekang Xu conceptualized and wrote the paper, Lei Yang and Shuting Wu conducted data mining, Yunxiang Feng handled literature citation, and Zhengdong Deng and Jianming Wang supervised and directed the study.

Acknowledgements

We extend our appreciation to the study participants, the researchers who supplied the genomic data, the reviewers, and our families for their support.

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Table1. Summary of GWAS Data for Mendelian Randomization Studies on Air Pollution, Blood Lipid Levels, and Cholelithiasis

Note：Dataset: Identifies the source of each dataset used in the analysis. Number of SNPs: The total number of SNPs used as instrumental variables in the Mendelian randomization analysis; Consortium: Names the research consortium or database providing the data. "NA" indicates that this information is not available. MRC-IEU stands for Medical Research Council Integrative Epidemiology Unit.

Table2. Impact of Air Pollution on Cholelithiasis in European Cohorts

Note：Beta: The estimated effect size indicating how air pollution influences cholelithiasis and blood lipid levels; p: The p-value showing the statistical significance of the association between air pollution and the outcomes; P (Cochran’s Q heterogeneity test): The p-value from Cochran's Q test, evaluating the heterogeneity among SNPs used as instruments for air pollution; P (MR-Egger intercept test): The p-value from the MR-Egger intercept test, assessing directional pleiotropy, which indicates whether SNPs affect cholelithiasis and blood lipids through pathways other than air pollution; P (MR-PRESSO global test): The p-value from the MR-PRESSO global test, detecting and correcting for horizontal pleiotropy, which assesses if there are pleiotropic effects influencing the association between air pollution and the outcomes.

Table3. Impact of Air Pollution on Cholelithiasis in East Asian Cohorts.

Note: Refer to the notes under the previous tables for indicator and test explanations.

Table4. Impact of Air Pollution on Blood Lipid Levels in European Cohorts Using the IVW

Note: Refer to the notes under the previous tables for indicator and test explanations.

Table5. Impact of Air Pollution on Blood Lipid Levels in East Asian Cohorts Using the IVW

Note: Refer to the notes under the previous tables for indicator and test explanations.

No competing interests reported.

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Assessing the Influence of Air Pollution on cholelithiasis Formation and Blood Lipid Levels: A Two-Sample Mendelian Randomization Study

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Abstract

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1. Introduction

2. Research Methods

2.1. Design

2.2. Data sources

2.3. Instrumental Variable Selection

2.4. Genetic Instrumental Variable Analysis

2.5. Sensitivity analysis

2.6. Statistical analysis

3. Analysis Results

3.1. Air pollution and cholelithiasis

3.2. Air pollution and blood lipids

4. Discussion

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