Fruit Intake and Respiratory Health: Results from Mendelian Randomization

doi:10.21203/rs.3.rs-3250514/v1

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Fruit Intake and Respiratory Health: Results from Mendelian Randomization

https://doi.org/10.21203/rs.3.rs-3250514/v1

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Background

Respiratory disease contributes to a substantial burden of disease and mortality. It continues to impact human health and the quality of life under the continuous advancements in prevention and treatment. As reported by previous research, dietary factors might be regarded as latent risk factors for lung disease, suggesting that a vegetarian diet can effectively reduce mortality.

Methods

In this study, genome-wide association studies (GWAS) were used to conduct Mendelian randomization (MR) analyses to explore the causal effect of fruit intake on respiratory disease burden including chronic obstructive pulmonary disease, bronchitis, emphysema, and asthma. MVMR was carried out to validate the results under the influence of the other kind of fruit intake.

Results

There was weak evidence for a possible causal relationship between fresh fruit intake and respiratory diseases, whereas a substantial and strong causality was found between dried fruit intake and the four outcomes (COPD_IVW: OR (95% CI) = 0.32 (0.22, 0. 48), P value < 0.001; asthma_IVW: OR (95% CI) = 0.59 (0.44, 0.79), P value < 0.001; bronchitis_IVW: OR (95% CI) = 0.50 (0.35, 0.73), P value < 0.001; emphysema_IVW: OR (95% CI) = 0.15 (0.05, 0.42), P value < 0.001), with stability confirmed by tests and MVMR.

Conclusions

Our study strengthens the evidence for a positive causal relationship between dried fruit intake and four common respiratory outcomes but fails to show an association between fresh fruit intake and the outcomes, and the reliability of the dietary intervention could be strengthened by further validation.

Fruit intake

Respiratory health

Mendelian randomization

The prevalence of lung diseases has elevated them to a position of paramount concern in global health. Based on information from the World Health Organization, lung diseases are the leading cause of death worldwide, which causes approximately 4 million fatalities annually. In the last few years, extensive research endeavors have been undertaken to propel the advancement of their prevention and treatment modalities after recognizing the damaged implications of lung diseases on quality of life [1–4].

Notably, targeted attention must be directed toward pivotal risk factors, including dietary patterns [5], lifestyle choices, and occupational exposures [6], to prevent these lung diseases effectively. Evidential investigations have stressed the potential of dietary modifications and shifts in culinary behaviors in reducing mortality from lung disease. For instance, vegetarianism displays a significantly reduced Prevalence of respiratory and digestive system diseases compared to non-vegetarians [7].

Epidemiological research has revealed that adding foods rich in antioxidants to your usual diet may reduce the risk of developing chronic lung disease [8]. These studies suggest that consuming abundant quantities of fresh fruits and vegetables is a preventive measure for lung diseases and positively impacts pulmonary function [9]. The antioxidants and vitamins in vegetables and fruits have been associated with a decreased risk of lung cancer, COPD, and other lung diseases. The consumption of fruits, vegetables, and vitamin E has been linked to lower rates of COPD, improved lung function (FEV1), and reduced long-term mortality from COPD among smokers and non-smokers [10, 11]. Observational studies have also demonstrated that fresh fruits and antioxidant vitamins exhibit a more pronounced protective effect on early and childhood asthma. Moreover, increasing the general intake of fruits and vegetables is an effective approach to reducing the risk of asthma [12]. Significantly, lung diseases are interconnected with various systemic diseases and conditions, including heart disease and chronic kidney disease (CKD) [13,14].

While traditional observational studies are prone to errors due to variables such as reverse causality, bias, and confusion, researchers are increasingly focusing on establishing causal relationships, not just the correlations between exposure factors and outcomes. One method to help assess causality is Mendelian randomization (MR), which utilizes genetic variations to infer causal relationships. By employing instrumental variables (IVs) like single nucleotide polymorphisms (SNPs), MR helps determine whether a specific influencing factor has a causal effect on a particular biological outcome by comparing differences between populations with distinct genetic variations. Since genetic variations are independent of an individual’s environment and lifestyle, MR provides more reliable evidence of causal relationships compared with other observational studies.

In this study, a two-sample MR design was employed to investigate the association between dried fruits and fresh fruits consumption and chronic obstructive pulmonary disease, asthma, bronchitis, and emphysema.

2.1 Variables

2.1.1 Exposure

As the exposure, fruit intake was subdivided into fresh fruit intake and dried fruit intake. Datasets for fruit intake were acquired from ieu open gwas (Fresh fruit intake: ukb-b-3881, sample size = 446462; Dried fruit intake: ukb-b-16576, sample size = 421764), and the collection was conducted through the questions: “About how many pieces of fresh fruit would you eat per day? (Count one apple, one banana, 10 grapes, etc., as one piece; put '0' if you do not eat any)” and “About how many pieces of dried fruit would you eat per day? (Count one prune, one dried apricot, 10 raisins as one piece; put '0' if you do not eat any)” with answers over 50 for fresh fruit intake or over 100 for dried fruit intake deemed as invalid.

2.1.2 Outcome

COPD, asthma, bronchitis, and emphysema, the respiratory disease with high importance in the field of public health, were regarded as the outcome. The summary statistics were stretched from FinnGen r8, samplesizes for the four endpoints were COPD: 16410 cases versus 283589 controls; asthma: 37253 cases versus 187112 controls; bronchitis: 49078 cases versus 293421 controls; emphysema: 1655 cases versus 283589 controls, with the definition of each phenotype was able to be retrieved at https://r8.finngen.fi.

2.2 Study design

Figure 1 generalized the whole study design as the flow chart. Mendelian randomization was deemed as the main method exploring causalities from fruit intake on the four phenotypes of lung disease throughout the whole study. The study was teared apart into discovery and validation, the preliminary results of Single-variable MR were utilized to provide directions and foreshadowing for the final conclusion in the part of discovery, scatter plots, funnel plots, and Leave-One-Out analyses were conducted to provide visual judgement, heterogeneity and pleiotropy test and steiger test were also attached to evaluate the sensitivity of the results. Then Multivariable MR using filtered and combined instrumental variants was conducted to validate the causal relationships under the adjustment of potential confounding and interaction-modifying effect from the other type of fruit intake. The design of the research process was under the instruction of the STROBE-MR statement [15].

2.2.1 Selection of instrumental variables

The rationale of the part of SVMR was shown in Fig. 2. The procedure of selection was based on three key assumptions (InSIDE hypothesis) in the MR analysis process: 1) The instrumental variables were closely related to the intake levels of fruit intake, and could effectively affect the intake levels; 2) the IVs only affected the risk of the targeted disease through the intake levels of fresh fruit and dried fruit; 3) The IVs were independent of any confounding factors [16]. Thus, we set P values for association with exposure phenotypes < 5e-8 as the foremost criteria for selecting candidate SNPs, and only those with r2 > 0.001 and clump distance < 10,000 kb were kept to clumped for identifying independent loci. Phenoscanner was applied as the tool recognizing outcome-related or confounding-related factors, while the confounders were defined as the predominant risk factors (smoke, air pollution, respiratory virus, occupational and environmental exposures (e.g., to dust, air pollution, sulfur dioxide, or nitrogen dioxide), obesity, and α1 antitrypsin deficiency) [17–19]. F-statistics for all SNPs were beyond 10, hinting the feasibility of considering the absence of weak instrumental bias. After retrieving and harmonizing the corresponding SNPs’ effect on the outcome, excluding the palindromic SNPs and correcting strand for non-palindromic SNPs. MR-PRESSO test was applied to exclude the outlier SNPs and revalidate the stability with heterogeneity and pleiotropy test additionally conducted respectively [20]. MR-Egger and Cochran's Q tests were introduced to assess heterogeneity and pleiotropy among the SNPs. When both the P-values of Cochran's Q and the intercept of the MR-Egger test were greater than 0.05, additional MR estimation analyses would be carried out. SNPs of SVMR were combined as the instrumental variables of MVMR, while absent SNPs were all excluded.

2.2.2 Analyses of MR estimates

In SVMR, Three MR methods were used to estimate the relationship between fruit intake and the endpoints: inverse variance weighting (IVW), weighted median (WM), and MR-Egger. The IVW estimate was employed as the principal metric to assess the outcomes, while MR-Egger and WM approaches were utilized to validate whether the exposure had a positive or negative impact on the outcome. Despite the potential lower efficiency of MR-Egger and WM compared to the IVW method, they could yield more reliable findings in situations where scenario aggregation is less precise [21]. In cases where 1) the estimates of the three methods were consistent; 2) the IVW results demonstrated statistical significance (Bonferroni correction was applied: P < 0.0125 as four times MR were conducted); 3) Heterogeneity, pleiotropy, and steiger directional test passed did scatter plots constructed, and Leave-One-Out analyses and funnel plots were conducted as a final step in the sensitivity analysis. Conversely, if the estimates were incongruous or the IVW results did not exhibit statistical significance, it would lead to the conclusion that there is no discernible causal relationship between the given exposure and the outcome.

Considering the possibility that the other type of fruit intake served as a confounder affecting the causality, MVMR was introduced as validation in the entire study which was used to use genetic variants associated with multiple, potentially related exposures to estimate the effect of each exposure on a single outcome respectively. MVMR-IVW was performed to inspect the effect scale and statistical significance, which provide further stability assessment of SVMR results.

Package “TwoSampleMR” on R (4.2.1 ver.) was utilized to carried out primary statistical analyses including SVMR and MVMR, full documentation was able to be retrieved at https://mrcieu.github.io/TwoSampleMR.

Forest plots for SVMR and MVMR were shown in Figs. 3 and 8, with Scatter plots, Leave-One-Out plots, funnel plots combined as Figs. 3–6 and Supplementary Files 1–4 for each causal relationship from the exposure on the outcome. Table 1 revealed the results of heterogeneity, pleiotropy, and Steiger directional tests

Table 1: Heterogeneity, pleiotropy, and Steiger directional tests for SVMR. IVW, Inverse Variance Weighted .

Exposure	Outcome	P-value for Heterogeneity test (Cochran’s Q)		P-value for Pleiotropy test (MR-Egger intercept)	P-value for Steiger directional test
Exposure	Outcome	MR-Egger	IVW	P-value for Pleiotropy test (MR-Egger intercept)	P-value for Steiger directional test
Fresh fruit intake	COPD	0.211	0.106	0.031	4.189e-113 for True
	Asthma	0.038	0.027	0.147	3.024e-80 for True
	Bronchitis	0.250	0.242	0.281	4.187e-143 for True
	Emphysema	0.775	0.802	0.771	6.718e-85 for True
Dried fruit intake	COPD	0.935	0.951	0.933	6.563e-68 for True
	Asthma	0.189	0.184	0.316	2.389e-50 for True
	Bronchitis	0.562	0.484	0.177	1.474e-147 for True
	Emphysema	0.906	0.921	0.667	2.603e-90 for True

3.1 Influence of fresh fruit on respiratory health

Significant results from fresh fruit on asthma were discovered (asthma_IVW: OR (95% CI) = 0.57 (0.40, 0.81), P = 0.002 < 0.0125 with correspondent effect directions of MR-Egger and Weighted Median), while little evidence suggesting the causality from fresh fruit on COPD, bronchitis, and emphysema (all P values for IVW > 0.0125). Concerning on validating the causal influence of fresh fruit on the risk of asthma, we found potentially indicated heterogeneity (P for Cochran’s Q test_IVW = 0.027 < 0.05) which approves the possible lack of replicability. All Steiger directional tests didn’t suggest any reversal causality.

3.2 Influence of dried fruit on respiratory health

In contrast, relatively intensive causalities from dried fruit intake on the liability of all respiratory diseases were disclosed with statistical significance: COPD_IVW: OR (95% CI) = 0.32 (0.22, 0.48), P value < 0.001; asthma_IVW: OR (95% CI) = 0.59 (0.44, 0.79), P value < 0.001; bronchitis_IVW: OR (95% CI) = 0.50 (0.35, 0.73), P value < 0.001; emphysema_IVW: OR (95% CI) = 0.15 (0.05, 0.42), P value < 0.001 with correspondent effect directions of all MR-Egger and Weighted Median, which revealed that with each standard difference (SD) of dried fruit intake per day, the risk of endpoints declines by approximately 68% for COPD, 41% for asthma, 50% for bronchitis, and 85% for emphysema. All heterogeneity and pleiotropy tests and vision inspection strengthened the reliability of the four detected causal relationships. All Steiger directional tests didn’t suggest any reversal causality.

3.3 Independent fruit intake effect on respiratory health based on MVMR

Under the adjustment of the other kind of fruit intake, an independent effect was observed to validate the unbiased results in SVMR. The causal effect of dried fruit intake on respiratory health was steadily observed (COPD_IVW: OR (95% CI) = 0.33 (0.20, 0.54), P value < 0.001; asthma_IVW: OR (95% CI) = 0.64 (0.93, 0.44), P value = 0.018; bronchitis_IVW: OR (95% CI) = 0.52 (0.33, 0.81), P value = 0.004; emphysema_IVW: OR (95% CI) = 0.13 (0.04, 0.40), P value < 0.001), while still no significant causal relationships between fresh fruit intake and respiratory health were reported.

This study employs a comprehensive analytical approach, incorporating various established MR analysis methods, to investigate the potential causal association between the consumption of fresh and dried fruits and four respiratory diseases, specifically asthma, COPD, and the two composite phenotypes of COPD - emphysema and bronchitis.

Much research conducted [22–25] has consistently demonstrated that the consumption of fresh fruits can effectively mitigate the risk of those mentioned above four pulmonary diseases. However, the impact of dried fruit consumption on asthma remains unclear, as there is a lack of comprehensive understanding in this area. Notably, Wenwen Yang et al.'s recent MR analysis study revealed a positive association between dried fruit intake and a decreased likelihood of developing asthma [26]. Conversely, a previous survey failed to provide conclusive evidence supporting a causal link between dried fruit consumption and asthma [27]. It is important to note that limited research has been conducted to explore the relationship between dried fruit intake and asthma. Therefore, this MR study takes dried fruit intake as an exposure factor to explore its causal relationship with the four aforementioned pulmonary diseases.

In modern epidemiological research, the relationship between fresh fruit intake and COPD has been verified in many studies [28–30]. However, traditional observational studies still have biases caused by reverse causality and fuzzy time series. Few studies have demonstrated the relationship between fresh fruit intake and emphysema, bronchitis, and asthma. Since emphysema and bronchitis share similar clinical characteristics with COPD, the MR results of the three diseases' comprehensive study are more reasonable. Therefore, we conducted a Mendelian randomization analysis on fresh fruit intake and the four pulmonary diseases mentioned above.

Based on the above findings, this MR study demonstrates that dried fruit intake protects the four pulmonary diseases mentioned above. In comparison, no evidence suggests a causal effect of fresh fruit intake on these four pulmonary diseases.

Based on extant research, the consumption of dried fruits exhibits potential implications for preventing and managing chronic obstructive pulmonary disease (COPD). Dried fruits encompass diverse chemical constituents, such as quercetin (a flavonoid) and ellagic acid (a polyphenol), which possess antioxidant properties. Flavonoids exert robust antioxidant activity by blocking and clearing free radicals [31]. Quercetin can protect and reduce macrophages from oxidative stress caused by exposure to cigarette smoke by reducing white blood cell levels, histological changes in lung tissue patterns, and changes in lung function [32]. The oxidative stress levels negatively correlate with patients' lung function, Henry Jay Forman et al. reported. The result indicates that oxidative stress occurs in the lungs and the whole body of COPD patients and contributes to the pathogenesis of the disease [33]. Polyphenols, another chemical component of dried fruits, affect COPD differently. They capture free radicals or donate electrons to free radicals to reduce cellular oxidative stress damage caused by free radicals. Research has found that ellagic acid can inhibit the growth and formation of various bacteria and reduce bacterial adhesion in the lungs, thereby reducing inflammation caused by bacterial infections. In addition, ellagic acid can alleviate neutrophil chemotaxis and reduce inflammation in NCI-H292 cells and RAW 264.7 macrophages, exhibiting anti-inflammatory effects [34]. Ellagic acid has great potential for protecting the lungs from damage caused by bacterial infections in COPD. Therefore, we speculate that the chemical components contained in dried fruits can explain the correlation between eating dried fruits and the risk of COPD, but the effect of fresh fruits on this remains to be discovered.

Indeed, this study has several advantages. First, the MR analysis mitigates biases caused by confounding and reverse causality since alleles are randomly arranged at conception, compared to inherent limitations in observational epidemiological studies. Second, MR reduces unnecessary time and cost expenditures as well as confounding SNP biases, as SNPs are determined at conception while achieving highly reliable results. Then, MVMR allows us to investigate the independent causal effect of the exposures on the outcomes considering the interaction between the exposures, working as the validation of the results. Last but not least, few MR studies to date on the causal relationship between fruit intake and asthma, COPD, bronchitis, and emphysema, while low fruit intake is a globally significant risk factor for mortality, and these four pulmonary diseases have a high global incidence. Using MR analysis to reveal their causal relationships with fruit intake could provide new insights for clinical trials and potentially influence public health policies for preventing pulmonary disease.

However, this MR study still has some limitations. Firstly, our study population was limited to the European region, and further exploration is needed to verify whether the results are consistent in other regions. Secondly, we should pay more attention to the intake of different types of fresh and dried fruits and the constituents of fruits. Future studies on the continuum of fruit intake could also be attempted.

To recapitulate, this study highlights the potential of dried fruit intake to mitigate the risk of respiratory disease and emphasizes the importance of altering dietary patterns to promote respiratory health. To confirm these findings and to gain a more comprehensive understanding of the relationship between fruit intake and respiratory disease, further research and longitudinal studies are warranted.

Data Share Statement

Data described in the manuscript, code book, and analytic code will be made available upon request pending application.

Ethical approval

No additional ethics approval was needed because all data in the study was previously collected, analyzed, and published.

Declaration of competing interest

The authors declare no conflicts of interest.

Consent for publication

Not applicable.

Funding

The study did not receive any funding.

Author contribution

LWZ and ZZY contributed to data enrollment, statistical analysis, study design, manuscript writing, and proofreading, CJP, YZH, WMH, and WLL contributed to the statistical analysis and composing of the manuscript, and GWJ, GXG contributed to the project design and administration. All authors have granted their approval for the manuscript.

Acknowledgments

We appreciate the time and effort given by participants and investigators of the UK Biobank and the MRC-IEU consortium. We are grateful for instructions from Prof. Xiong Chen and Prof. Jia-Hao Cai on methodologies and the details of the study design.

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SupplementaryFigure1.pdf
Supplementary Figure 1: Scatter plot, Leave-One-Out plot, and funnel plot for the effect of fresh fruit intake on COPD.
SupplementaryFigure2.pdf
Supplementary Figure 2: Scatter plot, Leave-One-Out plot, and funnel plot for the effect of fresh fruit intake on asthma.
SupplementaryFigure3.pdf
Supplementary Figure 3: Scatter plot, Leave-One-Out plot, and funnel plot for the effect of fresh fruit intake on bronchitis.
SupplementaryFigure4.pdf
Supplementary Figure 4: Scatter plot, Leave-One-Out plot, and funnel plot for the effect of fresh fruit intake on emphysema.
Legends.docx
STROBEchecklistv4combined.pdf

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Fruit Intake and Respiratory Health: Results from Mendelian Randomization

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Abstract

Background

Methods

Results

Conclusions

Figures

1. Introduction

2. Materials and methods

2.1 Variables

2.1.1 Exposure

2.1.2 Outcome

2.2 Study design

2.2.1 Selection of instrumental variables

2.2.2 Analyses of MR estimates

3. Result

3.1 Influence of fresh fruit on respiratory health

3.2 Influence of dried fruit on respiratory health

3.3 Independent fruit intake effect on respiratory health based on MVMR

4. Discussion

Declarations

References

Supplementary Files

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