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. 2024 Feb 13;19(2):e0298123. doi: 10.1371/journal.pone.0298123

Caffeinated beverages intake and risk of deep vein thrombosis: A Mendelian randomization study

Tong Lin 1,*, Haiyan Mao 1, Yuhong Jin 1
Editor: Eyüp Serhat Çalık2
PMCID: PMC10863885  PMID: 38349931

Abstract

This study aimed to explore the potential link between coffee and tea consumption and the risk of deep vein thrombosis (DVT) through Mendelian randomization (MR) analysis. Employing the MR, we identified 33 single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) for coffee intake and 38 SNPs for tea intake. The investigation employed the inverse-variance weighted (IVW) method to evaluate the causal impact of beverage consumption on DVT risk. Additionally, MR-Egger and MR-PRESSO tests were conducted to assess pleiotropy, while Cochran’s Q test gauged heterogeneity. Robustness analysis was performed through a leave-one-out approach. The MR analysis uncovered a significant association between coffee intake and an increased risk of DVT (odds ratio [OR] 1.008, 95% confidence interval [CI] = 1.001–1.015, P = 0.025). Conversely, no substantial causal effect of tea consumption on DVT was observed (OR 1.001, 95% CI = 0.995–1.007, P = 0.735). Importantly, no significant levels of heterogeneity, pleiotropy, or bias were detected in the instrumental variables used. In summary, our findings suggest a modestly heightened risk of DVT associated with coffee intake, while tea consumption did not exhibit a significant impact on DVT risk.

Introduction

Deep vein thrombosis (DVT) is a pathological condition characterized by the formation of one or more blood clots in the deep veins of the body, typically located in the lower extremities. Although DVT may present with leg pain or swelling, it can also be asymptomatic [1]. More seriously, its potential to cause pulmonary embolism (PE), a life-threatening complication that arises when a clot dislodges and obstructs blood flow within the lungs, underscores its clinical significance [2]. The development of DVT is influenced by lifestyle factors, environmental conditions, and various genetic predispositions, such as sedentary habits, obesity, cancer, and post-surgery effects [3]. While lifestyle factors like sedentary behavior and obesity are strongly linked to DVT, the precise impact of dietary elements, including the consumption of caffeinated beverages, on DVT remains uncertain.

Coffee and tea are the two most widely consumed caffeinated beverages globally, both containing biologically active compounds, with caffeine being the most well-known among them. These compounds have been shown to provide various beneficial effects on human health [4,5]. Caffeine has been found to impact the cardiovascular system, causing a rapid increase in heart rate and blood pressure. However, when consumed in moderation, caffeine can potentially reduce the risk of developing cardiovascular disease and may even act as a preventative measure against it [6]. A single study conducted on an older women cohort has explored the link between coffee intake and venous thrombosis in a prospective manner. The findings suggested a slight inverse correlation between coffee consumption and VTE, but after taking into account variables such as body mass index (BMI) and diabetes, the association was no longer significant [7]. Additionally, Enga et al. conducted a prospective cohort study that observed a U-shaped relationship between coffee consumption and venous thromboembolism. Specifically, moderate coffee intake was linked to a decreased risk of venous thromboembolism [8]. These two studies suggest a possible inverse association between coffee and DVT, although the evidence remains inconclusive. Unfortunately, no studies have been found to investigate the association between tea consumption and venous thrombosis. To date, the majority of research has focused on investigating the role of coffee or tea in the pathogenesis of arterial thrombosis and cardiovascular disease (CVD) (e.g. myocardial infarction) [9–12]. As a result, our current understanding of the impact of coffee or tea on the risk of DVT remains limited. However, the association between caffeinated beverages and DVT has not been clearly confirmed in observational studies, and confounding and reverse causality are possible.

Mendelian randomization (MR) is a powerful method that uses genetic variants as instrumental variables to investigate causality between an exposure and an outcome. The use of MR in the study of coffee or tea intake with DVT has several advantages over observational studies. First, genetic variants are randomly allocated at conception, which eliminates the potential for confounding and reverse causality that can occur in observational studies. Second, the effects of genetic variants on coffee or tea intake are not subject to the same bias as self-reported dietary data, reducing measurement error. Finally, MR analysis can provide estimates of causal effects that are less likely to be biased by unmeasured confounding or reverse causality, providing more robust evidence for causal inference. Therefore, the use of MR in investigating the association between coffee or tea intake and DVT risk can provide more reliable and valid results.

Materials and methods

Study design

In order to assess the potential causal relationship between caffeinated beverages and DVT, we conducted a two-sample Mendelian randomization analysis [13]. The study adhered to the MR protocol, shown in Fig 1. It rests on three fundamental assumptions underlying the MR study. First, it is assumed that single-nucleotide polymorphisms (SNPs) are highly correlated with the consumption of caffeinated beverages such as coffee or tea. Second, it is assumed that these SNPs are independent of any potential confounding factors that could influence the outcome being studied. Finally, it is assumed that the effects of the SNPs on the development of DVT are solely mediated through the consumption of caffeinated beverages.

Fig 1. There are three fundamental assumptions underlying the Mendelian randomization study.

Fig 1

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Ethical approval and data sources

This article utilized data from genome-wide meta-analysis (GWAS) [14] that has been ethically reviewed and is publicly available. The summary-level data used in the analysis pertained to traits of interest and were obtained from predominantly European individuals, including both males and females. Specifically, the study focused on coffee intake (https://gwas.mrcieu.ac.uk/datasets/ukb-b-5237/) and tea intake (https://gwas.mrcieu.ac.uk/datasets/ukb-b-6066/) in a European population consisting of 428,860 and 447,485 study subjects, respectively. The summary data for deep vein thrombosis (DVT) were obtained from the MRC Integrative Epidemiology Unit Consortium (MRC-IEU) in 2018 and were included in UK Biobank (https://gwas.mrcieu.ac.uk/datasets/ukb-b-12040/). This data set comprised a total of 462,933 participants, including 9,241 DVT patients and 453,692 controls.

Genetic instrumental variables

In our study, we utilized a set of quality control criteria based on the GWAS summary coffee and tea data to select eligible genetic instrumental variables (IVs). Firstly, we employed independent genetic variants that exhibited significant associations with each exposure (p < 5 × 10−8) for each instrument. Subsequently, we carried out the clumping procedure using a window size >10,000 kb and R2 < 0.001 to eliminate linkage disequilibrium (LD). Secondly, we removed SNPs with a minor allele frequency (MAF) of less than 0.01. Thirdly, to mitigate potential pleiotropic effects, we relied on Phenoscanner (https://www.phenoscanner.medschl.cam.ac.uk), a database housing genotype-phenotype associations, to validate the integrity of the chosen instrumental variables [15]. Established risk factors for DVT, including obesity, cancer, and a history of venous thromboembolism, are well-supported in current literature [3]. Utilizing the Phenoscanner platform, we systematically excluded SNPs associated with these known risk factors, thereby reducing the likelihood of confounding influences. Lastly, we calculated the F-statistic (excluded SNPS with F<10), since the included IVs were susceptible to weak IVs [16].

Statistical analysis

To investigate the potential causal association between Coffee intake, tea intake and the risk of DVT, we used inverse variance weighted (IVW) [17] analysis as the primary method for Mendelian randomization analysis, complemented by weighted-median method [18], MR-Egger method [19], weighted mode and simple mode. Subsequently, Cocrane’s Q test and MR-Egger regression were used to assess the presence of heterogeneity and pleiotropy among SNPs, respectively. Furthermore, to test for outlier SNPs, we used MR-PRESSO and performed "leave-one-out" analyses, excluding one SNP at a time to assess the stability of our results. If the IVW method yielded a significant result (p < 0.05) and provided that the beta values of the other methods exhibited a consistent direction, we considered it a positive finding, even if other methods were not significant and no pleiotropy or heterogeneity was identified [20,21]. In cases where horizontal pleiotropy was identified but not heterogeneity, we selected the MR-Egger method. If heterogeneity was detected without pleiotropy, we utilized the weighted-median method or the multiplicative random-effects IVW method. The MR results were reported as odds ratios (OR) with corresponding confidence intervals (CI) and visualized using forest plots and scatter plots. We conducted all analyses using the TwoSampleMR and MRPRESSO packages in R (version 4.2.1).

Results

Regarding coffee intake as the exposure factor, we excluded four SNPs (rs1421085, rs62064918, rs476828, rs56113850) associated with risk factors for DVT by Phenoscanner, particularly those linked to obesity and cancer. Additionally, we removed one SNP (rs10119174) exhibiting palindromic allele frequencies related to coffee intake. Similarly, in the context of tea intake as the exposure factor, we excluded rs9937354 due to its association with cancer by Phenoscanner, and rs2783129 due to its palindromic allele frequencies related to tea intake and their correlation with risk factors for DVT. After the clumping process, we identified 33 SNPs (S1 Appendix) and 38 SNPs (S2 Appendix) as instrumental variables to investigate the genetic association between coffee and tea intake and the risk of DVT, respectively. The two-sample MR analysis suggested a modest association, demonstrating that genetically predicted coffee intake was marginally associated with a slight increase in the risk of DVT (OR 1.008, 95% CI = 1.001–1.015, P = 0.025). However, the results from the MR analysis showed no significant causal effect of tea intake on DVT (OR 1.001 95% CI = 0.995–1.007, P = 0.735). In term of orientation and magnitude, there was the consistent result observed in the method of the weighted median and MR-Egger (Table 1). This was further illustrated through scatter plots, encompassing both the weighted mode and simple mode analyses (Figs 2 and 3).

Table 1. Mendelian randomization estimates of the associations between caffeinated beverages intake and risk of deep vein thrombosis.

Exposure Methods of MR Number of SNP Beta OR (95% CI) P P For
heterogeneity
test		 P For
MR-Egger intercept		 P For
MR-PRESSO
(outliers = 0)
Coffee intake IVW 32 0.0082 1.008
(1.001–1.015)		 0.025 0.451 0.234 0.482
MR Egger 32 0.0009 1.001
(0.987–1.015)		 0.905 0.474
Weighted median 32 0.0031 1.003
(0.993–1.013)		 0.548
Tea intake
 IVW 37 0.0010 1.001
(0.995–1.007)		 0.735 0.193 0.964 0.208
MR Egger 37 0.0008 1.001
(0.987–1.015)		 0.917 0.163
Weighted median 37 0.0012 1.001
(0.993–1.010)		 0.781
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MR: Mendelian randomization; IVW: Inverse variance weighted, SNP: Single-nucleotide polymorphism; OR: Odds ratio; CI: Confidence interval.

Fig 2. Scatter plot for the causal effect of coffee intake on DVT risk.

Fig 2

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The slope of the straight line indicates the magnitude of the causal association.

Fig 3. Scatter plot for the causal effect of tea intake on DVT risk.

Fig 3

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The slope of the straight line indicates the magnitude of the causal association.

To ensure the robustness of our findings, we conducted sensitivity analyses. Firstly, Cochran’s Q test indicated no heterogeneity among the IVs for both coffee (PIVW = 0.451, PMR Egger = 0.474, Table 1) and tea (PIVW = 0.193, PMR Egger = 0.163, Table 1). The symmetry of the funnel plot further supported the absence of heterogeneity (Fig 4). Secondly, the MR-Egger regression results suggested no overall horizontal pleiotropy among all IVs for both coffee (P = 0.234, Table 1) and tea (P = 0.964, Table 1). Additionally, the MR-PRESSO global test did not provide evidence of pleiotropy (P > 0.05, Table 1). Finally, the leave-one-out sensitivity analysis, which involved removing one SNP at a time, yielded consistent results (Fig 5). Based on our analysis, there appears to be a noteworthy link between genetically predicted coffee intake and a slightly elevated risk of DVT. However, our investigation did not reveal any causal effect between tea intake and this risk. These conclusions were substantiated by multiple sensitivity analyses, underscoring the reliability of our findings.

Fig 4.

Fig 4

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Funnel plot for the overall heterogeneity in the effect of coffee intake (A) and tea intake (B) on DVT risk.

Fig 5.

Fig 5

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Leave-one-out analysis of the effect of coffee intake (A) and tea intake (B) on DVT risk.

Discussion

Deep Vein Thrombosis (DVT) is a significant contributor to cardiovascular disease and it is strongly associated with incidence, mortality and healthcare costs globally. Accurate diagnosis and timely elimination of DVT are crucial for reducing the risk of complications and improving patients’ quality of life [22]. Therefore, it is imperative to accurately assess the risk factors in DVT patients.

Coffee and tea, the world’s top two caffeinated drinks, offer remarkable preventive qualities. Within them lie bioactive dietary polyphenols, presenting a range of valuable therapeutic effects like antioxidant properties, heart health support, neuroprotective abilities, and aid against obesity and high blood pressure [4,5,23]. To date, the majority of research has focused on investigating the role of coffee or tea in the pathogenesis of arterial thrombosis and cardiovascular disease (e.g., myocardial infarction) [24]. However, on the formation of DVT have not been well evaluated. There is currently no conclusive assessment regarding whether coffee and tea have a preventive effect on the formation of DVT. Based on our analysis, there appears to be a noteworthy link between genetically predicted coffee intake and a slightly elevated risk of DVT. Conversely, our results showed no significant association between tea intake and DVT risk in beverages containing caffeine.

Early studies have indicated that certain components in coffee, apart from caffeine, may have the ability to inhibit platelet aggregation, which suggests a potential protective effect against cardiovascular disease [25]. It is widely acknowledged that venous thromboembolism and arterial thrombosis are characterized by distinct underlying mechanisms, locations and treatment modalities. Arterial thrombosis is distinguished by vascular endothelial injury and heightened shear stress, commonly affecting the coronary arteries and cerebrovascular system. Inversely, venous thromboembolism arises from venous stasis and hypercoagulability, typically involving the lower limb veins and pulmonary arteries [26]. Moreover, the effects of coffee on blood coagulation function remain a topic of controversy. A small-scale randomized controlled trial found no significant impact on factor VII levels and fibrinolytic activity after 9 weeks of coffee consumption [27]. In contrast, an earlier experiment demonstrated an immediate increase in fibrinolytic activity upon coffee intake [28]. A recent study discovered reduced levels of von Willebrand factor and factor VIII among coffee drinkers, but found no association with fibrinogen or anticoagulant proteins [29]. These disparate results highlight the complexity of the relationship between coffee and hemostatic factors. Similarly, certain components found in tea, such as polyphenols, catechin, are believed to have anticoagulant and antiplatelet agents properties [30].

However, research has indicated that the consumption of unfiltered coffee has been associated with elevated levels of blood cholesterol and low-density lipoproteins [31]. This effect may be attributed to the presence of diterpenoids in coffee, that have been found to elevate plasma cholesterol levels, leading to increased blood viscosity [32]. Consequently, hyperlipidemia and hyper-cholesterol levels can constitute to a risk of developing conditions such as atherosclerosis and venous thrombosis [33,34]. A meta-analysis reviewed published clinical studies on the relationship between coffee intake and venous thromboembolism (VTE). By including three studies that met the criteria, the results showed that consuming 1–4 cups of coffee per day was associated with an 11% increase in VTE risk, while consuming ≥5 cups of coffee per day was associated with a 25% decrease in risk [35]. Nevertheless, there is insufficient clinical evidence at present to support the preventive effects of coffee on DVT. Research in this area remains limited and results are conflicting.

A Mendelian randomization study showed that tea consumption can reduce the risk of arterial thrombosis [36]. Besides, there seems to be a lack of sufficient research on the relationship between tea consumption and DVT. While this study’s findings may not apply to DVT, it suggests that certain components in tea may have antithrombotic effects. Overall, there is currently insufficient evidence to suggest a link between tea consumption and DVT.

In addition, our research is restricted to populations of European ancestry. While this may mitigate bias caused by population stratification, we are still uncertain if the findings can be extrapolated to other populations. Additionally, the presence of different varieties of coffee and tea could potentially impact the research results. Despite these limitations, our study has several advantages. Firstly, this is the first MR study to evaluate the causal relationship between caffeinated beverages like coffee and tea and the risk of DVT. Secondly, this MR study is based on a large sample of GWAS data from European populations, providing us with sufficient power to estimate causal relationships. Thirdly, the study results are unlikely to be influenced by confounding factors.

Conclusion

This study utilized Mendelian randomization to investigate the direct impact of coffee and tea consumption on the risk of DVT, a condition associated with severe complications like pulmonary embolism. Employing genetic markers as substitutes for beverage consumption, our findings revealed a marginal elevation in DVT risk with increased coffee intake. Conversely, no substantial effect on DVT risk was observed with tea consumption.

Supporting information

S1 Appendix. Results obtained from Mendelian randomization analysis investigating the association between coffee consumption and deep vein thrombosis.

(XLSX)

Click here for additional data file. (17.3KB, xlsx)
S2 Appendix. Results obtained from Mendelian randomization analysis investigating the association between tea consumption and deep vein thrombosis.

(XLSX)

Click here for additional data file. (18.3KB, xlsx)

Data Availability

All data are linked to the GWAS database. Data for coffee intake was obtained from (https://gwas.mrcieu.ac.uk/datasets/ukb-b-5237/). Data for tea intake was obtained from (https://gwas.mrcieu.ac.uk/datasets/ukb-b-6066/). The summary data for DVT was obtained from (https://gwas.mrcieu.ac.uk/datasets/ukb-b-12040/).

Funding Statement

The author(s) received no specific funding for this work.

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Decision Letter 0

Eyüp Serhat Çalık

28 Dec 2023

PONE-D-23-30773Caffeinated Beverages Intake and Risk of Deep Vein Thrombosis: A Mendelian Randomization StudyPLOS ONE

Dear Dr. Lin,

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Additional Editor Comments:

Congratulations to the authors for their valuable study and efforts. Your manuscript has been evaluated by two reviewers and their suggestions are given below. Please respond to these suggestions point by point and make the necessary edits to your manuscript.

In addition, I would like to know; in the conclusion section of your article, you say that higher coffee intake is associated with a slight increase in DVT, but in the results section, can you give a measure of this higher coffee intake? Is there such a measure in genetic variants? Can you specify?

Finally, please have your manuscript professionally edited for language.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: First of all, I want to congratulate the group of Lin and co-workers for their efforts! And I want to thank the journal respectively editor for the allowance to review this interesting manuscript. In the following I will go through the following points step by step: relevance, formals / language, material and methods, results, table, figures, conceptualization, conclusion of this review.

Relevance:

For my understanding the author's tackle a topic of relevance.

Formals / Language:

I am not a native speaker; therefore, I usually consult native speakers or language polishing services to have the English checked. I personally feel like, that such a revision of the English would improve the manuscript. For example, at some points there are redundancies, typos, and at least for my feeling potentially misleading phrasings. One example for the phrasing issue can be found in the lines 47 to 49. I am uncertain whether the wording should be "performed U-shaped relationship" or "observed an U-shaped relationship". One example for a typo can be found in line 92, as I think it should be history instead of “History”.

The abbreviation “VTE” is not correctly introduced. The abbreviation is used first in line 45, and introduced in line 48.

Several abbreviations are introduced repeatedly. One example is “IV” for instrumental variables. Once it is introduced in line 54. Second, it is introduced again in line 118. Please, check this.

Material and Methods:

Yet, I don't have experience in using Mendelian Randomization. Thus, I do not think, that I am competent enough to comment on this.

In line 91 and 92 the authors write “currently, there are established risk factors for DVT, such as obesity, cancer, history of venous thromboembolism and so on”. Why do we find this sentence in the material and methods section? There is no further reference to this in this section of the manuscript.

Results:

For my personal feeling very limited results for complete original article (all results are displayed in 24 lines, 1 table, and 2 figures).

Table:

No comment.

Figures:

Figure 1 – How can be assumend, only looking on an single nucleotide polymorphism level, there only is one mediation – knowing all the risk factos pointed out in the manuscript. For my personal understanding of such a complex entity as deep vein thrombosis, such an assumption is at least a questionable simplification.

Conceptualization:

From a general pathological point of view, the analyses performed must be scrutinized.

The authors point out several times, that their study provides information on causality (e.g., lines 10, 15, 59, 197). But, they only assess. Furthermore, they underline that there are known (and for my feeling important) risk factors for deep vein thrombosis such as cancer or obesity. From my perspective, these are potential confounders respectively mediators are only partially addressed on the level of single nucleotide polymorphisms (SNP). Thus, for my understanding, the statement of providing “causality” overestimates the results of the study.

Conclusion of this review:

Taken together I would recommend a rejection and reconceptualization of the study. I truly believe, that there is important information in this approach, but how it is at least reported in this manuscript it is for my feeling not suitable at the moment. The concise and narrowly circumscribed results, for my feeling, would fit something like, for example a “short communication” (or whatever the respective journal names it).

Reviewer #2: 1. The authors of this study investigated the potential causal relationship between coffee and tea intake and the risk of deep vein thrombosis (DVT) using Mendelian randomization (MR) analysis. The research design is appropriate! Nevertheless, I am a bit concerned about the statistical analysis. In particular, the authors reported for the OR =1.001 for the coffee intake and 95% CI = (1.001, 1.015) with p-value .025. The CI is an open interval meaning the endpoints are not part of the CI. Perhaps, this can be explained by the round-off error. Therefore, I would recommend reporting more decimal digits.

2. While the statistical significance can be supported by the p-value, I am wondering if the finding is practically significant.

3. The statements in Lines 141-144 need rephrasing.

4. Lines 288-289: Why did the authors capitalize the title. Furthermore, the year is 1997 not "n.d."

**********

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Reviewer #1: No

Reviewer #2: No

**********

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While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2024 Feb 13;19(2):e0298123. doi: 10.1371/journal.pone.0298123.r002

Author response to Decision Letter 0

8 Jan 2024

Response to Reviewers

Dear editor,

I wish to extend my sincerest gratitude to you and reviewers. Your expertise and dedication in guiding our manuscript through the review process have been invaluable. Your insightful comments and constructive feedback have significantly enhanced the quality of our work. Your thorough assessment has not only strengthened the manuscript but also provided us with invaluable perspectives and suggestions.

We deeply appreciate the time and effort you've dedicated to reviewing and improving our manuscript. Your input has been instrumental in refining our research.

Thank you once again for your invaluable support and guidance.

Warm regards,

Tong Lin

Point-by-point reply to editorial comments:

1.In addition, I would like to know; in the conclusion section of your article, you say that higher coffee intake is associated with a slight increase in DVT, but in the results section, can you give a measure of this higher coffee intake? Is there such a measure in genetic variants? Can you specify?

Response: Thank you for your suggestion. Through Mendelian randomization analysis, we found a linear correlation between coffee intake and DVT. Although the linear slope is small (as demonstrated in Figure 2 of the revised article), it suggests a mild increase in DVT risk with increased coffee intake. The ambiguity in our expression led to the editor's question, and we have made the necessary modifications to clarify this in the revised manuscript. At present, we haven't obtained data on the effects of high-concentration coffee intake on genetics, hence limiting further exploration of its relationship with DVT.

2.Finally, please have your manuscript professionally edited for language.

Response: We appreciate your suggestion and understand the importance of ensuring the language in our manuscript meets professional standards. We have taken your feedback into account and will ensure that our manuscript undergoes professional editing to enhance its language quality before the final submission. Thank you for highlighting this aspect, and we are committed to presenting our research in the most clear and polished manner possible.

Point-by-point reply to Reviewers' comments

Reviewers' comments:

Reviewer #1:

1.Formals / Language: I am not a native speaker; therefore, I usually consult native speakers or language polishing services to have the English checked. I personally feel like, that such a revision of the English would improve the manuscript. For example, at some points there are redundancies, typos, and at least for my feeling potentially misleading phrasings. One example for the phrasing issue can be found in the lines 47 to 49. I am uncertain whether the wording should be "performed U-shaped relationship" or "observed an U-shaped relationship". One example for a typo can be found in line 92, as I think it should be history instead of “History”. The abbreviation “VTE” is not correctly introduced. The abbreviation is used first in line 45, and introduced in line 48. Several abbreviations are introduced repeatedly. One example is “IV” for instrumental variables. Once it is introduced in line 54. Second, it is introduced again in line 118. Please, check this.

Response: We truly appreciate your valuable feedback and understanding regarding the importance of linguistic accuracy in scholarly manuscripts. We acknowledge that ensuring a high standard of English is crucial for conveying our research effectively. Your specific examples of potential redundancies, typos, and phrasing concerns are extremely helpful. We will make a concerted effort to address these concerns by revising the manuscript to eliminate redundancies, correct any typographical errors—such as the one highlighted in line 92 ('History' to be changed to 'history')—and modify potentially misleading phrases, marking these revisions in red throughout the text. We have adjusted the wording from 'performed U-shaped relationship' to 'observed a U-shaped relationship' as suggested and have highlighted these modifications in the revised sentences. We have reviewed the manuscript meticulously to ensure that all abbreviations are introduced upon their first appearance and then consistently used throughout the document without repetition.

2.Material and Methods: Yet, I don't have experience in using Mendelian Randomization. Thus, I do not think, that I am competent enough to comment on this. In line 91 and 92 the authors write “currently, there are established risk factors for DVT, such as obesity, cancer, history of venous thromboembolism and so on”. Why do we find this sentence in the material and methods section? There is no further reference to this in this section of the manuscript.

Response: Thank you for your feedback. Why mention DVT-related risk factors such as obesity, cancer, and history of venous thrombosis in the research methodology? This is because the Mendelian randomization study needs to adhere to three fundamental assumptions. First, it is assumed that single-nucleotide polymorphisms (SNPs) are strongly associated with the consumption of caffeinated beverages like coffee or tea. Second, it is assumed that these SNPs are independent of any potential confounding factors that could affect the studied outcome. Finally, it is assumed that the effects of SNPs on the development of DVT are exclusively mediated through the consumption of caffeinated beverages. Obesity, cancer, a history of venous thrombosis, and other risk factors fall under the second assumption as confounding factors. Therefore, in eliminating the SNPs we've selected, we need to exclude those influenced by confounding factors such as obesity, cancer, a history of venous thrombosis, and factors currently regarded as high-risk factors for DVT. That's why we mention them in the research methodology.

3.Results: For my personal feeling very limited results for complete original article (all results are displayed in 24 lines, 1 table, and 2 figures).

Response: Thank you for your feedback. We understand your concern regarding the limited display of results in our original article. While it may seem that our study exhibits a limited scope of outcomes, it aligns with the methodology involving the use of the two-sample Mendelian randomization. Taking your valuable input into account, we have made efforts to address this concern by including two additional figures, Figure 2 and Figure 3, to further elucidate the relationship between coffee and tea consumption in relation to DVT in the revised version.

4.Figures: Figure 1 – How can be assumend, only looking on an single nucleotide polymorphism level, there only is one mediation – knowing all the risk factos pointed out in the manuscript. For my personal understanding of such a complex entity as deep vein thrombosis, such an assumption is at least a questionable simplification.

Response: Thank you for your thoughtful consideration. The assumption we made regarding the mediation through a single-nucleotide polymorphism (SNP) level stems from the application of Mendelian randomization in our study design. While we acknowledge the complexity inherent in deep vein thrombosis (DVT), the Mendelian randomization framework operates under certain assumptions to establish causal relationships. In the context of our study, the assumption of SNP mediation is based on the fundamental principles of Mendelian randomization. This approach allows us to explore causality by leveraging genetic variants as proxies for exposures. However, we understand and appreciate the multifactorial nature of DVT, involving various risk factors beyond the SNP level. Our aim in assuming SNP mediation through caffeinated beverage consumption was to establish a specific pathway as a focus within the broader complexity of DVT etiology. We agree that DVT is a multifaceted condition influenced by numerous factors, and our study's approach, utilizing Mendelian randomization, centers on delineating specific causal relationships at a genetic level within this intricate landscape.

We greatly appreciate the reviewer's suggestions. To provide a more in-depth understanding of the principles behind the two-sample Mendelian randomization study, we have added a section titled 'Study Design' within the methodology. This aims to offer readers a deeper insight into the fundamental principles of this method. Additionally, in response to the reviewer's feedback, we have modified Figure 1 to make it more intuitive and easily comprehensible. These adjustments are intended to ensure that our research methodology and findings are presented clearly to the readers. We are grateful for the valuable guidance provided by the reviewer, which has contributed to the quality of our study.

5.Conceptualization: From a general pathological point of view, the analyses performed must be scrutinized. The authors point out several times, that their study provides information on causality (e.g., lines 10, 15, 59, 197). But, they only assess. Furthermore, they underline that there are known (and for my feeling important) risk factors for deep vein thrombosis such as cancer or obesity. From my perspective, these are potential confounders respectively mediators are only partially addressed on the level of single nucleotide polymorphisms (SNP). Thus, for my understanding, the statement of providing “causality” overestimates the results of the study.

Response: We appreciate your thorough evaluation of our study. Your insights regarding conceptualization and the assessment of causality are duly noted. Our intention was to highlight potential causal pathways between single-nucleotide polymorphisms (SNPs) associated with caffeinated beverage consumption and the risk of deep vein thrombosis (DVT). However, we acknowledge the complexity inherent in inferring causality solely from SNP associations. While our study aimed to elucidate specific genetic associations, we understand the limitations in comprehensively addressing known risk factors like cancer or obesity, which may act as potential confounders or mediators at levels beyond SNPs. Your point about the statement on causality is well-taken, and upon reflection, we recognize the need for caution in our claims. We will modify our assertions in the manuscript to accurately reflect the scope of our findings as associations rather than definitive causal relationships. Your feedback prompts us to refine our interpretations and ensures the accuracy and integrity of our study. Thank you for your valuable input.

Reviewer #2:

1.The authors of this study investigated the potential causal relationship between coffee and tea intake and the risk of deep vein thrombosis (DVT) using Mendelian randomization (MR) analysis. The research design is appropriate! Nevertheless, I am a bit concerned about the statistical analysis. In particular, the authors reported for the OR =1.001 for the coffee intake and 95% CI = (1.001, 1.015) with p-value .025. The CI is an open interval meaning the endpoints are not part of the CI. Perhaps, this can be explained by the round-off error. Therefore, I would recommend reporting more decimal digits.

Response: Thank you for your careful review and insightful observations regarding our study's statistical analysis. We acknowledge and deeply regret the oversight that led to the error in reporting the odds ratio (OR) for coffee intake. In the original data, the OR obtained using the IVW statistical method was indeed 1.008209, mistakenly rounded to 1.001. We have rectified this error by accurately adjusting the reported OR to 1.008, and we have conducted a thorough reevaluation of all data presented in the table to ensure precision and accuracy. We appreciate your suggestion to report more decimal digits to avoid open intervals in confidence intervals. Your guidance has been invaluable in ensuring the accuracy of our findings. We apologize for any confusion caused and are grateful for the opportunity to correct this oversight.

2.While the statistical significance can be supported by the p-value, I am wondering if the finding is practically significant.

Response: Thank you for your evaluation and concern. The issue of practical significance is indeed crucial. While there have been studies linking coffee intake to DVT, we acknowledge the presence of uncertainties and potential research biases in those studies. Taking this into consideration, the Mendelian randomization study design allows us to better mitigate confounding factors. This method aids in reducing the interference of other variables on the study outcomes, thereby facilitating a clearer assessment of the relationship between coffee intake and DVT. We will further explore these points in depth while discussing practical significance.

3.The statements in Lines 141-144 need rephrasing.

Response: Thank you for your careful review. The sentence has been polished and highlighted in red in the refined rendition: “Coffee and tea, the world's top two caffeinated drinks, offer remarkable preventive qualities. Within them lie bioactive dietary polyphenols, presenting a range of valuable therapeutic effects like antioxidant properties, heart health support, neuroprotective abilities, and aid against obesity and high blood pressure”.

4.Lines 288-289: Why did the authors capitalize the title. Furthermore, the year is 1997 not "n.d."

Response: Thank you for your guidance and feedback. We apologize for the issues with the citation format. We've identified that it was due to the version of the reference manager and have now thoroughly revised the reference format in accordance with the requirements of the journal "PLOS ONE." We've cross-checked the journal's guidelines and reorganized the citations to ensure compliance with the specified requirements.

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file. (24.3KB, docx)

Decision Letter 1

Eyüp Serhat Çalık

21 Jan 2024

Caffeinated Beverages Intake and Risk of Deep Vein Thrombosis: A Mendelian Randomization Study

PONE-D-23-30773R1

Dear Dr. Lin,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Eyüp Serhat Çalık

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Acceptance letter

Eyüp Serhat Çalık

2 Feb 2024

PONE-D-23-30773R1

PLOS ONE

Dear Dr. Lin,

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Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Appendix. Results obtained from Mendelian randomization analysis investigating the association between coffee consumption and deep vein thrombosis.

    (XLSX)

    Click here for additional data file. (17.3KB, xlsx)
    S2 Appendix. Results obtained from Mendelian randomization analysis investigating the association between tea consumption and deep vein thrombosis.

    (XLSX)

    Click here for additional data file. (18.3KB, xlsx)
    Attachment

    Submitted filename: Response to Reviewers.docx

    Click here for additional data file. (24.3KB, docx)

    Data Availability Statement

    All data are linked to the GWAS database. Data for coffee intake was obtained from (https://gwas.mrcieu.ac.uk/datasets/ukb-b-5237/). Data for tea intake was obtained from (https://gwas.mrcieu.ac.uk/datasets/ukb-b-6066/). The summary data for DVT was obtained from (https://gwas.mrcieu.ac.uk/datasets/ukb-b-12040/).

    Articles from PLOS ONE are provided here courtesy of PLOS

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