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RESEARCH ARTICLE
Caffeinated beverages intake and risk of deep
vein thrombosis: A Mendelian randomization
study
Tong LinID*, Haiyan Mao, Yuhong Jin
Department of Critical Care Medicine, Ningbo Medical Center Lihuili Hospital Ningbo, Zhejiang, The People’s
Republic of China
*kai893@foxmail.com
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 instrumen-
tal 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 con-
sumption 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 extremi-
ties. 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 complica-
tion 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, environ-
mental conditions, and various genetic predispositions, such as sedentary habits, obesity, can-
cer, 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.
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OPEN ACCESS
Citation: Lin T, Mao H, Jin Y (2024) Caffeinated
beverages intake and risk of deep vein thrombosis:
A Mendelian randomization study. PLoS ONE
19(2): e0298123. https://doi.org/10.1371/journal.
pone.0298123
Editor: Eyu¨p Serhat C¸alık, Ataturk University
Faculty of Medicine, TURKEY
Received: September 25, 2023
Accepted: January 19, 2024
Published: February 13, 2024
Peer Review History: PLOS recognizes the
benefits of transparency in the peer review
process; therefore, we enable the publication of
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editorial history of this article is available here:
https://doi.org/10.1371/journal.pone.0298123
Copyright: ©2024 Lin et al. This is an open access
article distributed under the terms of the Creative
Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in
any medium, provided the original author and
source are credited.
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-
Coffee and tea are the two most widely consumed caffeinated beverages globally, both con-
taining 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 poten-
tially 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 sug-
gested 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. Specifi-
cally, 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 con-
firmed in observational studies, and confounding and reverse causality are possible.
Mendelian randomization (MR) is a powerful method that uses genetic variants as instru-
mental 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 die-
tary 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, provid-
ing 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 out-
come 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.
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
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Caffeinated beverages and risk of deep vein thrombosis
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6066/). The summary data for DVT was obtained
from (https://gwas.mrcieu.ac.uk/datasets/ukb-b-
12040/).
Funding: The author(s) received no specific
funding for this work.
Competing interests: The authors have declared
that no competing interests exist.
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 sum-
mary data for deep vein thrombosis (DVT) were obtained from the MRC Integrative Epidemi-
ology 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 indepen-
dent 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 R
2
<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 pleio-
tropic 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 fac-
tors, thereby reducing the likelihood of confounding influences. Lastly, we calculated the F-sta-
tistic (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 Men-
delian 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-
Fig 1. There are three fundamental assumptions underlying the Mendelian randomization study.
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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, par-
ticularly 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 sig-
nificant 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 2and 3).
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 (P
IVW
= 0.451, P
MR
Egger
= 0.474, Table 1) and tea (P
IVW
= 0.193, P
MR 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
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
PFor
MR-Egger intercept
PFor
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
MR: Mendelian randomization; IVW: Inverse variance weighted, SNP: Single-nucleotide polymorphism; OR: Odds ratio; CI: Confidence interval.
https://doi.org/10.1371/journal.pone.0298123.t001
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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 sensi-
tivity analyses, underscoring the reliability of our findings.
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
Fig 2. Scatter plot for the causal effect of coffee intake on DVT risk. The slope of the straight line indicates the
magnitude of the causal association.
https://doi.org/10.1371/journal.pone.0298123.g002
Fig 3. Scatter plot for the causal effect of tea intake on DVT risk. The slope of the straight line indicates the
magnitude of the causal association.
https://doi.org/10.1371/journal.pone.0298123.g003
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and timely elimination of DVT are crucial for reducing the risk of complications and improv-
ing 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 cardio-
vascular 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.
Fig 4. Funnel plot for the overall heterogeneity in the effect of coffee intake (A) and tea intake (B) on DVT risk.
https://doi.org/10.1371/journal.pone.0298123.g004
Fig 5. Leave-one-out analysis of the effect of coffee intake (A) and tea intake (B) on DVT risk.
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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, typi-
cally involving the lower limb veins and pulmonary arteries [26]. Moreover, the effects of cof-
fee 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 imme-
diate 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 associ-
ated 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, hyperlipid-
emia and hyper-cholesterol levels can constitute to a risk of developing conditions such as ath-
erosclerosis 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 insuffi-
cient 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 relation-
ship 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 cur-
rently 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 pulmo-
nary embolism. Employing genetic markers as substitutes for beverage consumption, our
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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)
S2 Appendix. Results obtained from Mendelian randomization analysis investigating the
association between tea consumption and deep vein thrombosis.
(XLSX)
Author Contributions
Conceptualization: Tong Lin.
Data curation: Tong Lin.
Formal analysis: Tong Lin.
Software: Haiyan Mao.
Writing – original draft: Tong Lin, Yuhong Jin.
Writing – review & editing: Haiyan Mao, Yuhong Jin.
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