Tooth loss and risk of cardiovascular disease and stroke: A dose-response meta analysis of prospective cohort studies
Tooth loss and risk of cardiovascular disease and stroke: A dose-response meta analysis of prospective cohort studies
Fei Cheng 2 3
Mi Zhang 2 3
Quan Wang 1 3
Haijun Xu 2 3
Xiao Dong 2 3
Zhen Gao 2 3
Jiajuan Chen 2 3
Yunjie Wei 2 3
Fen Qin 0 3
0 Department of Obstetrics and Gynecology, Taihe Hospital, Hubei University of Medicine , Shiyan, Hubei , China
1 Department of Stomatology, Taihe Hospital, Hubei University of Medicine , Shiyan, Hubei , China
2 Department of Cardiology, Taihe Hospital, Hubei University of Medicine , Shiyan, Hubei , China
3 Editor: Ping-Hsun Wu, Kaohsiung Medical University Hospital , TAIWAN
Conflicting results identifying the association between tooth loss and cardiovascular disease and stroke have been reported. Therefore, a dose-response meta-analysis was performed to clarify and quantitatively assess the correlation between tooth loss and cardiovascular disease and stroke risk. Up to March 2017, seventeen cohort studies were included in current meta-analysis, involving a total of 879084 participants with 43750 incident cases. Our results showed statistically significant increment association between tooth loss and cardiovascular disease and stroke risk. Subgroups analysis indicated that tooth loss was associated with a significant risk of cardiovascular disease and stroke in Asia and Caucasian. Furthermore, tooth loss was associated with a significant risk of cardiovascular disease and stroke in fatal cases and nonfatal cases. Additionally, a significant dose-response relationship was observed between tooth loss and cardiovascular disease and stroke risk. Increasing per 2 of tooth loss was associated with a 3% increment of coronary heart disease risk; increasing per 2 of tooth loss was associated with a 3% increment of stroke risk. Subgroup meta-analyses in study design, study quality, number of participants and number of cases showed consistent findings. No publication bias was observed in this meta-analysis. Considering these promising results, tooth loss might provide harmful health benefits.
Data Availability Statement: All relevant data are
within the paper and its Supporting Information
Funding: The authors received no specific funding
for this work.
Competing interests: The authors have declared
that no competing interests exist.
Cardiovascular disease affects millions of people in developed and developing countries that is
now a public health crisis. Despite the decline in the mortality rate of developed countries,
cardiovascular disease is still the main cause of death and has caused serious social and economic
distress on a global scale over the past few decades. In low and middle-income countries, the
incidence of cardiovascular disease has risen sharply [1±3]. By 2020, cardiovascular disease is
expected to be the leading cause of morbidity and mortality in most developing countries[
The etiology of cardiovascular disease involves both genetic and environmental factors.
Therefore, understanding the impact of environmental factors on cardiovascular disease will help to
prevent cardiovascular disease.
Oral cavity is an important part of the body, and is starts in digestive system, mainly by the
lip and cheek, tongue and palate, salivary glands, teeth and jaw, with mastication, swallowing,
speech and feeling, and other functions, which maintain the normal shape of maxillofacial.
Oral health is an important part of human health. The World Health Organization (WHO)
identifies dental health as one of the top ten criteria for human health. Poor oral health may
increase systemic inflammation, resulting in a local overly aggressive immune response, and
thus could have important implications for cardiovascular disease. Periodontal disease and
tooth loss are two common oral health measures[
]. Tooth loss has been considered to impact
quality of life[
], and been known to considerably influence food choice, diet, nutrition intake,
Previous studies have examined the correlation between tooth loss and cardiovascular
disease and stroke risk[8±24]. However, the result remains controversial. Additionally, no study
to clarify and quantitative assessed tooth loss in relation to tooth loss and cardiovascular
disease and stroke risk. Thus, we performed this dose-response meta-analysis to clarify and
quantitative assessed the correlation between tooth loss and tooth loss and cardiovascular disease
and stroke risk.
Our meta-analysis was designed following the preferred reporting items for systematic reviews
and meta-analyses (PRISMA Compliant) statement(S1 Checklist)[
PubMed and EMBASE were searched for studies that contained risk estimates for the
outcomes of coronary heart disease and were published update to April 2017, with keywords
including ªCoronary heart diseaseº [MeSH] ORºstrokeº [MeSH] OR ªCardiovascular
Diseasesº [MeSH] OR ªCoronary Diseaseº [MeSH] OR ªmyocardial infarctionº [MeSH] AND
ªdentitionº [MeSH] ORºtooth lossº [MeSH] ORºedentulousº [MeSH]. The search strategy is
shown in detail in S1 List.
Two independent researchers investigate information the correlation between tooth loss and
cardiovascular disease and stroke risk: outcome was coronary heart disease and stroke. To
ensure the correct identification of qualified research, the two researchers read the reports
independently, and the disagreements were resolved through consensus by all of the authors.
Use standardized data collection tables to extract data. Each eligible article information was
extracted by two independent researchers. We extracted the following information: first
author; publication year; mean value of age; country; study name; sex; cases and participants;
the categories of tooth loss; relative risk or odds ratio (OR). We collect the risk estimates with
]. According to the Newcastle-Ottawa scale, quality assessment was
performed for non-randomized studies[
]. The disagreements were resolved through
consensus by all of the authors.
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Fig 1. Flow diagram of the study selection process.
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We pooled relative risk estimates to measure the association between tooth loss and
cardiovascular disease and stroke risk; the hazard ratio were considered equivalent to the relative risk
]. Results in different subgroups of tooth loss and cardiovascular disease and stroke risk
were treated as two separate reports.
Due to different definitions cut-off points in the included studies for categories, we
performed a relative risk estimates by using the method recommended by Greenland, Longnecker
and Orsini and colleagues[
]. A flexible meta-regression based on restricted cubic spline
(RCS) function was used to fit the potential non-linear trend, and generalized least-square
method was used to estimate the parameters. This procedure treats tooth loss (continuous
data) as an independent variable and logRR of diseases as a dependent variable, with both tails
Dietrich et al(2008)
Howell et al(2001)
Hung et al(2004)
Tuominen et al
Abnet et al(2005)
Elter et al(2004)
Holmlund et al
Hujoel et al(2000)
Joshipura et al(1996)
Joshy et al(2016)
Jung et al(2016)
Liljestrand et al
Noguchi et al(2015)
Schwahn et al(2013)
Tu et al(2007)
Vedin et al(2015)
Watt et al(2012)
Male and Female
Male and Female
Age at baseline
of the curve restricted to linear. A P value is calculated for linear or non-linear by testing the
null hypothesis that the coefficient of the second spline is equal to zero[
We use STATA software 12.0 (STATA Corp, College Station, TX, USA) to evaluate the
relationships between tooth loss and risk of coronary heart disease and stroke. By using Q test and
I2 statistic to assess heterogeneity among studies. Random-effect model was chosen if PQ<
0.10 or I2>50%, otherwise, fixed-effect mode was applied. Begg's and Egger's tests were to
assess the publication bias of each study. P< 0.05 was considered signifcant for all tests.
5 teeth lost, 1.0 (reference);7, 1.68 (1.13, 2.52);
10, 1.55 (0.94, 2.56);13, 2.12 (1.26, 3.60);
6 teeth lost, 1.0 (reference);8, 0.90 (0.60, 1.35);
11, 1.13 (0.75, 1.69);17, 1.13(0.71, 1.78),
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A total of 2810 studies from Medline, 3246 studies from Embase. After removing duplicates
study, 3028 studies were identifed. reviewing their titles and abstracts, 2978 citations were
excluded. The remaining 50 citations were assessed in more detail for eligibility by reading the
full text. Among them, 11 studies were excluded due to no relevant outcome measure; 15
studies were excluded due to no human studies; 3 study was excluded due to lack of detailed
information; 4 study was excluded due to review; 1 study was excluded due to conference abstract.
Fig 2. Forest plots for meta-analysis of tooth loss and risk of cardiovascular disease.
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After review reference of studies, one article was identified. Finally, 28 studies were used for
the final data synthesis. The flow chart of literature searching was presented in Fig 1.
The characteristics of the included studies of tooth loss and risk of coronary heart disease and
stroke are shown in the Tables 1 and 2.
Tooth loss and cardiovascular disease risk
Twenty-eight independent reports from seventeen studies investigated the association between
tooth loss and risk of coronary heart disease. Compared with the lowest tooth loss, tooth loss is
significantly associated with a higher risk of cardiovascular disease (RR:1.52; 95% CI, 1.37±
1.69; P < .001)(Fig 2). Subgroups analysis indicated that tooth loss is associated with a
significantly increasement of coronary heart disease risk in Asia (RR:1.38; 95% CI, 1.21±1.56; P <
.001)(Table 3) and Caucasian(RR:1.55; 95% CI, 1.35±1.75; P < .001)(Table 3). Furthermore,
tooth loss was associated with a significantly cardiovascular disease risk in fatal cardiovascular
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Fig 3. Dose-response relationship between tooth loss and risk of cardiovascular disease.
disease (RR:1.31; 95% CI, 1.19±1.43; P < .001) (Table 3) and nonfatal cardiovascular disease
(RR:1.56; 95% CI, 1.27±1.85; P < .001) (Table 3). Also, tooth loss was associated with a
significantly risk of coronary heart disease in male (RR:1.92; 95% CI, 1.34±2.50; P < .001) (Table 3)
and female (RR:1.48; 95% CI, 1.20±1.76; P < .001) (Table 3). Additionally, a significant
doseresponse relationship was observed between tooth loss and coronary heart disease risk.
Increasing per 2 of tooth loss was associated with a 3% increment of coronary heart disease
risk (RR:1.03; 95% CI, 1.02±1.04; P < .001) (Fig 3).
Tooth loss and stroke risk
Eight independent reports from eight studies investigated the association between tooth loss
and risk of stroke. Compared with the lowest tooth loss, tooth loss is significantly associated
with a higher risk of stroke (RR:1.18; 95% CI, 1.11±1.25; P < .001)(Fig 4). Subgroups analysis
indicated that tooth loss is associated with a significantly incensement of stroke risk in Asia
(RR:1.12; 95% CI, 1.01±1.23; P < .001) (Table 3) and Caucasian (RR:1.25; 95% CI, 1.18±1.32;
P < .001) (Table 3). Additionally, a significant dose-response relationship was observed
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Fig 4. Forest plots for meta-analysis of tooth loss and risk of stroke.
between tooth loss and stroke risk. Increasing per 2 of tooth loss was associated with a 3%
increment of stroke risk (RR:1.03; 95% CI, 1.02±1.04; P < .001) (Fig 5).
Subgroup analysis was performed to check the stability of the primary outcome. Subgroup
meta-analyses in study design, study quality, number of participants and number of cases
showed consistent findings (Table 3).
Each studies in this meta-analysis were performed to evaluate the publication bias by both
Begg's funnel plot and Egger's test. P>0.05 was considered no publication bias. The results
show no obvious evidence of publication bias was found in the relationship between tooth loss
and cardiovascular disease and stroke risk (S1 Table). A funnel plot for publication bias
assessment is illustrated in S1 and S2 Figs.
Recently, tooth loss has been found to be associated with decreased risks of lung cancer,
colorectal cancer, prostate cancer, breast cancer and pancreatic cancer[
]. However, as for tooth
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Fig 5. Dose-response relationship between tooth loss and risk of stroke.
loss and coronary heart disease and stroke risk, there are several unsolved issues. First, the
relationship between tooth loss and cardiovascular disease and stroke risk is remains controversial.
Some studies found that tooth loss was associated with a increase risk of coronary heart disease
and stroke, whereas others failed to fnd relationship between tooth loss and cardiovascular
disease and stroke risk. Furthermore, the dose-response relationship between tooth loss and
coronary heart disease and stroke risk has not been described.
In the current meta-analysis was based on seventeen cohort study, with a total of 879084
participants with 43750 incident cases. Thus, this meta analysis provides the most up-to-date
epidemiological evidence supporting tooth loss is harmful for cardiovascular disease and
stroke. A dose-response analysis revealed that increasing tooth loss (per 2 increment) was
associated with a 3% increment of coronary heart disease risk, increasing tooth loss (per 2
increment) was associated with a 3% increment of stroke risk. Furthermore, tooth loss was
associated with a significantly cardiovascular disease and stroke risk in Asia and Caucasian.
Also, tooth loss was associated with a significantly risk of cardiovascular disease in male and
female. Additionally, tooth loss was associated with a significantly cardiovascular disease and
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stroke risk in fatal cases and nonfatal cases. Subgroup meta-analyses by various factors also
showed consistent findings.
Several plausible pathways may reasonable for the relationship between tooth loss and
cancer. The influence of chronic inflammation on cancer development is one possible pathwa.
Chronic systemic inflammation linked to periodontal disease. People with few or no teeth
would this have an increased risk of systemic diseases such as cardiovascular disease and
]. Secondly, the main cause of teeth loss is dental caries, and carbohydrate intake is
the dental caries cause. Carbohydrate intake was associated with increased risk cardiovascular
disease and stroke, therefore teeth loss indirect effects risk of cardiovascular disease and stroke
]. Third, the progress of tooth damage destroys normal periodontal tissue, allowing oral
microbial accumulation deep into oral tissue, thereby promoting its growth, thus resulting in
cardiovascular disease and stroke[
]. Fourth, Tooth loss is the ultimate stage of periodontal
disease and may be associated with an increase in C-reactive protein (CRP), which itself is
implicated in atherosclerosis and thus in the occurrence of stroke[
]. Thus, tooth loss and
cancer seems to be closely related.
To our knowledge, this is the first study to identify and quantify the potential dose-response
association between tooth loss and cardiovascular disease and stroke risk in a large cohort of
both men and women. Although, we performed this meta-analysis very carefully, however,
some limitations must be considered in the current meta-analysis. First, we only select
literature that written by English, which may have resulted in a language or cultural bias, other
language should be chosen in the further. Second, in the subgroup analysis in different ethnic
population, there might be insufficient statistical power to check an association.
In conclusion, our dose±response meta-analysis suggests tooth loss was independently
associated with deleterious coronary heart disease and stroke risk increment. In the future,
largescale and population based association studies must be performed to help identify the putative
causal role that tooth loss plays in increasing the incidence of these diseases.
S1 Table. Publication bias analysis of the meta-analysis.
S1 Fig. Begg's funnel plot for assessment of publication bias of tooth loss and risk of
S2 Fig. Begg's funnel plot for assessment of publication bias of tooth loss and risk of
S1 List. The detail of search strategy.
S1 Checklist. The detail of PRISMA checklist.
This study received no specific external funding. Authors have disclosed no conflicts of
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Data curation: Fei Cheng, Mi Zhang, Xiao Dong, Zhen Gao.
Formal analysis: Fei Cheng, Mi Zhang, Jiajuan Chen.
Investigation: Quan Wang.
Methodology: Fei Cheng, Jiajuan Chen.
Software: Quan Wang, Haijun Xu, Zhen Gao, Yunjie Wei, Fen Qin.
Supervision: Fen Qin.
Validation: Haijun Xu, Xiao Dong, Yunjie Wei.
Writing ± original draft: Fen Qin.
Writing ± review & editing: Fen Qin.
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1. Ford ES , Capewell S. Coronary heart disease mortality among young adults in the U.S. from 1980 through 2002: concealed leveling of mortality rates . Journal of the American College of Cardiology . 2007 ; 50 ( 22 ): 2128 ± 32 . https://doi.org/10.1016/j.jacc. 2007 . 05 .056 PMID: 18036449 .
2. Roger VL , Go AS , Lloyd-Jones DM , Benjamin EJ , Berry JD , Borden WB , et al. Heart disease and stroke statisticsÐ2012 update: a report from the American Heart Association. Circulation . 2012 ; 125 ( 1 ):e2± e220 . https://doi.org/10.1161/CIR.0b013e31823ac046 PMID: 22179539
3. Roger VL , Go AS , Lloyd-Jones DM , Benjamin EJ , Berry JD , Borden WB , et al. Executive summary: heart disease and stroke statisticsÐ2012 update: a report from the American Heart Association . Circulation. 2012 ; 125 ( 1 ): 188 ± 97 . https://doi.org/10.1161/CIR.0b013e3182456d46 PMID: 22215894 .
4. Celermajer DS , Chow CK , Marijon E , Anstey NM , Woo KS . Cardiovascular disease in the developing world: prevalences, patterns, and the potential of early disease detection . Journal of the American College of Cardiology . 2012 ; 60 ( 14 ): 1207 ± 16 . https://doi.org/10.1016/j.jacc. 2012 . 03 .074 PMID: 22858388 .
5. Pihlstrom BL , Michalowicz BS , Johnson NW . Periodontal diseases . Lancet (London, England) . 2005 ; 366 ( 9499 ): 1809 ±20. https://doi.org/10.1016/s0140- 6736 ( 05 ) 67728 - 8 PMID: 16298220 .
6. Gerritsen AE , Allen PF , Witter DJ , Bronkhorst EM , Creugers NH . Tooth loss and oral health-related quality of life: a systematic review and meta-analysis. Health and quality of life outcomes . 2010 ; 8 : 126 . https://doi.org/10.1186/ 1477 -7525-8-126 PMID: 21050499
7. Adegboye AR , Twetman S , Christensen LB , Heitmann BL . Intake of dairy calcium and tooth loss among adult Danish men and women . Nutrition (Burbank , Los Angeles County, Calif). 2012 ; 28 ( 7 ±8): 779 ± 84 . https://doi.org/10.1016/j.nut. 2011 . 11 .011 PMID: 22459555 .
8. Howell TH , Ridker PM , Ajani UA , Hennekens CH , Christen WG . Periodontal disease and risk of subsequent cardiovascular disease in U.S. male physicians . Journal of the American College of Cardiology . 2001 ; 37 ( 2 ): 445 ± 50 . PMID: 11216961 .
9. Hujoel PP , Drangsholt MT , Spiekerman C , DeRouen TA . Periodontal disease and risk of coronary heart disease . Jama . 2001 ; 285 ( 1 ): 40 ± 1 . PMID: 11150099 .
10. Hung HC , Joshipura KJ , Colditz G , Manson JE , Rimm EB , Speizer FE , et al. The association between tooth loss and coronary heart disease in men and women . Journal of public health dentistry . 2004 ; 64 ( 4 ): 209 ± 15 . PMID: 15562943 .
11. Joshipura KJ , Rimm EB , Douglass CW , Trichopoulos D , Ascherio A , Willett WC . Poor oral health and coronary heart disease . Journal of dental research . 1996 ; 75 ( 9 ): 1631 ±6. https://doi.org/10.1177/ 00220345960750090301 PMID: 8952614 .
12. Joshy G , Arora M , Korda RJ , Chalmers J , Banks E. Is poor oral health a risk marker for incident cardiovascular disease hospitalisation and all-cause mortality? Findings from 172 630 participants from the prospective 45 and Up Study . BMJ open . 2016 ; 6 ( 8 ):e012386. https://doi.org/10.1136/bmjopen-2016 - 012386 PMID: 27577588
13. Jung YS , Shin MH , Kim IS , Kweon SS , Lee YH , Kim OJ , et al. Relationship between periodontal disease and subclinical atherosclerosis: the Dong-gu study . Journal of clinical periodontology . 2014 ; 41 ( 3 ): 262 ± 8. https://doi.org/10.1111/jcpe.12204 PMID: 24256094 .
14. Liljestrand JM , Havulinna AS , Paju S , Mannisto S , Salomaa V , Pussinen PJ . Missing Teeth Predict Incident Cardiovascular Events, Diabetes, and Death . Journal of dental research . 2015 ; 94 ( 8 ): 1055 ± 62 . https://doi.org/10.1177/0022034515586352 PMID: 25991651 .
15. Noguchi S , Toyokawa S , Miyoshi Y , Suyama Y , Inoue K , Kobayashi Y . Five-year follow-up study of the association between periodontal disease and myocardial infarction among Japanese male workers: MY Health Up Study . Journal of public health (Oxford, England) . 2015 ; 37 ( 4 ): 605 ± 11 . https://doi.org/10. 1093/pubmed/fdu076 PMID: 25293424 .
16. Schwahn C , Polzer I , Haring R , Dorr M , Wallaschofski H , Kocher T , et al. Missing, unreplaced teeth and risk of all-cause and cardiovascular mortality . International journal of cardiology . 2013 ; 167 ( 4 ): 1430 ±7. https://doi.org/10.1016/j.ijcard. 2012 . 04 .061 PMID: 22560949 .
17. Tu YK , Galobardes B , Smith GD , McCarron P , Jeffreys M , Gilthorpe MS . Associations between tooth loss and mortality patterns in the Glasgow Alumni Cohort . Heart (British Cardiac Society) . 2007 ; 93 ( 9 ): 1098 ± 103 . https://doi.org/10.1136/hrt. 2006 .097410 PMID: 17164486
18. Tuominen R , Reunanen A , Paunio M , Paunio I , Aromaa A . Oral health indicators poorly predict coronary heart disease deaths . Journal of dental research . 2003 ; 82 ( 9 ): 713 ±8. https://doi.org/10.1177/ 154405910308200911 PMID: 12939356 .
19. Vedin O , Hagstrom E , Budaj A , Denchev S , Harrington RA , Koenig W , et al. Tooth loss is independently associated with poor outcomes in stable coronary heart disease . European journal of preventive cardiology . 2016 ; 23 ( 8 ): 839 ± 46 . https://doi.org/10.1177/2047487315621978 PMID: 26672609 .
Watt RG , Tsakos G , de Oliveira C , Hamer M. Tooth loss and cardiovascular disease mortality riskÐ results from the Scottish Health Survey . PloS one . 2012 ; 7 ( 2 ):e30797. https://doi.org/10.1371/journal. pone. 0030797 PMID: 22363491
21. Holmlund A , Holm G , Lind L . Number of teeth as a predictor of cardiovascular mortality in a cohort of 7,674 subjects followed for 12 years . Journal of periodontology . 2010 ; 81 ( 6 ): 870 ±6. https://doi.org/10. 1902/jop. 2010 .090680 PMID: 20350152 .
22. Abnet CC , Qiao YL , Dawsey SM , Dong ZW , Taylor PR , Mark SD . Tooth loss is associated with increased risk of total death and death from upper gastrointestinal cancer, heart disease, and stroke in a Chinese population-based cohort . International journal of epidemiology . 2005 ; 34 ( 2 ): 467 ± 74 . https:// doi.org/10.1093/ije/dyh375 PMID: 15659476 .
23. Dietrich T , Jimenez M , Krall Kaye EA , Vokonas PS , Garcia RI . Age-dependent associations between chronic periodontitis/edentulism and risk of coronary heart disease . Circulation . 2008 ; 117 ( 13 ): 1668 ± 74 . https://doi.org/10.1161/CIRCULATIONAHA.107.711507 PMID: 18362228
24. Elter JR , Champagne CM , Offenbacher S , Beck JD . Relationship of periodontal disease and tooth loss to prevalence of coronary heart disease . Journal of periodontology . 2004 ; 75 ( 6 ): 782 ± 90 . https://doi.org/ 10.1902/jop. 2004 . 75 .6.782 PMID: 15295942 .
25. Stroup DF , Berlin JA , Morton SC , Olkin I , Williamson GD , Rennie D , et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group . Jama. 2000 ; 283 ( 15 ): 2008 ± 12 . PMID: 10789670 .
26. Durrleman S , Simon R . Flexible regression models with cubic splines . Statistics in medicine. 1989 ; 8 ( 5 ): 551 ± 61 . PMID: 2657958 .
27. Stang A . Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses . European journal of epidemiology . 2010 ; 25 ( 9 ): 603 ±5. https://doi. org/10.1007/s10654-010-9491-z PMID: 20652370 .
28. Xu C , Zeng XT , Liu TZ , Zhang C , Yang ZH , Li S , et al. Fruits and vegetables intake and risk of bladder cancer: a PRISMA-compliant systematic review and dose-response meta-analysis of prospective cohort studies . Medicine . 2015 ; 94 ( 17 ):e759. https://doi.org/10.1097/MD.0000000000000759 PMID: 25929912
29. Orsini N , Li R , Wolk A , Khudyakov P , Spiegelman D . Meta-analysis for linear and nonlinear doseresponse relations: examples, an evaluation of approximations, and software . American journal of epidemiology . 2012 ; 175 ( 1 ): 66 ± 73 . https://doi.org/10.1093/aje/kwr265 PMID: 22135359
30. Hiraki A , Matsuo K , Suzuki T , Kawase T , Tajima K. Teeth loss and risk of cancer at 14 common sites in Japanese. Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology . 2008 ; 17 ( 5 ): 1222 ±7. https://doi.org/10.1158/ 1055 - 9965 .epi- 07 -2761 PMID: 18483345 .
31. Awan Z , Genest J . Inflammation modulation and cardiovascular disease prevention . Eur J Prev Cardiol . 2015 ; 22 ( 6 ): 719 ± 33 . https://doi.org/10.1177/2047487314529350 PMID: 24711609 .
32. He J , Li Y , Cao Y , Xue J , Zhou X. The oral microbiome diversity and its relation to human diseases . Folia Microbiol (Praha) . 2015 ; 60 ( 1 ): 69 ± 80 . https://doi.org/10.1007/s12223-014-0342-2 PMID: 25147055 .
33. Dehghan M , Mente A , Zhang X , Swaminathan S , Li W , Mohan V , et al. Associations of fats and carbohydrate intake with cardiovascular disease and mortality in 18 countries from five continents (PURE): a prospective cohort study . Lancet . 2017 ; 390 ( 10107 ): 2050 ±62. https://doi.org/10.1016/S0140- 6736 ( 17 ) 32252 - 3 PMID: 28864332 .
34. You Z , Cushman M , Jenny N , Howard G . Tooth loss, systemic inflammation, and prevalent stroke among participants in the reasons for geographic and racial difference in stroke (REGARDS) study . Atherosclerosis . 2009 ; 203 ( 2 ): 615 ±9. https://doi.org/10.1016/j.atherosclerosis. 2008 . 07 .037 PMID: 18801482 .