Causal association between periodontitis and systemic diseases: a systematic review and meta-analysis of mendelian randomization studies.

This meta-analysis followed the updated 2020 guidelines of the Preferred Reporting Items for Systematic Reviews [ 15 ]. The PROSPERO database lists this meta-analysis under the registration number CRD42024581585. We conducted a thorough search of electronic databases, such as China National Knowledge Infrastructure (CNKI), WanFang data, PubMed, Web of Science and Science Direct, with the last update on September 1, 2024. The search terms included (“periodontitis” OR “periodontics” OR “periodontal”) and “mendelian randomization”. we also screened reference lists. Eligible studies had to meet specific criteria to be included in this review. (1) mendelian randomization analysis should be used to explore the causal relationship between periodontitis and systemic diseases; (2) periodontitis is identified as the exposure; (3) systemic diseases are identified as the outcome; (4) the studies can be genome-wide association studies that incorporated mendelian randomization in their analyses. On the other hand, certain criteria led to the exclusion of studies: (1) these included research involving non-human subjects; (2) conference abstracts, editorials, or review articles; (3) publications not in Chinese or English; (4) the full text was not accessible. In cases where multiple studies reported identical results within the same population, only the most recently published study was selected for inclusion. The selection procedure involved two reviewers (YH Z, CR Z), who independently assessed the literature. During the initial screening phase, they reviewed the titles and abstracts to identify articles that fulfilled the inclusion criteria. Following this, a detailed examination of the full texts was conducted in the second screening phase. In cases where the two reviewers had differing opinions, a third investigator (JX H), was brought in to facilitate a discussion aimed at reaching a consensus. Additionally, the selected studies underwent a thorough verification process by another investigator (Y H) to ensure the accuracy and reliability of the findings. Two reviewers (YH Z, CR Z) independently conducted the data extraction, followed by a verification of the accuracy of the extracted data by a third investigator (JX H). For each MR study, we systematically gathered several key details, including the family name of the first author, the year of publication, participant age, ethnic background, cohort characteristics, genetic instrument, sample size, the disease being investigated, key findings, the relative risk estimate expressed as odds ratio (OR), and the corresponding 95% confidence interval (CI). A complete quality review was conducted, with a focus on adherence to the Strengthening the Reporting of Mendelian Randomization Studies (STROBE-MR) Guidelines, as mentioned in the source [ 16 ]. These recommendations were carefully changed after an extensive analysis of multiple papers that discussed the quality evaluation procedures used to record MR research, as indicated in sources [ 17 ]. Following this stringent assessment, the quality evaluation scores were transformed into a percentage format, where scores below 75% were considered to indicate a high risk of bias, scores ranging from 75% to 85% were categorized as medium risk of bias, and scores exceeding 85% were deemed to reflect a low risk of bias, thus providing a clear framework for evaluating the reliability. STATA software, especially version 16.0 produced by Stata Corporation, was used to conduct a complete meta-analysis of the MR connections. In this investigation, data were pooled for meta-analysis only when at least three separate cohorts assessing the probable causal link between periodontitis and each specific systemic illness were discovered. The ORs and 95% CIs for periodontitis in connection to each systemic illness were aggregated using a random-effects or fixed-effects model, depending on the degree of heterogeneity detected across the studies. The I² statistic was used to assess study heterogeneity. An I² value below 50% indicates low heterogeneity and the fixed-effects model was used, whereas a value above 50% indicates strong heterogeneity, and the random-effects model was used to combine and analyze the increased variability among studies. Sensitivity analysis was adopted to evaluate the stability of the results of this meta-analysis. We would compare the results to the original data after removing one study and using the others to conduct a meta-analysis to see if there was a significant difference between the results. Then we continued the process till all studies were removed once. Publication bias occurs when studies with statistically significant results are more likely to be published and reported in meta-analyses, while research with non-significant or invalid results are ignored. This bias can skew meta-analysis results in favor of studies with substantial findings, reducing the analysis’s accuracy and dependability. To assess the existence of publication bias in the included studies, we first performed an initial evaluation through visual inspection of the symmetry of the funnel plot. Subsequently, we conducted a quantitative analysis using the Egger’s linear regression test [ 18 ]. We fitted the regression model: standardized normal deviate (effect size / standard error) = α + β × (1 / standard error). The deviation of the intercept α reflects the asymmetry of the funnel plot. A t-test was performed on the intercept α; a P-value < 0.05 indicated statistically significant publication bias.

The database searches returned a total of 610 records, of which 332 remained after removing duplicates. Seventy-eight MR studies were enrolled in the systematic review, and thirty-four researches were included in the meta-analysis. (Fig.  1 ) The number of MR studies for each disease category, diseases included in meta-analysis and whether the respective disease category is included in the discussion was counted. (Table  1 ) The basic information of the seventy-eight MR studies was collated. (Additional File 1) About the quality assessment, the quality evaluation scores of four researches were over 90%; the quality evaluation scores of twenty-four researches were between 80% and 90%; the quality evaluation scores of six researches were below 80%. (Supplement 1) Fig. 1 Literature screening flowchart for this review Literature screening flowchart for this review Table 1 The 78 MR studies cover 34 disease categories within 19 diseases number category lib_num included diseases discussion 1 cancer 9 Gastric cancer Y 2 inflammatory bowel disease and subtypes(ulcerative colitis and Crohn’s disease) 7 inflammatory bowel disease ulcerative colitis Crohn’s disease Y 3 arthritis(rheumatoid arthritis (RA), osteoarthritis (OA) and Ankylosing spondylitis) 6 rheumatoid arthritis (RA) Y 4 diabetes and complications 4 diabetes Y 5 Alzheimer’s Disease 4 Alzheimer’s Disease Y 6 mental illness 4 depressive disorder Y 7 Sjogren syndrome 3 Sjogren syndrome Y 8 COVID-19 3 None Y 9 stroke and subtypes 3 stroke Ischemic stroke Cardiogenic (CE) stroke Small vessel occlusion Y 10 NAFLD 3 NAFLD Y 11 obstetrics and gynaecology(Adverse Pregnancy Outcomes) 3 None Y 12 Coronary Atherosclerosis 3 Coronary Atherosclerosis N 13 COPD 2 None N 14 asthma 2 None N 15 Chronic Gastritis, gastric ulcer 2 None Y 16 Parkinson’s disease 2 Parkinson’s disease Y 17 psoriasis 2 psoriasis Y 18 brain atrophy 2 None Y 19 thyroid disease 2 hypothyroidism hyperthyroidism Y 20 sleep-related diseases 2 None Y 21 SLE 2 None N 22 lung function (FEV1,FVC, FEV1/FVC ratio) 1 None N 23 Polycystic ovary syndrome (PCOS) 1 None N 24 preeclampsia 1 None N 25 systolic, diastolic blood pressure (SBP, DBP) and pulse pressure (PP)) 1 None Y 26 glomerular filtration rate (eGFR) and blood urea nitrogen (BUN) 1 None N 27 erectile dysfunction (ED) 1 None N 28 benign prostatic hyperplasia (BPH) 1 None N 29 migraine 1 None N 30 Urinary system stones 1 None N 31 lipid levels (LDL, HDL, TG, and TC) 1 None N 32 infectious endocarditis 1 None N 33 osteoporosis 1 None N 34 telomere length (TL) 1 None N The number of MR studies for each disease category, diseases included in meta-analysis and whether the respective disease category is included in the discussion. Note the following points: 1. Some disease categories encompass multiple diseases or assessment indicators. Only diseases with a cohort count of three or more in the relevant literature were included in the meta-analysis. For example, the category of “obstetrics and gynaecology” includes three studies, but none of the diseases within this category have a cohort count of three or more, and thus were not included in the meta-analysis 2. Some MR studies included multiple diseases, resulting in overlap between different categories 3. A single disease may include multiple cohorts. Therefore, diseases with fewer than three studies may still be included in the meta-analysis (e.g., Parkinson's disease, psoriasis, hypothyroidism, hyperthyroidism, SLE) The 78 MR studies cover 34 disease categories within 19 diseases inflammatory bowel disease ulcerative colitis Crohn’s disease stroke Ischemic stroke Cardiogenic (CE) stroke Small vessel occlusion hypothyroidism hyperthyroidism The number of MR studies for each disease category, diseases included in meta-analysis and whether the respective disease category is included in the discussion. Note the following points: 1. Some disease categories encompass multiple diseases or assessment indicators. Only diseases with a cohort count of three or more in the relevant literature were included in the meta-analysis. For example, the category of “obstetrics and gynaecology” includes three studies, but none of the diseases within this category have a cohort count of three or more, and thus were not included in the meta-analysis 2. Some MR studies included multiple diseases, resulting in overlap between different categories 3. A single disease may include multiple cohorts. Therefore, diseases with fewer than three studies may still be included in the meta-analysis (e.g., Parkinson's disease, psoriasis, hypothyroidism, hyperthyroidism, SLE) We used data obtained through the inverse-variance weighted (IVW) and MR-Egger methods to evaluate the causal links between periodontitis and Alzheimer’s disease (AD) (Fig.  2 A-B), Parkinson’s disease (PD) (Fig.  2 C-D), stroke and its subtypes (ischemic stroke, cardioembolic stroke, small vessel stroke) (Fig.  2 E-H), coronary atherosclerosis (Fig.  2 I), depression (Fig.  2 J), psoriasis (Fig.  2 K), non-alcoholic fatty liver disease (NAFLD) (Fig.  3 A-B), Sjögren’s syndrome (Fig.  3 C-D), rheumatoid arthritis (RA) (Fig.  3 E-F), diabetes (Fig.  3 G-H), inflammatory bowel disease (IBD) and its subtypes (Crohn’s disease, ulcerative colitis) (Fig.  3 I-L, O-P), hypothyroidism (Fig.  3 Q-R), hyperthyroidism (Fig.  3 S), and gastric cancer (Fig.  3 M-N). The results indicated that periodontitis had no significant causal relationship with AD, PD, coronary atherosclerosis, RA, hypothyroidism, hyperthyroidism, gastric cancer, psoriasis, Sjögren’s syndrome, or IBD. However, significant causal relationships were found between periodontitis and stroke, NAFLD, depression, and diabetes. Specific data are as follows. Fig. 2 Forest plots of studies that evaluate the casual effect between periodontitis and systemic diseases. Alzheimer’s disease ( A - B ), Parkinson’s disease ( C - D ), stroke and its subtypes (ischemic stroke, cardioembolic stroke, small vessel stroke) ( E - H ), coronary atherosclerosis ( I ), depression ( J ), psoriasis K Forest plots of studies that evaluate the casual effect between periodontitis and systemic diseases. Alzheimer’s disease ( A - B ), Parkinson’s disease ( C - D ), stroke and its subtypes (ischemic stroke, cardioembolic stroke, small vessel stroke) ( E - H ), coronary atherosclerosis ( I ), depression ( J ), psoriasis K Fig. 3 Forest plots of studies that evaluate the casual effect between periodontitis and systemic diseases. Non-alcoholic fatty liver disease ( A - B ), Sjögren’s syndrome ( C - D ), rheumatoid arthritis ( E - F ), diabetes ( G - H ), inflammatory bowel disease and its subtypes (Crohn’s disease, ulcerative colitis) ( I - L , O - P ), hypothyroidism ( Q - R ), hyperthyroidism ( S ), and gastric cancer M - N Forest plots of studies that evaluate the casual effect between periodontitis and systemic diseases. Non-alcoholic fatty liver disease ( A - B ), Sjögren’s syndrome ( C - D ), rheumatoid arthritis ( E - F ), diabetes ( G - H ), inflammatory bowel disease and its subtypes (Crohn’s disease, ulcerative colitis) ( I - L , O - P ), hypothyroidism ( Q - R ), hyperthyroidism ( S ), and gastric cancer M - N We then meta-analyzed studies that used the IVW methods to evaluate the relationship between periodontitis and stroke. The results showed a positive causal effect between periodontitis and cardioembolic stroke (IVW, OR: 1.03[1.00-1.05]). There was no causal relationship between periodontitis and ischaemic stroke (IVW, OR: 1.00[0.99–1.01]), small vessel stroke (IVW, OR: 1.00[0.97–1.03]), and the whole stroke (IVW, OR: 0.99[0.98–1.01]). The meta-analysis of MR studies using the IVW method indicated a causal relationship between periodontitis and NAFLD (IVW, OR: 1.10 [1.04–1.17]). However, the MR-Egger analysis suggested no causal relationship (MR-Egger, OR: 1.09 [0.99–1.22]). The meta-analysis of MR studies using the IVW method indicated a causal relationship between periodontitis and depression (IVW, OR: 1.02 [1.00-1.05]). The meta-analysis of MR studies using both IVW and MR-Egger methods yielded different results. The IVW method suggested a causal relationship between periodontitis and diabetes (IVW, OR: 1.02 [1.00-1.03]), while the MR-Egger method did not (MR-Egger, OR: 0.99 [0.96–1.03]). In this study, utilizing the one-by-one exclusion procedure, the pooled odds ratios (ORs) for the associations between periodontitis and cardioembolic stroke (Fig.  4 E), depression (Fig.  4 J), diabetes (Fig.  4 R), and non-alcoholic fatty liver disease (Fig.  4 L) did not change directionally after the exclusion of any single study. Furthermore, the confidence intervals remained highly overlapping with those from the original analysis, indicating that the results were not unduly influenced by any individual study. (Fig.  4 ) Fig. 4 The results of sensitivity analysis. Removing one study and using the others to conduct a meta-analysis. Alzheimer’s disease ( A - B ), Parkinson’s disease ( C - D ), stroke and its subtypes (ischemic stroke, cardioembolic stroke, small vessel stroke) ( E - H ), coronary atherosclerosis ( I ), depression ( J ), psoriasis ( K ), non-alcoholic fatty liver disease ( L - M ), Sjögren’s syndrome ( N - O ), rheumatoid arthritis ( P - Q ), diabetes ( R - S ), inflammatory bowel disease ( T - U ), ulcerative colitis ( V - W ), gastric cancer ( X - Y ), Crohn’s disease ( Z - AA ), hypothyroidism ( BB - CC ), hyperthyroidism ( DD ) The results of sensitivity analysis. Removing one study and using the others to conduct a meta-analysis. Alzheimer’s disease ( A - B ), Parkinson’s disease ( C - D ), stroke and its subtypes (ischemic stroke, cardioembolic stroke, small vessel stroke) ( E - H ), coronary atherosclerosis ( I ), depression ( J ), psoriasis ( K ), non-alcoholic fatty liver disease ( L - M ), Sjögren’s syndrome ( N - O ), rheumatoid arthritis ( P - Q ), diabetes ( R - S ), inflammatory bowel disease ( T - U ), ulcerative colitis ( V - W ), gastric cancer ( X - Y ), Crohn’s disease ( Z - AA ), hypothyroidism ( BB - CC ), hyperthyroidism ( DD ) To evaluate potential publication bias, funnel plots and Egger’s tests were visually inspected for asymmetry. The funnel plot for the primary outcome (association between periodontitis and systemic diseases) demonstrated symmetry.(Fig.  5 ) However, for studies examining the association between periodontitis and Sjögren’s syndrome, periodontitis and diabetes, Egger’s test yielded a significant result (Sjögren’s syndrome_MR: α = -1.08, 95% CI: -1.08 to -1.08, p  = 1.02E-5; diabetes_IVW: α = -2.22, 95% CI: -3.58 to -0.85, p  = 0.03; diabetes_MR: α = 1.50, 95% CI: 0.98 to 2.02, p  = 4.81E-3), indicating the potential presence of publication bias.(Table 2 ). Table 2 The results of Egger’s tests for publication bias analysis Diseases Estimate 95% confidence interval p -value depression 0.18936659 -2.6726042 3.05133734 0.91789735 RA_ivw 0.45143125 -0.5363136 1.43917607 0.41141564 RA_MR 0.90881788 -1.0486952 2.866331 0.40456799 NAFLD_ivw -1.6824476 -6.2130626 2.8481675 0.54238463 NAFLD_MR 0.39418928 -5.5667964 6.35517491 0.90873348 coronary artery_ivw 0.69495533 -0.6287364 2.01864703 0.36161974 ischaemic stroke_ivw 0.63354388 -1.2871096 2.55419733 0.54644221 stroke_ivw 0.44183929 -0.4081561 1.29183468 0.38328715 cardioembolic stroke_ivw 0.79630314 -0.6088887 2.201495 0.31723262 small vessel stroke_ivw 0.17188094 -2.4072821 2.75104399 0.90116962 AD_ivw 0.80969633 -1.0667351 2.68612779 0.48674138 AD_MR 0.33804337 -0.6381244 1.31421117 0.62037397 hyperthyroidism_ivw -0.674706 -2.1748082 0.82539614 0.44293064 hypothyroidism_ivw 1.76257842 0.67232255 2.85283429 0.05053266 hypothyroidism_MR 0.73525825 0.44408719 1.02642931 0.12691841 Psoriasis_ivw 0.04687511 -0.4236278 0.51737802 0.86322079 Gastric Cancer_ivw 2.2667845 -1.3421468 5.87571578 0.34341652 Gastric Cancer_MR 0.33340323 -3.5928635 4.25967001 0.88311894 Parkinson’s Disease_ivw 1.0307119 -2.1102327 4.17165653 0.63612948 Parkinson’s Disease_MR 0.2355674 -0.4181505 0.88928526 0.60852172 Sjögren’s Syndrome_ivw -0.2072876 -0.5521246 0.13754949 0.32366835 Sjögren’s Syndrome_MR -1.0772875 -1.0773214 -1.0772537 1.0216E-05 Diabetes_ivw -2.2190814 -3.5834398 -0.854723 0.03328381 Diabetes_MR 1.49946723 0.98003209 2.01890237 0.00480919 IBD_ivw 0.27296549 -0.6827059 1.22863691 0.59974747 IBD_MR -0.3800539 -2.1497372 1.3896295 0.70214505 CD_ivw -1.6581331 -3.4984546 0.1821885 0.1755782 CD_MR -0.0294452 -1.1613596 1.10246922 0.96397039 UC_ivw 0.2129947 -0.8273662 1.25335559 0.70211921 UC_MR 0.91946892 -0.8987238 2.73766168 0.37770367 Alzheimer's disease (A-B), Parkinson's disease (C-D), stroke and its subtypes (ischemic stroke, cardioembolic stroke, small vessel stroke) (E-H), coronary atherosclerosis (I), depression (J), psoriasis (K), non-alcoholic fatty liver disease (L-M), Sjögren's syndrome (N-O), rheumatoid arthritis (P-Q), diabetes (R-S), inflammatory bowel disease (T-U), ulcerative colitis (V-W), gastric cancer (X-Y), Crohn's disease (Z-AA), hypothyroidism (BB-CC), hyperthyroidism (DD) The results of Egger’s tests for publication bias analysis Alzheimer's disease (A-B), Parkinson's disease (C-D), stroke and its subtypes (ischemic stroke, cardioembolic stroke, small vessel stroke) (E-H), coronary atherosclerosis (I), depression (J), psoriasis (K), non-alcoholic fatty liver disease (L-M), Sjögren's syndrome (N-O), rheumatoid arthritis (P-Q), diabetes (R-S), inflammatory bowel disease (T-U), ulcerative colitis (V-W), gastric cancer (X-Y), Crohn's disease (Z-AA), hypothyroidism (BB-CC), hyperthyroidism (DD) Fig. 5 The results of publication bias analysis. Alzheimer’s disease ( A - B ), Parkinson’s disease ( C - D ), stroke and its subtypes (ischemic stroke, cardioembolic stroke, small vessel stroke) ( E - H ), coronary atherosclerosis ( I ), depression ( J ), psoriasis ( K ), non-alcoholic fatty liver disease ( L - M ), Sjögren’s syndrome ( N - O ), rheumatoid arthritis ( P - Q ), diabetes ( R - S ), inflammatory bowel disease ( T - U ), ulcerative colitis ( V - W ), gastric cancer ( X - Y ), Crohn’s disease ( Z - AA ), hypothyroidism ( BB - CC ), hyperthyroidism ( DD ) The results of publication bias analysis. Alzheimer’s disease ( A - B ), Parkinson’s disease ( C - D ), stroke and its subtypes (ischemic stroke, cardioembolic stroke, small vessel stroke) ( E - H ), coronary atherosclerosis ( I ), depression ( J ), psoriasis ( K ), non-alcoholic fatty liver disease ( L - M ), Sjögren’s syndrome ( N - O ), rheumatoid arthritis ( P - Q ), diabetes ( R - S ), inflammatory bowel disease ( T - U ), ulcerative colitis ( V - W ), gastric cancer ( X - Y ), Crohn’s disease ( Z - AA ), hypothyroidism ( BB - CC ), hyperthyroidism ( DD )

Periodontitis is a chronic multifactorial inflammatory disease associated with dysbiotic plaque biofilms and characterized by progressive destruction of the tooth-supporting apparatus, leading to the destruction of periodontal attachment structures, tooth loosening, displacement, and eventual loss [ 1 ]. Its pathogenesis is closely related to various factors, including microbial infection, host immune response, and lifestyle [ 2 ]. A study on the prevalence of periodontitis among U.S. adults from 2009 to 2014 found that 42.2% (standard error ± 1.4) of adults aged 30 or older had periodontitis, with 7.8% having severe periodontitis and 34.4% having mild to moderate periodontitis. The prevalence increased with age [ 3 ]. In India, a cross-sectional study of 1,000 individuals under 18 found that 42.3% of minors had periodontitis [ 4 ]. In China, the periodontal health status is concerning. The 2017 Fourth National Oral Health Epidemiological Survey reported that the periodontal health rate in the 35–44 age group was only 9.1%. Over the decade from 2005 to 2015, the periodontal health rate in the 35–44 and 65–74 age groups significantly declined, with increased detection rates of gingival bleeding and deep periodontal pockets [ 5 ]. These data reflect the significant challenges in periodontal health management across different countries. The connection between periodontitis and systemic disorders is receiving attention, with research revealing that periodontitis is associated with a variety of conditions; one study found that the triglyceride-glucose index correlates with moderate/severe periodontitis risk, which is partially mediated by high systolic blood pressure [ 6 ]. Observational studies on the relationship between periodontitis and systemic diseases often face risks of reverse causality and unmeasured confounding factors. While these studies can reveal potential associations, the lack of randomized controls and interventions makes it difficult to establish causality. These associations may be influenced by other factors such as lifestyle, genetic background, and comorbidities [ 7 ]. In recent years, many studies have used MR to explore the relationship between periodontitis and various systemic diseases, including hypertension [ 8 ], chronic obstructive pulmonary disease (COPD) [ 9 ], cancer [ 10 ], and sleep deprivation [ 11 ]. Mendelian Randomization (MR) is a method that uses genetic variants associated with exposure differences as instrumental variables to estimate the causal effect of exposure on disease development [ 12 ]. Applying Mendel’s law of segregation to observational studies provides a new perspective for causal inference. The core of this method lies in using genetic variants (SNPs) as instrumental variables to control for potential confounding factors, enhancing the validity of causal inference. Genetic variants are used as instrumental variables because they are randomly assigned from parents to offspring, are typically unrelated to other risk factors, and have no direct relationship with the disease, satisfying the requirements for instrumental variables [ 13 ]. SNP selection is critical in genetic epidemiology, requiring three key assumptions: (1) a significant association between SNPs and exposure, confirmed by correlation or regression; (2) independence from confounding factors to prevent bias; and (3) exclusion of other pathways, ensuring effects are mediated through exposure, validated by experimental design and statistical models [ 14 ]. Over the past decade, the number of MR studies using whole-genome sequencing data has significantly increased, particularly in exploring the causal relationship between periodontitis and various systemic diseases. However, the diversity and inconsistency of existing study results have prompted further investigation in this field. This systematic review and meta-analysis aim to integrate published MR study results to clarify the potential causal relationship between periodontitis and systemic diseases.

The relationship between periodontitis and various systemic diseases remains complex and multifaceted, with inconsistent findings across different study designs. Future research should focus on addressing these limitations through larger, more diverse cohorts and the exploration of biological mechanisms underlying the observed associations.

The discussion encompasses a comprehensive array of 22 distinct disease categories, each of which is robustly supported by at least two independent studies, ensuring a solid foundation for our analysis. We meticulously examine the findings derived from previous observational studies concerning these diseases, delving into the intricate details of their results. Furthermore, we investigate the reasons for the discrepancies that often arise between the results obtained from observational studies and those derived from MR studies, aiming to uncover the factors that contribute to these differences. On the whole, while observational studies frequently report associations, MR analyses often fail to establish definitive causal links, highlighting the influence of confounding factors and the limitations of observational studies. In addition, we seek to elucidate the underlying biological mechanisms that intricately link periodontitis to these various diseases, providing a clearer understanding of how oral health can influence overall health outcomes. For stroke, we included three studies [ 19 – 21 ]. While one study found a causal relationship between chronic periodontitis and cardioembolic stroke [ 21 ], the other studies found no association between genetically predicted aggressive periodontitis and ischemic stroke or its subtypes. Our meta-analysis also indicated a causal relationship between periodontitis and cardioembolic stroke but not with overall stroke or other subtypes. A meta-analysis of observational studies suggested that periodontitis may be a risk factor for stroke, particularly ischemic stroke [ 22 ]. However, observational studies are often confounded by factors such as smoking, which is a significant risk factor for both periodontitis and cardiovascular diseases [ 23 , 24 ]. Therefore, the observed association between these two diseases may be influenced by a range of confounding factors. Additionally, some MR studies included in our analysis used a limited number of instrumental variables [ 20 ], which may have affected the study conclusions. A mediation analysis by Souvik Sen et al. [ 25 ]. suggested that atrial fibrillation mediates the association between periodontitis and stroke. Some studies have shown that periodontitis increases the risk of NAFLD [ 26 ], while other studies support a reverse causal relationship [ 27 ], and there are also studies that believe there is no causal relationship between the two [ 28 ]. However, the SNP selected as the instrumental variable in this study did not show a strong association with periodontitis, suggesting the possibility of a weak instrumental variable problem. Previous epidemiological studies have shown that periodontitis is related to NAFLD-related conditions, with lower prevalence of NAFLD-related conditions associated with more frequent tooth brushing and lower severity of periodontitis [ 29 , 30 ], and multiple liver enzymes used as surrogate markers of hepatocyte injury are significantly correlated with the severity of periodontitis [ 31 ]. Day and James [ 32 ] proposed the “two-hit” hypothesis to explain the pathogenesis of NAFLD: the “first hit” is fat transformation caused by insulin resistance due to chronic inflammation, and the “second hit” is gut-derived bacterial endotoxins, which promote inflammation and thus accelerate disease progression. Although the three included studies found no causal relationship between periodontitis and depression [ 33 – 35 ], the meta-analysis results suggested that periodontitis promotes the occurrence of depression (OR = 1.02, 95% CI = 1.00-1.05). Our findings are consistent with previous observational studies, indicating a positive association between periodontitis and depression. A meta-analysis of case-control studies found a positive correlation between periodontal disease and depression (OR = 1.70, 95% CI = 1.01–2.83). A meta-analysis of 18 studies found that subjects with periodontal disease had higher depression and anxiety scale scores [ 36 ]. A longitudinal analysis using data from Taiwan’s National Health Insurance program compared 12,709 newly diagnosed periodontitis cases with 50,832 matched controls and found a 76% increased risk of depression over 10 years after adjusting for confounders (hazard ratio = 1.76; 95% CI: 1.53–1.89) [ 37 ]. Animal experiments provide compelling evidence for the causal mechanism between periodontitis and depression. A preclinical in vivo study found that Fusobacterium nucleatum could directly invade the brains of rats under the induction of periodontitis and chronic stress, suggesting that periodontal pathogens may cross the blood-brain barrier and cause neuroinflammation [ 38 ]. Another study showed that Pg -treated mice exhibited depressive-like behaviors, with these behavioral changes associated with increased levels of activated astrocytes in the hippocampus and decreased levels of brain-derived neurotrophic factor and astrocytic p75 neurotrophic receptors [ 39 ]. Some studies suggest that there is no causal relationship between periodontitis susceptibility and blood glucose characteristics (fasting blood glucose, fasting insulin, glycated hemoglobin) or type 2 diabetes [ 40 , 41 ]. In the field of observational studies, there is a complex and profound bidirectional association between periodontitis and type 2 diabetes, which can be explained by various mechanisms. One possible explanation is that diabetes may directly affect the composition of the oral microbiota, leading to dysbiosis [ 42 ]. However, the most widely explored mechanism in studies to date is related to inflammatory pathways. Numerous studies have repeatedly shown that when these two comorbidities coexist, inflammatory markers in the body are significantly elevated, showing a mutually reinforcing relationship [ 43 ]. Additionally, studies have shown that treatment for periodontitis can effectively reduce the periodontal inflammatory burden, thereby positively and significantly affecting glycated hemoglobin levels in the blood [ 44 ]. On the other hand, studies have pointed out that Gram-negative bacteria in periodontal pockets can lead to increased inflammatory indicators in the serum, further deepening the interaction and impact between periodontitis and diabetes [ 45 ]. Periodontitis and type 2 diabetes are both multifactorial diseases, characterized by individuals being affected by risk factors over the years. Confounding factors (such as smoking, age, obesity, socioeconomic status, etc.) may explain the differences between these findings and the conclusions of observational studies [ 46 ]. Moreover, the MR method assumes that genetic variants as instrumental variables are perfect, i.e., they are completely correlated with the exposure factor and do not directly affect the outcome. However, this may not be the case in reality, especially when genetic effects are influenced by the environment or lifestyle, which may lead to inconsistencies between MR results and observational studies. The pathophysiological process may be more complex than genetic effects, and a single genetic marker may not fully capture the relationship between exposure and outcome. Three of the four studies analyzed found no causal relationship between periodontitis and RA [ 47 – 49 ], whereas one MR research found a causal link [ 50 ]. The meta-analysis found no causal link between periodontitis and RA. Previous epidemiological researches have revealed an association between periodontitis and RA. A meta-analysis discovered that patients with RA had a 1.13 times higher incidence of periodontitis than healthy controls [ 51 ]. Additionally, a meta-analysis of six case-control studies reported that periodontitis was associated with a significant increase in RA disease activity, with an average increase of 0.74 in the Disease Activity Score 28 compared to non-periodontitis patients [ 52 ]. A case-control study including participants from the Korean National Health and Nutrition Examination Survey found that the incidence and severity of knee osteoarthritis were associated with periodontitis [ 53 ]. However, not all studies have reached the same conclusion. A case-control study from the Swedish RA Epidemiology Investigation found no evidence of increased periodontitis prevalence in patients with confirmed RA compared to healthy controls [ 54 ]. The oral microbiome may be a shared risk factor for both RA and periodontitis. The periodontal pathogen Porphyromonas gingivalis ( Pg ), a Gram-negative anaerobic bacterium, is characterized by the expression of peptidylarginine deiminase and the citrullination process. Citrullinated proteins and peptidylarginine deiminase are detected in inflamed gingival tissues, with their expression increasing with the severity of inflammation [ 55 ]. Peptidylarginine deiminase mediates the development of RA through citrullination, leading to the production of anti-citrullinated protein antibodies, which are diagnostic biomarkers for RA [ 56 ]. The gut microbiome is considered an environmental factor in the development and progression of RA. Sato et al.. found that Pg -induced changes in the gut microbiome were associated with the exacerbation of collagen-induced arthritis, with increased serum interleukin 17 (IL-17) levels and a higher proportion of T helper cell 17 (Th17) cells in lymphocytes [ 57 ]. These results suggest that Pg plays a unique role in the link between periodontitis and RA by affecting the gut microbiome composition. The MR analysis included populations of European ancestry, so whether the results are representative of the entire population remains to be verified. Additionally, there may be overlapping participants in the exposure and outcome studies, but the extent of sample overlap is difficult to estimate. The SNPs used as genetic instruments had weak associations with periodontitis subtypes and osteoarthritis, with a P-value threshold < 1 × 10^-5. The limited number of SNPs selected as instrumental variables may explain only a small portion of the exposure variation and affect the statistical power of the causal estimates. Only one study investigated the association between periodontitis and hypertension, finding a significant association [ 8 ]. The study randomized 101 patients with moderate/severe periodontitis and hypertension into an intensive periodontal treatment group (scaling and root planing/chlorhexidine; n = 50) or a control periodontal treatment group (scaling; n = 51), with the primary outcome being the mean 24-hour ambulatory systolic blood pressure. Compared to the control group, intensive periodontal treatment improved periodontal status and significantly reduced systolic blood pressure at 2 months. A meta-analysis found that participants with moderate to severe and severe periodontitis had a 20–50% increased likelihood of hypertension when defined by a systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg, or the use of antihypertensive medications [ 58 ]. A systematic review including 20 studies with 226,025 elderly individuals indicated an positive association between periodontal disease and hypertension [ 59 ]. Another retrospective study showed that among treated hypertensive adults, those with periodontitis had an average systolic blood pressure approximately 2.3 to 3 mmHg higher. Moreover, periodontitis was associated with multiple adjusted antihypertensive treatment failure, with more severe periodontitis correlating with a higher likelihood of blood pressure control. Two MR studies included in our analysis did not demonstrate any effect of periodontitis on psoriasis [ 47 , 60 ]. A meta-analysis incorporating nine case-control studies revealed that individuals with periodontitis had a 2.87-fold increased risk of developing psoriasis compared to those without periodontitis [ 61 ]. Although there is some pathogenic linkage between these two diseases due to a common immune response, MR studies do not support a causal relationship between them, as the estimated relative risk is close to zero. One possible explanation is that the previously observed association between periodontitis and psoriasis may be coincidental or confounded by unknown factors. Moreover, the causal or reverse relationship between periodontitis and psoriasis cannot be determined in observational studies, as most individuals with periodontitis have systemic health issues [ 62 ]. Additionally, the majority of psoriasis patients suffer from multiple comorbidities, including rheumatological, cardiovascular, and psychiatric complications [ 63 ]. Therefore, these comorbidities, especially those sharing the same inflammatory pathways, may account for the association between periodontitis and psoriasis. Psoriasis patients often have higher levels of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and IL-17, which also play a key role in the pathogenesis of periodontitis [ 64 ]. One MR study found that genetic susceptibility to periodontitis was associated with a higher risk of PD [ 65 ], but another MR study indicated no causal relationship between the two [ 66 ]. However, it is noteworthy that this study also had some potential limitations that require detailed discussion: First, MR calculations cannot explicitly point out whether a certain disease will affect the onset risk of another disease at a specific period in an individual’s life, and this defect may affect the interpretation of the study results. Second, when there is a significant genetic-environmental interaction, such as in periodontitis, MR may yield less accurate conclusions, further affecting the reliability of the study. Additionally, due to the limited number of genome-wide association studies (GWAS) in other populations, this analysis was primarily based on studies of European descent, which undoubtedly restricts the applicability and generalizability of these results in a broader population. Notably, the weak correlation between periodontitis and PD due to the higher p-values of the instruments used also poses challenges for interpreting the results. Moreover, the lack of overlapping instruments between the two genomic studies of periodontitis may indicate that the selected instrumental variables (IVs) are relatively weak, further affecting the study’s conclusions. Previous studies have shown associations between the two conditions: a cross-sectional study revealed a higher prevalence of periodontitis in patients with PD, although the authors noted that this conclusion was confounded by upper limb degeneration [ 67 ]. However, another study showed that even with good oral hygiene, periodontitis patients still exhibit local inflammation in the periodontal tissues [ 68 ]. From a biological perspective, the association between periodontitis and a range of complex diseases appears to be a profound manifestation of systemic inflammation, closely related to the dissemination of periodontal pathogens’ products throughout the body. This dissemination not only affects oral health but may also have a potential impact on brain tissue, leading to a series of neurological issues. Studies have shown that IgG levels against Pg are significantly associated with impaired delayed memory and computational ability, drawing attention to the relationship between oral health and cognitive function [ 69 ]. One MR study’s IVW estimate showed that periodontitis has a causal relationship with increased susceptibility and severity of COVID-19 [ 70 ], but another study concluded that there is no causal relationship between periodontitis and COVID-19 hospitalization risk, susceptibility, or severity [ 71 ]. Periodontitis and COVID-19 have previously been linked in epidemiological studies: evidence suggests that periodontal symptoms are associated with COVID-19 severity (increased risk of intensive care unit admission, need for assisted ventilation, and death) [ 72 , 73 ]. However, confounding factors such as aging, obesity, diabetes, hypertension, and cardiovascular disease are associated with both COVID-19 severity and periodontitis [ 74 – 76 ], thus threatening the validity of observational study results, meaning that these studies may overestimate the association between periodontitis and COVID-19. From a microbiological perspective, periodontal pathogens may silently enter the lungs through the complex oral-lung axis or via saliva transmission, and by stimulating the release of inflammatory cytokines, further exacerbate the severe pulmonary infections caused by SARS-CoV-2, creating a vicious cycle [ 77 ]. Additionally, periodontal inflammation is not just a local response; it significantly enhances systemic inflammatory and innate immune responses by promoting the production of reactive oxygen species, leading to irreversible DNA damage in cells. This induced DNA damage may ultimately lead to dysfunction of pulmonary epithelial cells, providing a favorable environment for SARS-CoV-2 invasion and further worsening the severity of the infection [ 78 ]. In-depth bioinformatics analysis revealed that Myozenin 2, an important molecule, plays a key role in the pathogenesis and immune infiltration of both COVID-19 and periodontitis. Using the least absolute shrinkage and selection operator (LASSO) regression analysis, Myozenin 2 was found to be significantly downregulated in both diseases, suggesting its potential inhibitory role in disease progression. Moreover, Myozenin 2 showed significant positive correlations with multiple biomarkers, including activated B cells, memory B cells, effector memory CD4 T cells, Th17 cells, T follicular helper cells, and Th2 cells, further revealing its potential importance in immune responses [ 79 ]. Periodontitis is generally suggestively associated with IBD [ 47 , 80 – 82 ]. Periodontitis is considered an important risk factor for ulcerative colitis, a view strongly supported by a large-scale cohort study conducted in South Korea, which showed a significant association between the two [ 83 ]. Although the GWAS summary statistics used in one study were primarily from European participants, limiting the direct applicability of the results to other populations, this finding has still attracted widespread attention and discussion [ 82 ]. Additionally, a preclinical study further confirmed this view, showing that the presence of periodontitis significantly increased the secretion of various inflammatory factors in the colon of ulcerative colitis model mice, including TNFα, which not only exacerbated the inflammatory response but also worsened the pathological damage to the colon tissue, further revealing the complex interaction between periodontitis and ulcerative colitis [ 84 ]. Studies have shown a close association between oral microbiota diversity and intestinal inflammation, with specific oral bacteria significantly promoting this process. In particular, scientists have isolated a bacterium called Klebsiella from the saliva of patients with Crohn’s disease, which can colonize the colon and induce proliferation of Th1 cells in the lamina propria, ultimately leading to colonic tissue damage and exacerbated inflammatory responses [ 85 ]. Moreover, by gavage of saliva from periodontitis patients or specific periodontitis-related microorganisms (e.g., Pg ) into wild-type mice, studies have found that the gut microbiota of these mice show high similarity to the substances used for gavage, further revealing the complex link between oral and gut health [ 86 ]. Some studies have suggested a potential causal relationship between genetic susceptibility to periodontitis and an increased risk of hypothyroidism (OR: 1.24 [1.05–1.46]) [ 87 ], while others have indicated a causal relationship between periodontitis and hyperthyroidism [ 47 ]. These conclusions are consistent with previous observational studies. One study assessed the oral health status of 100 patients with thyroid dysfunction and found that, compared to the control group, patients with thyroid disease had more severe dental caries and periodontal destruction, with higher rates of gingival bleeding, attachment loss, and dental caries [ 88 ]. Another cohort study in South Korea investigated the relationship between thyroid-stimulating hormone levels and periodontitis in 1,423 individuals with periodontitis and found that low thyroid-stimulating hormone levels were significantly associated with a higher prevalence of periodontitis [ 89 ]. A retrospective study analyzing data from 2,069 patients in the Big Mouth Dental Database from 2011 to 2021 showed no statistically significant association between periodontal disease and thyroid disease [ 90 ]. Periodontal pathogens are not limited to the oral cavity; they may have profound effects on overall health, particularly by potentially interfering with the function of the endocrine system, including the normal operation of the thyroid gland. Although the exact mechanisms are still under active investigation, the scientific community generally believes that the imbalance of the oral microbiota, especially the disharmonious coexistence of harmful and beneficial microorganisms, can lead to an increased inflammatory burden within the body, thereby adversely affecting thyroid health [ 91 ]. Periodontitis and chronic periodontitis are causally related to low birth weight and pelvic peritoneal endometriosis, but not to other adverse pregnancy outcomes such as menstrual irregularities, endometriosis, and its subtypes [ 92 – 94 ]. A previous retrospective study indicated that the more severe the periodontal disease in pregnant women, the higher the incidence of preterm birth and low birth weight infants [ 95 ]. However, another prospective study showed that after controlling for confounding factors, periodontal disease in pregnant women is not a risk factor for preterm low birth weight infants [ 96 ]. Both observational and laboratory studies have limitations, including confounding bias, small sample size, and chance. MR can effectively overcome these limitations by utilizing robust SNPs from large databases. Periodontitis may lead to adverse pregnancy outcomes through the following pathways: First, key pathogens of periodontal disease can disrupt host immune regulation, disturb oral ecological balance, and increase the risk of adverse pregnancy outcomes through immune system dysregulation [ 97 ]. Second, oral bacteria such as Pg and Fusobacterium nucleatum are prone to spread to the placenta and induce intrauterine infections [ 98 ]. Additionally, pathogens, cytokines, and mediators in the blood may enter and stimulate the liver to produce acute phase reactants such as C-reactive protein, activating systemic inflammatory responses. Inflammatory mediators enter the placenta-fetus through the bloodstream, exacerbating intrauterine inflammation [ 94 ]. There is no evidence to suggest that periodontitis is associated with sleep characteristics [ 99 , 100 ]. However, a study based on NHANES data from 2009 to 2014 indicated that individuals with less than 7 h of sleep are at a higher risk of developing periodontitis, and this factor has a synergistic effect with individuals under 45 years old, females, and high-income individuals [ 99 ]. A meta-analysis incorporating 11 cross-sectional studies showed that short sleep duration (≤ 5 h) significantly increases the risk of periodontitis [ 101 ]. Another study found that compared to women with ≤ 5 h of sleep, women with 6–8 h and ≥ 9 h of sleep had an increased prevalence of periodontitis [ 102 ]. Shift workers with sleep duration of ≤ 5 h or ≥ 9 h had a higher risk of periodontitis, but day workers with sleep duration of ≤ 5 h or ≥ 9 h did not have a higher risk of periodontitis [ 103 ]. For the differences between observational and MR results, adjusting for confounding effects of age, gender, race, education level, BMI, family income, and baseline physical activity may only moderately reduce their impact on observational study results, while MR provides a higher level of evidence [ 99 ]. One study showed that periodontitis has no causal effect on the thickness and surface area of the entire cerebral cortex, but for functional cortical areas, compared with the control group, periodontitis patients had larger surface areas of the inferior temporal lobe, lateral orbitofrontal cortex, medial orbitofrontal cortex, and temporal pole cortex, and thicker entorhinal cortex [ 104 ]. Another MR study showed that periodontitis had no causal relationship with the surface area, thickness of the entire cerebral cortex, and bilateral hippocampal volume [ 105 ]. Previous observational studies have shown inconsistent results: a survey of an elderly participant cohort in the Atherosclerosis Risk in Communities (ARIC) study showed that periodontal disease was not related to brain volume changes [ 106 ], while another study showed that in middle-aged and elderly groups, fewer teeth in patients with mild periodontitis were associated with faster left hippocampal atrophy, and more teeth in patients with severe periodontitis were associated with faster atrophy [ 107 ]. The problems of this study include a limited sample size ( n = 179) and an older cohort age (≥ 75 years), which may threaten the validity of the conclusion. Additionally, observational studies may omit confounding factors of varying degrees, such as certain outcome-related genes (apolipoprotein E gene), socioeconomic factors, diet, lifestyle, and other potential outcome-related confounding factors, and therefore may not accurately describe the correlation between exposure and outcome [ 13 ]. Three studies showed that there was no association between periodontal disease and AD [ 68 , 105 , 108 ]. An MR investigation of the exploratory cohort in one literature revealed that periodontitis is a risk factor for Alzheimer’s disease, however data from the validation cohort in that literature contradicted this finding [ 109 ]. A survey of an aged participant cohort in the ARIC trial found no relationship between periodontal disease and amyloid-beta positive [ 106 ], despite the fact that extracellular amyloid-beta peptide deposition is one of the features of AD [ 110 ]. The mechanisms of mutual relationship between periodontitis and Alzheimer’s disease are as follows. According to Li et al. [ 111 ], periodontitis and brain degeneration may be linked through continuous systemic inflammation, with distinct mechanisms including direct bacterial invasion, invasion of inflammatory factors, and indirect pathways involving leptomeningeal cells as inflammation signal transducers. Additionally, cognitive impairment in AD patients may lead to poor oral hygiene, thereby worsening periodontitis [ 112 ]. Some research implies a causative association between periodontitis and oral cancer [ 113 ], whereas another study found no causal relationship in either direction [ 114 ]. A case-control research found that considerable gingival recession is strongly related with the risk of oral cancer (OR = 1.83, 95% CI, 1.10; 3.04) [ 115 ], and other meta-analyses corroborate the link between periodontitis and oral cancer (OR = 3.21, 95% CI = 2.25–4.16) [ 116 ]. In contrast to the conclusions of the above observational studies, the results of a case-control study showed that after adjusting for age, gender, country, education, tobacco pack-years, cumulative alcohol consumption, and all other oral health variables, did not raise the incidence of oral cancer [ 117 ], implying that observational studies that assume a link between the two may be influenced by these confounding variables. Existing research has revealed that Fusobacterium nucleatum is an active bacterial species in the oral cavity of periodontitis patients [ 118 ], and its proliferation can create an environment conducive to tumor growth [ 119 ]. Some studies suggest that periodontitis raises the risk of stomach cancer [ 113 , 120 ], whereas other documents argue that there is no proof that periodontitis does [ 114 , 121 ]. An observational study found that periodontitis is a risk factor for the occurrence or development of gastric cancer, and even after controlling for potential confounding factors (such as age, gender, body mass index, and smoking history), the risk of gastric cancer in the periodontitis group was still higher than in the control group [ 43 ], but this study had significant publication bias, reducing the credibility of the conclusion. Some research suggests that there is no significant causal association between periodontitis and esophageal cancer [ 113 , 114 , 120 , 122 ], and vice versa [ 114 , 122 ]. A meta-analysis [ 123 ] suggests that there is a link between the two (HR 1.39, 95% CI 1.15–1.68), although we are more inclined to believe that this strong correlation is influenced by confounding factors, given studies have shown that the two share several risk factors [ 124 ]. The literature supporting the association suggests that the inflammatory process may modulate the relationship between the two. In particular, periodontitis can considerably raise inflammatory markers and promote inflammatory response molecules, which in turn lead to the generation of reactive oxygen species and other metabolites, hence encouraging the incidence of cancer [ 125 ]. One MR investigation discovered no causal link between periodontitis and breast cancer [ 126 ]. An observational research of 5,110 breast cancer patients revealed no link between periodontal disease and breast cancer risk [ 127 ]. Furthermore, several studies have found that periodontal disease may increase the risk of developing breast cancer. A meta-analysis found that periodontal disease increases the risk of breast cancer by 1.22 times [ 128 ]. A case-control study confirms the link between periodontal disease and breast cancer, revealing that the incidence of breast cancer in patients with periodontal disease is considerably higher than in the healthy control group [ 129 ]. Many studies are observational and cannot totally rule out the influence of confounding factors like smoking, drinking, and other lifestyle choices. As a result, while the meta-analysis provides useful insights, additional prospective studies and randomized controlled trials are required to confirm the causal association between periodontal disease and breast cancer and investigate potential causes. Some research suggests a statistically significant link between periodontitis and the risk of colorectal cancer [ 10 ], whereas another study found no bidirectional causal linkage between periodontitis, colorectal cancer, and pancreatic cancer [ 118 ]. According to Hu et al. [ 130 ]. , the severity of periodontitis is associated with an increased risk of colorectal cancer. A prospective research of monozygotic twins by Manish Arora et al. [ 131 ]. similarly corroborated this conclusion (hazard ratio = 1.62, 95% CI: 1.13, 2.33), while an investigation of three cohorts and one meta-analysis found no link between periodontitis and the risk of colorectal cancer [ 132 ]. A plausible causative mechanism between periodontal disease and colorectal cancer incidence could be oral microbial dysbiosis and migration to places outside the oral cavity. This idea is supported by evidence that Gram-negative Fusobacterium nucleatum and Fusobacterium nucleatum interact with the inflammatory process associated with periodontal disease [ 118 , 133 ], and that this bacteria is commonly found in colorectal cancer tissues [ 134 , 135 ], so it can be speculated that Gram-negative Fusobacterium nucleatum in the oral cavity of periodontitis patients are transferred to the colorectum through various pathways, mediating the causal relationship between the two [ 114 ]. The literature reveals that there is no correlation between periodontitis and pancreatic cancer [ 10 , 114 ], and a subgroup study of pancreatic cancer shows that periodontitis has no causal relationship with pancreatic cancer regardless of gender or smoking status [ 10 ]. This finding contradicts prior meta-analyses of observational studies, even after accounting for common risk factors [ 136 ]. Based on observational and magnetic resonance studies, it is reasonable to speculate that periodontal disease has no causal relationship with the occurrence of pancreatic cancer, but is related to cancer progression, with the specific mechanism being that cancer cells are affected by oxidative stress [ 137 ], inflammation, or immune response [ 138 ] associated with periodontitis. There is no evidence to suggest that PD has a significant impact on the risk of developing hepatocellular carcinoma [ 114 , 139 ]. Previous observational studies have suggested a correlation between the two, with Yang et al. [ 140 ] concluding in a study of Finnish male smokers that an increase in the number of teeth lost is associated with an increased risk of hepatocellular carcinoma. Akio et al. [ 141 ]. found in an observational study of Japanese individuals that, after adjusting for potential confounding factors, there is a significant positive correlation between the number of teeth lost and the risk of esophageal cancer. The concept of the oral-gut-liver axis may explain the correlation between periodontitis and hepatocellular carcinoma [ 142 ], that is, oral microbiota can invade the gut and weaken the gut barrier, thereby increasing the migration of gut bacteria and their metabolites to the liver, which may lead to the development of various chronic liver diseases. The differences between observational studies and MR may be due to interference from confounding factors, such as different age stratifications, different population environmental backgrounds, and biases in disease diagnosis. Two pieces of literature indicate that there is no association between periodontitis and lung cancer [ 10 , 114 ], and one MR study conducted subgroup analysis on lung cancer and its different subtypes, showing that regardless of smoking status, periodontitis has no causal relationship with various subtypes of lung cancer [ 10 ]. However, a nationwide cohort study in South Korea [ 143 ] showed that patients with chronic periodontitis have a higher risk of developing lung cancer than healthy individuals, and severe chronic periodontitis further increases the risk of lung cancer. Subgroup analysis also found that the risk of lung cancer in never-smokers was higher than that in smokers. Considering that this study is limited to the Korean population and there are errors in the diagnosis of periodontitis, we believe that this result is somewhat suspicious. Scannapieco and Mylotte [ 144 ] proposed four mechanisms to explain the role of oral bacteria in lung cancer: (1) Oral pathogens (such as Pg , Aggregatibacter actinomycetemcomitans ) are inhaled into the lungs, causing bronchitis and other respiratory infections. (2) Enzymes related to periodontal disease in saliva may change the mucosal surface, promoting the adhesion and colonization of respiratory pathogens. (3) Enzymes related to periodontal disease in saliva may destroy the salivary membrane of pathogenic bacteria, thereby preventing their clearance from the mucosal surface. (4) Cytokines originating from periodontal tissue may change the respiratory epithelium and promote pathogenic infections. Literature indicates that there is a significant positive genetic correlation between periodontitis and renal cancer, but no significant association with prostate cancer (PC), bladder cancer (BC), and testicular cancer (TC), and vice versa, no significant impact of urinary system cancers on periodontitis was observed [ 114 , 145 ]. Previous observational studies support the correlation between periodontitis and renal cancer: a longitudinal study involving 48,375 male health care professionals in the United States over 18 years showed that individuals with a history of periodontal disease had a 49% higher risk of renal cancer [ 146 ]. However, the conclusions of observational studies on prostate cancer and bladder cancer are inconsistent with MR studies: Dizdar et al. [ 147 ]. assessed the cancer risk of a group of patients with moderate to severe periodontitis and found that the risk of prostate cancer in men with periodontitis was significantly higher. A cohort study based on the Korean National Health Insurance cohort database showed that periodontal disease was associated with an increased risk of bladder cancer, and this association still existed even after controlling for confounding factors [ 148 ]. Li B. et al.. believe that the difference between MR and observational studies may be due to the small number of genetic tools, and the differences in periodontitis diagnostic criteria in different included cohorts will also lead to some biases [ 145 ]. The specific mechanisms of the relationship between periodontitis and urinary system cancers are still unclear, but there are two possible pathways: on the one hand, as a chronic inflammatory disease, periodontitis may lead to systemic inflammation, thereby promoting the development of cancer [ 149 ]. On the other hand, common genetic factors may partially explain the impact of periodontal disease on urinary and reproductive system cancers. Current research results do not support the existence of a bidirectional causal relationship between periodontitis and Sjögren’s syndrome [ 47 , 150 , 151 ]. A meta-analysis by Yang et al. [ 152 ]. showed an association between the two, but the high heterogeneity among the included studies makes the research results somewhat suspicious. A meta-analysis by Soares et al. [ 153 ]. found that patients with Sjögren’s syndrome had higher plaque index, gingival index, probing depth, and bleeding on probing than the control group, but most of the included studies were judged to have a high risk of bias. Sjögren’s syndrome (SS) is a chronic autoimmune disease, and reduced salivary flow is one of its main manifestations. Reduced salivary flow can lead to oral microbiota dysregulation, changes in microbial communities, and reduced microbial diversity [ 154 ], thereby being associated with periodontitis [ 155 ]. However, an experimental study showed that after treatment with pilocarpine, the salivary flow rate and volume of patients increased, but the periodontal indicators did not improve [ 156 ], indicating that reduced salivary flow is not an intermediary factor between Sjögren’s syndrome and periodontitis. The correlation between the two may be due to common disease-related genes or common molecular mechanisms [ 157 ]. One study believes that there is no causal relationship in any direction between periodontitis and chronic gastritis or gastric ulcer [ 158 ], another study believes that periodontitis may increase the risk of gastric ulcer [ 159 ], and previous observational studies have shown a correlation between the two: a cross-sectional study based on data from the Korean Genome and Epidemiology Study (KoGES) showed that after adjusting for hypertension, diabetes, hyperlipidemia, stroke, ischemic heart disease, periodontitis, body mass index, smoking, drinking, nutritional intake, and economic income and other factors, the correlation between periodontitis and the increased risk of chronic gastritis/digestive ulcer still exists [ 160 ], which may be due to the influence of confounding factors including Helicobacter pylori [ 161 ]. As is well known, Helicobacter pylori (H. pylori) is associated with a series of digestive system diseases including chronic gastritis and gastric ulcer [ 162 ], and the oral cavity is a potential reservoir of H. pylori [ 163 ]. A meta-analysis has shown that H. pylori positivity significantly increases the risk of periodontitis by 3.42 times [ 164 ], therefore, a reasonable speculation is that periodontitis may be related to chronic gastritis and gastric ulcer through H. pylori. Some studies believe that there is no causal relationship between the two [ 165 ], but there are documents indicating that asthma may be a protective factor for periodontitis [ 166 ]. For this, some people speculate that patients diagnosed with asthma may inadvertently reduce the risk of exposure to periodontitis risk factors by deliberately following a healthy diet and smoke-free lifestyle [ 167 ]. The more widely accepted hypothesis is the hygiene hypothesis, that is, the T lymphocytes of asthma patients are mainly transformed into T helper 2 (Th2) cells after antigen stimulation [ 168 ], characterized by an increase and hyperactivity of Th2 cells, and a dynamic balance between Th1 and Th2 cells, resulting in a decrease in the number and activity of Th1 cells, thereby reducing the corresponding production of Th2 cytokines such as IFN-r and IL-2. Evidence suggests that Th1 cells can exacerbate alveolar bone destruction and periodontal tissue inflammation, which is positively correlated with the progression of periodontitis, while Th2 cells can effectively reduce the degree of periodontitis and protect periodontal tissues in the early immune response of periodontitis, so asthma has a protective effect on periodontitis [ 169 ]. Unlike MR studies, previous observational studies believe that there is a positive correlation between the two: in a case-control study involving 260 subjects, researchers found that in adults in Jordan, the risk of periodontitis in people with bronchial asthma was significantly increased [ 170 ]. At the same time, a meta-analysis covering 21 research samples also concluded that there is a positive correlation between periodontitis and asthma [ 171 ]. Several possible mechanisms of this positive correlation have been proposed in the studies, which are not only thought-provoking but also worthy of our in-depth exploration and research. For example, inflammatory cells caused by periodontitis release an enzyme called matrix metalloproteinase, which plays an important role in the body and can effectively degrade structural proteins in respiratory tissues, thereby possibly leading to the occurrence of chronic bronchitis and asthma and other respiratory diseases [ 172 ]. However, on the other hand, some scholars’ observational results show that adults with asthma seem less likely to develop severe periodontitis [ 173 ], which further deepens our understanding and exploration of this complex relationship. One MR study believes that there is no causal relationship between the two [ 174 ], but there are also studies showing that periodontitis is a risk factor for COPD [ 9 ]. The National Health and Nutrition Examination Survey I (NHANESI) conducted an observational study on 23,808 people, finding an association between dental health and COPD in the community population [ 175 ], a meta-analysis including 75 survey studies also showed a significant positive correlation between periodontitis and COPD [ 176 ], a prospective controlled study also showed that periodontal basic treatment can reduce the frequency of acute attacks in COPD patients [ 177 ]; however, another prospective controlled study showed that periodontal debridement treatment for chronic periodontitis had no effect on the quality of life and condition of COPD patients [ 178 ]. The microscopic mechanisms between the two include bacterial colony migration and systemic inflammatory state. Specifically, Pg can migrate to the lungs, change the lung microbiota, and worsen chronic obstructive pulmonary disease [ 179 ]. Local periodontal inflammation can lead to the release of various pro-inflammatory cytokines into the bloodstream, including interleukin IL-6, IL-1α, and IL-1β, interferon-γ, and TNF-α [ 180 ], these inflammatory cytokines may be related to respiratory tract infections. The three MR studies we included did not detect a causal relationship between periodontitis and coronary atherosclerosis [ 19 , 20 , 181 ]. Similarly, the pooled analysis failed to identify a causal relationship, which is inconsistent with the findings of previous observational studies. A systematic review that incorporated 20 studies involving 226,025 elderly individuals revealed that periodontal disease, tooth count, general oral health, and xerostomia were associated with coronary heart disease [ 59 ]. Another case-control study demonstrated that, apart from age ( p < 0.047) and low-density lipoprotein cholesterol ( p < 0.001), periodontal inflammatory surface area ( p = 0.002) was a significant independent predictor of the severity of coronary atherosclerosis, thus establishing periodontal inflammatory surface area as an independent predictor of the severity of coronary atherosclerosis [ 182 ].The association between periodontitis and coronary atherosclerosis is mediated through two mechanisms: microbial invasion and infection, as well as inflammation and immunity [ 183 ]. On one hand, microbes (including periodontal pathogens such as Pg , Aggregatibacter actinomycetemcomitans , Prevotella intermedia , Tannerella forsythia , and Fusobacterium nucleatum ) can enter the bloodstream, invade endothelial and phagocytic cells of the arteries, and contribute to the progression and changes in atherosclerotic lesions. On the other hand, inflammatory mediators derived from periodontal lesions (such as C-reactive protein, matrix metalloproteinases, fibrinogen, and other hemostatic factors) can enter the systemic circulation and further accelerate the formation and progression of atherosclerosis through pathways such as oxidative stress. Both periodontitis and cardiovascular diseases are multifactorial conditions, sharing many common risk factors (such as smoking, hypertension, advanced age, and obesity) [ 184 , 185 ]. These shared risk factors may compromise the reliability of the results obtained from observational studies. The two MR analyses we included both indicated a causal relationship between periodontitis and systemic lupus erythematosus (SLE) [ 47 , 50 ]. This conclusion is largely supported by previous observational studies. Rutter-Locher et al. [ 186 ]. conducted a meta-analysis of four studies and found that the risk of periodontitis in SLE patients was significantly higher than that in the control group, with a risk ratio of 1.76 (95% CI 1.29–2.41, p = 0.0004). A case-control study from Taiwan included 7,204 SLE patients and 72,040 non-SLE patients matched for age, sex, and date of first diagnosis (as the control group). After stratification by age, sex, or diabetes status, the association between periodontitis and SLE risk remained significant and was dose-dependent, with more severe periodontitis associated with a higher risk of SLE [ 187 ] .The biological basis underlying the causal relationship between periodontitis and SLE may be infectious pathogens. It has been reported that periodontal pathogens may induce excessive activation of the immune response in SLE by maintaining high expression of TLRs in periodontal tissues, thereby accelerating the occurrence and progression of autoimmune reactions [ 188 ].

Although this study systematically assessed the potential causal relationships between periodontitis and various systemic diseases by integrating evidence from multiple Mendelian randomization (MR) studies, several limitations remain that need to be considered when interpreting the results. First, the MR studies included in this analysis were predominantly based on genome-wide association study (GWAS) data from populations of European ancestry. Therefore, the findings may not be directly generalizable to other ethnic or racial groups. Differences in genetic backgrounds, environmental exposures, and lifestyles among populations may affect the strength of associations between genetic instrumental variables and the exposure (periodontitis) as well as the outcomes (systemic diseases). Future studies should include more diverse ethnic populations to validate the generalizability of these causal associations. Second, the validity of MR analysis depends on the selected genetic instrumental variables (SNPs) satisfying three core assumptions: strong association with the exposure, independence from confounders, and influence on the outcome only through the exposure. However, some studies may suffer from weak instrument bias, where the selected SNPs are not strongly associated with periodontitis (e.g., due to lenient P-value thresholds or low F-statistics). This could reduce statistical power and introduce estimation bias. Additionally, the number of MR studies included for certain disease categories (e.g., some cancer subtypes) was limited, which may affect the robustness of the results and the statistical power of the tests. Third, inconsistent results between the inverse-variance weighted (IVW) and MR-Egger methods were observed for certain disease categories (e.g., NAFLD and depression), suggesting the potential presence of residual directional pleiotropy. In our study, the IVW-based meta-analysis yielded statistically significant results, whereas the MR-Egger analysis did not. We attribute this discrepancy to the different ways these methods handle pleiotropy. The IVW method assumes that all SNPs are valid instrumental variables, while the MR-Egger method relaxes the strict “exclusion restriction” assumption by allowing directional pleiotropy, provided that the scatterplot of SNP-exposure associations against SNP-outcome associations is linear. Under such conditions, the MR-Egger slope estimate (representing the effect of the exposure on the outcome) remains unbiased, effectively “adjusting” for directional pleiotropy. Fourth, a notable methodological limitation is the use of the conventional inverse-variance weighting (IVW) method for meta-analysis. This standard approach assigns weights to each MR study primarily based on the precision of its effect estimate but does not directly incorporate the inherent Type I error risk (alpha level) or the statistical power unique to each individual MR study into the weighting calculation. Consequently, our analysis may not fully account for the varying reliability and potential false-positive risks across the synthesized evidence. We acknowledge that more sophisticated meta-analytic techniques could further strengthen the robustness of the results. Future methodological refinements could involve developing weighting schemes that integrate factors such as p-values, statistical power, or Bayesian frameworks that incorporate prior probabilities. The exploration and application of these advanced models represent a promising direction for enhancing causal inference in future MR meta-analyses. Fifth, although sensitivity analyses supported the robustness of the main positive findings (e.g., associations between periodontitis and cardioembolic stroke, depression, diabetes, and NAFLD), caution is still warranted in interpretation. For instance, the association with coronary heart disease became statistically significant after excluding a specific study in the leave-one-out analysis, suggesting that the current non-significant finding may be unstable and sensitive to individual studies. Further high-quality MR studies are needed to clarify this relationship. Sixth, the risk of publication bias remains. We assessed this using funnel plots and Egger’s test, but the statistical power of these tests was limited for disease categories with few included studies. For meta-analyses where Egger’s test did not detect publication bias, it cannot be definitively concluded that such bias is absent. In addition to more well-designed MR studies in the future, promoting the pre-registration and open sharing of all MR analysis results—regardless of whether they are positive or negative—is crucial for reducing this bias and building an unbiased causal evidence base. Seventh, this review primarily focused on binary outcomes (disease occurrence) and did not delve into the dose-response relationship between the severity of periodontitis and the severity of systemic diseases. Moreover, MR analyses typically reflect lifelong exposure effects and may not capture causal effects of exposure during early life or specific time windows, which could limit their guidance for clinical intervention timing. Finally, although the MR method effectively controls for confounding and reverse causality, it remains an observational study based on “genetic proxies” and cannot replace direct evidence from randomized controlled trials (RCTs). The observed causal associations still require further validation of their biological plausibility and clinical relevance through experimental studies (e.g., animal models, molecular mechanisms) and interventional clinical trials. In summary, while this study provides genetic evidence for causal relationships between periodontitis and certain systemic diseases, readers should interpret the results in light of the above limitations. Future research should aim to expand population representativeness, optimize the selection of genetic instrumental variables, explore mediating mechanisms, and employ multidisciplinary validation to more comprehensively and precisely elucidate the complex links between periodontitis and systemic health.

Supplementary Material 1. Supplementary Material 1. Supplementary Material 2. Supplementary Material 2.