
==== Front
Sci Rep
Sci Rep
Scientific Reports
2045-2322
Nature Publishing Group UK London

39300119
72297
10.1038/s41598-024-72297-z
Article
Association of periodontitis with all-cause and cause-specific mortality among individuals with depression: a population-based study
Zhang Yonghuan 1
Lin Shanfeng 2
Chen Xuzhuo 3
Lan Hongbing 4
Li Weiqi liweiqi@stu.scu.edu.cn

5
Lin Li linli@cmu.edu.cn

1
1 https://ror.org/00v408z34 grid.254145.3 0000 0001 0083 6092 Department of Periodontology, School of Stomatology, China Medical University, Shenyang, Liaoning People’s Republic of China
2 https://ror.org/00v408z34 grid.254145.3 0000 0001 0083 6092 Department of Oroamxillofacial-Head and Neck Surgery, School of Stomatology, China Medical University, Shenyang, Liaoning People’s Republic of China
3 grid.16821.3c 0000 0004 0368 8293 Shanghai Key Laboratory of Stomatology, Department of Oral Surgery, Shanghai Ninth People’s Hospital, National Clinical Research Center for Oral Diseases, National Center for Stomatology, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
4 https://ror.org/02zhqgq86 grid.194645.b 0000 0001 2174 2757 Applied Oral Sciences and Community Dental Care, Faculty of Dentistry, The University of Hong Kong, Hong kong, China
5 grid.13291.38 0000 0001 0807 1581 State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, Sichuan University, Chengdu, Sichuan People’s Republic of China
19 9 2024
19 9 2024
2024
14 219174 7 2024
5 9 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
To detect the association between periodontitis and all-cause as well as cause-specific mortality rates among adults diagnosed with depression. Participants diagnosed with depression were selected from NHANES across three periods (1988—1994; 1999—2004; 2009—2014). Cox proportional hazards and Weibull accelerated failure time (AFT) models were utilized to calculate hazard ratios (HRs), time ratios (TRs), and their 95% confidence intervals (CIs) to evaluate the association between moderate-to-severe periodontitis and all-cause as well as cause-specific mortality among participants with depression. white blood counts and C-reactive protein were used to assess the mediating role of systemic inflammation. Among the 1,189 participants with a median follow-up of 9.25 years, 133 deaths were recorded. After adjusting for multiple variables, moderate-to-severe periodontitis was obvious associated with an increased risk of cancer-related mortality in individuals with depression (Cox: HR 3.22, 95% CI 1.51—6.83, P = 0.002; AFT: TR 0.70, 95% CI 0.52—0.94, P = 0.017). Neither WBC nor CRP significantly mediate the association between periodontitis and cancer-related mortality. The risk of cancer-related mortality rose with the severity of periodontitis (P for trend = 0.021). However, no association was observed between moderate-to-severe periodontitis and other kinds of mortality. Moderate-to-severe periodontitis is linked to an elevated risk of cancer-related mortality among adults diagnosed with depression, with the mortality risk increasing alongside the severity of periodontitis. No significant mediating effect of systemic inflammation was found in this association. These findings highlight the importance of addressing periodontal health in individuals with depression. By uncovering the association between periodontitis and mortality in this population, our study underscores the potential benefits of preventive dental care and periodontal treatment in reducing the risk of cancer-related mortality in individuals with depression.

Subject terms

Risk factors
Depression
Periodontitis
http://dx.doi.org/10.13039/501100001809 National Natural Science Foundation of China 81970942 Lin Li Liaoning Provincial Applied Basic Research Program Project2023JH2/101300042 Lin Li issue-copyright-statement© Springer Nature Limited 2024
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pmcIntroduction

Depression is a common mental disorder and affects over 180 million individuals worldwide1,2. Depression ranked third in terms of disease burden, and it is projected to become the primary cause of global overall disease burden by 20303,4. Depression not only leads to impaired functional outcomes and diminished quality of life but also associated with the occurrence and long-term prognosis of a range of physical diseases, such as cardiovascular diseases (CVD) and cancer1,5–7. Not solely attributable to the disorder itself, related medical comorbidities, social factors, and impaired functional outcomes contribute to the reduced quality of life in individuals experiencing depression1,7. Furthermore, depression is associated with shortened life expectancy and increased risk of mortality7–9. Studies indicate that the presence of comorbid conditions such as cardiovascular diseases in individuals with depression not only leads to higher healthcare utilization rates and costs but also increases the risk of mortality7,10–13. It is of great importance to identify modifiable factors for the prevention or delay of depression complications and premature death.

Periodontitis is the major inflammatory disease of the oral mucosa14. This chronic inflammatory condition gradually impacts the tissues that support teeth, ultimately leading to tooth loss15. Periodontitis increases the risk of various physical diseases including cardiovascular disease, diabetes mellitus, cancers, and depression14,16–19. Studies have also found close association between periodontitis and the mortality rates of individuals with physical diseases such as cancer, CVD, and diabetes20–23. In recent years, the association between periodontal status and neurological disorders has become a hot topic18,24–27, while the association between periodontitis and the onset of depression has also received increasing attention19,28–30.

While the association between periodontitis and depression has been widely reported19,29,31,32, there is barely studies explored the impact of periodontitis on the long-term survival among individuals with depression. Depression is associated with an increased risk of mortality, probably in part due to systemic inflammation. Based on this, we hypothesized that periodontitis may indirectly influence mortality among individuals with depression through systemic inflammation. To identify controllable risk factors that could prevent or delay premature mortality in depression, , we utilized this cohort of US with adults aged over 30 years to detect the potential association between moderate-to-severe periodontitis and all-cause as well as cause-specific mortality among individuals with depression. Additionally, we aimed to determine the role of systemic inflammation in mediating this association.

Results

Characteristics of depression participants

Among participants with depression in NHANES which representing the US population, the prevalence of moderate/severe periodontitis is 32.5% ± 2.0%. Over 14,927 person-years of follow-up (median follow-up of 9.25) of unweighted 1,189 participants, 133 all-cause deaths were recorded (28 due to CVD and 29 due to cancer).

Participants categorized as having moderate/severe periodontitis were older (mean age 50.9 ± 0.9 vs. 44.3 ± 0.5, P < 0.001), had a lower proportion of females (56.2% vs. 67.1%, P = 0.0066), were less likely to be non-Hispanic black (56.3% vs. 69.6%, P < 0.001), with a higher percentage of low SES (56.9% vs. 36.1%, P = 0.001), were more likely to be current smokers (42.7% vs. 33.6%, P = 0.041), were less likely to be heavy drinkers (22.6% vs. 33.9%, P = 0.010), had a higher proportion of inactive participants (33.2% vs. 26.5%, P = 0.040), and had a higher prevalence of comorbidities (hypertension: 54.4% vs. 43.1%, P = 0.005; hyperlipidemia: 69.6% vs. 55.6%, P = 0.001; diabetes: 22.4% vs. 14.9%, P = 0.013). Additionally, a greater proportion of participants were from the NHANES 2009–2014 periods (91.2% vs. 71.1%, P < 0.001). No differences were observed in marital status and nutritional status (BMI) details of demographic characteristics of participants could be found in Table 1 and Supplementary Table 3.Table 1 Baseline characteristics of participants with depressive disorder according to periodontal status.

			Periodontal status		
	Over all	No/ Mild periodontitis	Moderate/ Severe periodontitis		
Characteristics	Mean/ %*	SE*	Mean/ %	SE	Mean/ %	SE	P†	
No.(Unweighted)	1,189	764	425		
No.(Weighted)	12,493,474	4,057,109	8,436,365		
Age (years), mean	46.4	0.4	44.3	0.5	50.9	0.9	 < 0.001	
Age status, %							 < 0.001	
 < 45	50.1	1.9	58.4	2.7	32.8	3.5		
[45, 65)	41.1	1.8	34.8	2.7	54.2	3.5		
 ≥ 65	8.8	0.7	6.7	0.9	130	2.0		
Gender, Female	63.6	2.0	67.1	2.6	56.2	3.3	0.006	
Race/ ethnicity, %							 < 0.001	
Non-Hispanic white	65.3	2.3	69.6	2.4	56.3	3.8		
Non-Hispanic black	12.9	1.2	11.8	1.2	15.3	2.3		
Hispanic	16.6	1.8	14.8	1.8	20.3	2.7		
Other race/ ethnicity	5.2	0.8	3.8	0.6	8.2	2.1		
Marital status, %							0.635	
Married	51.9	1.9	51.2	2.8	53.3	3.1		
Never married	15.8	1.4	16.8	1.9	13.8	2.6		
Widowed/ Divorced/ Separated	32.3	1.7	32.0	2.3	32.9	2.9		
Socioeconomic Status, %							 < 0.001	
Low	42.8	2.4	36.1	2.6	56.9	3.7		
Medium	32.8	2.0	35.5	2.3	27.2	3.1		
High	24.4	2.1	28.4	2.5	15.9	3.2		
Smoking status, %							0.041	
Never smoker	41.3	2.1	43.6	2.6	36.7	3.3		
Former smoker	22.1	2.0	22.8	2.3	20.7	2.9		
Current smoker	36.5	2.1	33.6	2.3	42.7	3.1		
Drinking status, %							0.010	
Nondrinker	8.9	1.2	7.6	1.2	11.6	2.3		
Light/ moderate drinker	60.9	1.6	58.5	2.3	65.8	3.4		
Heavier drinker	30.3	1.7	33.9	2.3	22.6	3.2		
Physical status, %							0.040	
Inactive	28.7	20.0	26.5	2.5	33.2	3.0		
Insufficient	31.7	1.6	34.5	2.2	25.8	2.5		
Recommended	39.6	2.2	39.0	2.9	41.0	3.3		
BMI, Mean	30.7	0.3	30.4	0.5	31.2	0.5	0.297	
BMI status (kg/m2), %							0.372	
 < 25	25.3	2.0	26.9	2.6	22.0	2.8		
[25.0 -30)	28.3	2.1	28.3	2.9	28.2	2.8		
 ≥ 30	46.4	2.0	44.8	2.9	49.7	3.1		
Comorbidities, %								
Hypertension	46.8	1.9	43.1	2.3	54.4	3.5	0.005	
hyperlipidemia	61.0	1.8	56.8	2.4	69.6	2.7	0.001	
Diabetes mellitus	17.3	1.3	14.9	1.6	22.4	2.7	0.013	
Cohort period, %							 < 0.001	
NHANES III	10.3	1.1	12.8	1.5	5.2	1.5		
NHANES 1999–2004	12.0	1.8	16.1	3.1	3.4	1.3		
NHANES 2009–2014	77.6	2.0	71.1	3.2	91.3	2.0		
*Normally distributed continuous variables are described as means ± SEs; Categorical variables are presented as numbers (percentages). All estimates accounted for complex survey designs.

†The t test was used for continuous variables and the χ test for categorical variables.

Association between moderate-to-severe periodontitis and all kinds of mortality

The results from the CIF analysis indicated a significantly higher result of CVD-related mortality (P = 0.039) in the moderate-to-severe periodontitis, while no significant differences were detected in cancer-related mortality (P = 0.321) and other mortality rates (P = 0.058) (Fig. 1. A). In the univariate Kaplan–Meier (KM) analysis, moderate-to-severe periodontitis was significantly associated with all-cause (P < 0.001) and cancer-related (P < 0.001) mortality among participants with depression (Fig. 1. B-D). The absolute rates (crude) of all kinds of mortality for moderate/severe periodontitis were 13.66% (all-cause, 95% CI: 13.62—13.69), 2.90% (CVD-related, 95% CI: 2.88—2.92), and 3.98% (cancer-related, 95% CI: 3.96—4.00), respectively (Supplementary Table 4).Fig.1 Association between moderate-to-severe periodontitis and all kinds of mortality. (A): Cumulative incidence of different cause-specific mortality. (B): The weighted Kaplan–Meier analysis of periodontitis with all-cause survival. (C): The weighted Kaplan–Meier analysis of periodontitis with CVD- related survival; (D): The weighted Kaplan–Meier analysis of periodontitis with cancer-related survival.

After adjusting for multivariate covariates, moderate-to-severe periodontitis remained obvious associated with an increased risk of cancer-related mortality (hazard ratio [HR]: 3.22, 95% CI: 1.51—6.83, P = 0.002). No significant differences were found in all-cause and CVD-related mortality outcomes (Table 2). Consistent with the competing risk model, the Weibull AFT model revealed that moderate-to-severe periodontitis reduced the survival time for cancer-related mortality in participants with depression (Time ratio: 0.70, 95% CI: 0.52—0.94, P = 0.017), while no significant difference was found in all-cause or CVD-related mortality (Table 3).Table 2 HR (95% CIs) for All-cause and cause-specific mortality according to periodontitis.

	Periodontal status		
	No/ Mild periodontitis	Moderate/ Severe periodontitis	P	
All cause*	
Deaths/total (Unweighted)	73/764	60/425		
Deaths/total (Weighted)	487,055/4,057,109	704,249/8,436,365		
Model 1†	1.00 [Reference]	1.85 (1.10, 3.09)	0.019	
Model 2‡	1.00 [Reference]	1.28 (0.73, 2.27)	0.392	
Model 3§	1.00 [Reference]	1.31 (0.71, 2.41)	0.386	
Model 4¶	1.00 [Reference]	1.28 (0.70, 2.34)	0.419	
CVD cause	
Deaths/total (Unweighted)	15/764	13/425		
Deaths/total (Weighted)	103,484/4,057,109	127,066/8,436,365		
Model 1	1.00 [Reference]	1.87 (0.64, 5.47)	0.253	
Model 2	1.00 [Reference]	1.24 (0.37, 4.22)	0.726	
Model 3	1.00 [Reference]	1.30 (0.40, 4.22)	0.666	
Model 4	1.00 [Reference]	1.28 (0.40, 4.14)	0.674	
Cancer cause	
Deaths/total (Unweighted)	13/764	16/425		
Deaths/total (Weighted)	141,963/4,057,109	118,031/8,436,365		
Model 1	1.00 [Reference]	4.07 (1.77, 9.37)	0.001	
Model 2	1.00 [Reference]	2.81 (1.36, 5.81)	0.005	
Model 3	1.00 [Reference]	2.89 (1.37, 6.11)	0.005	
Model 4	1.00 [Reference]	3.22 (1.51, 6.83)	0.002	
*All-cause mortality used Cox proportional hazards model, and Cause-specific mortality used competing risk model.

†Model 1 was univariate analysis.

‡Model 2 included age (30–44, 45–64 or ≥ 65 years old), gender, race/ethnicity (non-Hispanic white, non-Hispanic black, Hispanic or other races), SES (Socioeconomic Status, low, middle, high), marital status (married/ living with partner, never married, widowed/ divorced/ separated).

§Model 3 additionally included smoking status (never smokers, former or current smokers), drinking status (nondrinker, heavier drinker, or light/ moderate drinker), physical activity status (inactive, insufficient, recommended) and BMI (body measure index, normal (≤ 24.9 [kg/m2]), overweight (25.0–29.9 [kg/m2]), and obesity (≥ 30.0 [kg/m2]) based on Model 2.

¶Model 4 was further adjusted for HTN status (hypertension, yes or no) , HPL (hyperlipidemia, yes or no),diabetes status (yes or no) and cohort period based on Model 3.

Table 3 Time Ratio (95% CIs) for All-cause and cause-specific mortality according to periodontitis by Weibull model.

	Periodontal status		
	No/ Mild periodontitis	Moderate/ Severe periodontitis	P	
All cause*	
Deaths/total (Unweighted)	73/764	60/425		
Deaths/total (Weighted)	487,055/4,057,109	704,249/8,436,365		
Model 1†	1.00 [Reference]	0.54 (0.34, 0.86)	0.009	
Model 2‡	1.00 [Reference]	0.82 (0.53, 1.28)	0.379	
Model 3§	1.00 [Reference]	0.81 (0.51, 1.29)	0.377	
Model 4¶	1.00 [Reference]	0.84 (0.54, 1.29)	0.420	
CVD cause	
Deaths/total (Unweighted)	15/764	13/425		
Deaths/total (Weighted)	103,484/4,057,109	127,066/8,436,365		
Model 1	1.00 [Reference]	0.39 (0.11, 1.46)	0.164	
Model 2	1.00 [Reference]	0.79 (0.20, 3.04)	0.730	
Model 3	1.00 [Reference]	0.75 (0.22, 2.57)	0.652	
Model 4	1.00 [Reference]	0.81 (0.26, 2.52)	0.709	
Cancer cause	
Deaths/total (Unweighted)	13/764	16/425		
Deaths/total (Weighted)	141,963/4,057,109	118,031/8,436,365		
Model 1	1.00 [Reference]	0.71 (0.53, 0.96)	0.024	
Model 2	1.00 [Reference]	0.70 (0.53, 0.93)	0.015	
Model 3	1.00 [Reference]	0.70 (0.51, 0.95)	0.023	
Model 4	1.00 [Reference]	0.70 (0.52, 0.94)	0.017	
*All-cause and Cause-specific mortality used Weibull accelerated failure time model.

†Model 1 was univariate analysis.

‡Model 2 included age (30–44, 45–64 or ≥ 65 years old), gender, race/ethnicity (non-Hispanic white, non-Hispanic black, Hispanic or other races), SES (Socioeconomic Status, low, middle, high), marital status (married/ living with partner, never married, widowed/ divorced/ separated).

§Model 3 additionally included smoking status (never smokers, former or current smokers), drinking status (nondrinker, heavier drinker, or light/ moderate drinker), physical activity status (inactive, insufficient, recommended) and BMI (body measure index, normal, overweight, and obesity) based on Model 2.

¶Model 4 was further adjusted for HTN status (hypertension, yes or no) , HPL (hyperlipidemia, yes or no), diabetes status (yes or no) and cohort period based on Model 3.

Over a 10-year follow-up period, the cumulative incidence of cancer-related mortality was 3.35% (95% CI: 2.93—4.17) for individuals with depression and moderate/severe periodontitis, with an absolute risk difference of 0.98% (95% CI: 0.55—1.40). Further details are provided in Supplementary Table 5.

Mediation impact of inflammatory markers on the association between periodontitis and cancer-related mortality

The mediation analysis indicates that while periodontitis has a direct negative association with cancer-related mortality when mediated by white blood counts (WBC), this effect is not statistically significant when mediated by C-reactive protein (CRP). Neither WBC nor CRP significantly mediate the association between periodontitis and cancer-related mortality, as the mediation effects through both are minimal and not statistically significant (Supplementary Table 6).

Trend test of periodontitis and stratified analyses

In trend test, the severity of periodontitis s was found an increasing trend for risk of cancer-related mortality (P for trend = 0.021), No significantly trend was found in other kinds of mortality (Table 4).Table 4 HR (95% CIs) for All-cause and cause-specific mortality according to status of periodontitis.

Outcomes	Events (Weighted), n/N	HR (95% CI)	P	
All cause				
No/Mild periodontitis	704,249/8,436,365	1.00 [Reference]		
Moderate periodontitis*	454,677/3,740,355	1.32 (0.71, 2.45)	0.380	
Severe periodontitis	32,378/316,754	0.92 (0.32, 2.68)	0.885	
P for trend		1.18 (0.74, 1.88)	0.489	
CVD cause				
No/Mild periodontitis	127,066/8,436,365	1.00 [Reference]		
Moderate periodontitis	88,048/3,740,355	1.18 (0.33, 4.19)	0.796	
Severe periodontitis	15,436/316,754	2.80 (0.53, 14.77)	0.225	
P for trend		1.38 (0.54, 3.53)	0.501	
Cancer cause				
No/Mild periodontitis	118,031/8,436,365	1.00 [Reference]		
Moderate periodontitis	135,133/3,740,355	3.64 (1.69, 7.85)	0.001	
Severe periodontitis	6,829/316,754	1.13 (0.11, 12.13)	0.919	
P for trend		2.00 (1.11, 3.60)	0.021	
*All-cause mortality used Cox proportional hazards model, and cause-specific mortality used competing risk model. All the models were adjusted for age (30–44, 45–64 or ≥ 65 years old), gender (male and female), race/ethnicity (non-Hispanic white, non-Hispanic black, Hispanic, and other races), SES (high, medium, and low level), marital status (married/living with partner, never married, widowed/ divorced/ separated), smoking status (current smokers, former smokers, and never smokers), drinking status (nondrinkers, heavier drinkers, and light/moderate drinkers), physical activity status (inactive, insufficient, recommended), BMI (body mass index, normal, overweight, and obesity), HTN status (hypertension, yes or no), HPL (hyperlipidemia status, yes or no), diabetes status (yes or no) and cohort period.

Stratified analysis was conducted to investigate the influence of various clinical phenotype on the outcomes (Table 4). Most HRs indicated a positive association between periodontitis and cancer-related mortality among participants with depression (Supplementary Table 7). Notably, in the subgroup aged ≥ 45 years, moderate/severe periodontitis exhibited a decreased association with cancer mortality (HR: 0.56, 95% CI: 0.05—6.58, P = 0.648).

Association between average CAL/ PPD and mortality

After adjusting for multiple variables, average CAL was obvious associated with an increased risk of cancer-related mortality (HR: 1.15, 95% CI: 1.00—1.31, P = 0.049). No obvious associations were observed between average PPD and cancer-related mortality (CAL: HR, 1.02; CI, 0.75—1.41, P = 0.881; PPD: HR, 0.73; CI, 0.28—1.91, P = 0.526), as well as other kinds of mortality among participants with depression (Table 5). There was no significant increasing trend observed across quartiles of average CAL/ PPD and cancer-related mortality (CAL: P for trend = 0.682; PPD: P for trend = 0.726), as well as other kinds of mortality (Supplementary Table 8—9). The RCS results revealed there is there is a nonlinear association between CVD-related mortality and PDD (P = 0.011), suggests that when mean PDD is below 1.316 mm, there is an inverse association, where the risk of CVD-related mortality decreases as mean PDD increases. Conversely, when mean PDD exceeds 1.316, the risk of CVD-related mortality shows a positive association, increasing as PDD rises. No other significant nonlinear relationship nor a monotonically increasing dose–response association between average CAL/PPD and mortality (Supplementary Fig. 4). Stratified analysis using RCS by age (< 45 or ≥ 45 years) and gender yielded similar results (Supplementary Fig. 5).Table 5 HR (95% CIs) for all-cause and cause-specific mortality according to mean PPD and CAL as exposure.

	Periodontal index	
	Mean CAL	Mean PPD	
	HR (95%CI)	P	HR (95%CI)	P	
All cause*					
Model 1†	1.34 (1.24, 1.44)	 < 0.001	1.20 (0.79, 1.82)	0.392	
Model 2‡	1.15 (1.00, 1.31)	0.049	1.01 (0.61, 1.66)	0.973	
Model 3§	1.17 (1.00, 1.37)	0.050	0.99 (0.58, 1.68)	0.960	
Model 4¶	1.14 (0.96, 1.37)	0.141	0.97 (0.57, 1.66)	0.912	
CVD-related					
Model 1	1.27 (1.03, 1.56)	0.027	0.97 (0.39, 2.40)	0.950	
Model 2	1.02 (0.70, 1.48)	0.919	0.76 (0.29, 2.00)	0.578	
Model 3	1.08 (0.77, 1.51)	0.642	0.80 (0.29, 2.23)	0.670	
Model 4	1.02 (0.75, 1.41)	0.881	0.73 (0.28, 1.91)	0.526	
Cancer-related					
Model 1	1.39 (1.19, 1.61)	 < 0.001	1.07 (0.43, 2.69)	0.883	
Model 2	1.14 (0.91, 1.41)	0.253	0.80 (0.31, 2.06)	0.642	
Model 3	1.14 (0.91, 1.42)	0.258	0.75 (0.27, 2.07)	0.575	
Model 4	1.15 (1.00, 1.31)	0.049	0.76 (0.30, 1.98)	0.578	
*All-cause mortality used Cox proportional hazards model, and cause-specific mortality used competing risk model.

†Model 1 was univariate analysis.

‡Model 2 included age (30–44, 45–64 or ≥ 65 years old), gender, race/ethnicity (non-Hispanic white, non-Hispanic black, Hispanic or other races), SES (Socioeconomic Status, low, middle, high), marital status (married/ living with partner, never married, widowed/ divorced/ separated).

§Model 3 additionally included smoking status (never smokers, former or current smokers), drinking status (nondrinker, heavier drinker, or light/ moderate drinker), physical activity status (inactive, insufficient, recommended) and BMI (body measure index, normal (≤ 24.9 [kg/m2]), overweight (25.0–29.9 [kg/m2]), and obesity (≥ 30.0 [kg/m2]) based on Model 2.

¶Model 4 was further adjusted for HTN status (hypertension, yes or no) , HPL (hyperlipidemia, yes or no), and diabetes status (yes or no) based on Model 3.

Sensitivity analyses

The results remained unaffected upon excluding participants with less follow-up (< 2 years, Supplementary Table 10) or those with cancer/ CVD (Supplementary Table 11). Similarly, there was no impact on the results when multiple interpolations were not conducted (Supplementary Table 12—13) or when participants with missing covariate values were excluded (Supplementary Table 14—15). The sensitivity analysis focused solely on MDD participants (Supplementary Table 16), yielding consistent results. The results across the two time periods also were consistent with the overall findings (Supplementary Table 17). After excluded deaths due to accidents and other causes not directly related to periodontitis, still not associated with all-cause mortality (Supplementary Table 18).

Discussions

This Prospective cohort study identified a significant link between moderate-to-severe periodontitis and cancer-cause mortality in a cohort of 1,189 adults with depression over a median follow-up period of 9.25 years. Notably, this is the first study to reveal such an association among US adults with depression. Moderate-to-severe periodontitis increased the risk of cancer-related mortality compared to those with no/mild periodontitis among individuals with depression. Additionally, this study is the pioneer in establishing the correlation between the severity of periodontitis and cancer-related mortality in adults with depression, as indicated by weighted multivariable modeling. Although the 10 year absolute risk difference showed a slight increase (0.98%), it is noteworthy for individuals with depression and healthcare providers, given the global disease burden associated with depression.

For the results of stratified analysis, unveiled a relatively consistent correlation between moderate-to-severe periodontitis and all kinds of mortality. Particularly noteworthy is the finding that, among older participants, moderate-to-severe periodontitis reduced the risk of cancer-related mortality. Previous studies have reported differences on mortality among participants with depression across various age groups. However, given the small sample size, it remains unclear whether periodontitis has varying impacts on younger and older participants with depression. A series of sensitivity analyses were conducted to validate the robustness of the findings. Exclusion of participants with short follow-up periods ensured stable results, while excluding those with cancer and CVD diagnoses aimed to safeguard the reliability of the findings. Sensitivity analyses for missing covariates were also performed to mitigate potential effects of multiple imputations on the results. Addressing exposure and outcome heterogeneity is crucial in observational studies. In this study, uniform diagnostic criteria for periodontitis across three time periods were implemented to enhance result reliability. Cohort period was included as a covariate for depression diagnosis due to differences in the three time periods. Furthermore, MDD was separately analyzed based on DSM-IV diagnosis as an outcome indicator, confirming the conclusions’ reliability. However, due to limited participant numbers, further analysis of the potential impact of cohort period through interaction analysis was challenging.

Previous studies have explored the link between periodontitis and mortality in adults with depression to a limited extent. However, there’s extensive literature on the association between periodontitis and depression32–34. In one controlled clinical study, 40 participants with periodontitis were compared with 41 age- and gender-matched controls, revealing an association between periodontitis severity and depression, which adversely affected quality of life 33. Similarly, a positive correlation between depression and moderate/severe periodontitis was observed in a study involving 539 adults from the 1982 Pelotas Birth Cohort 32. Furthermore, a meta-analysis of 40 studies indicated a positive association between periodontal disease and depression (OR = 1.70, 95% CI = 1.01–2.83)34. However, there's a scarcity of research exploring the long-term prognosis and survival of periodontitis in participants with depression. Although the impact of periodontitis on cancer-related mortality in participants with depression remains unclear, systemic inflammation may play a pivotal role.

Periodontitis is not associated with all-cause mortality, but it is correlated with cancer mortality. We believe this can be explained from several possible perspectives. Periodontitis may lead to immune system dysregulation, weakening the body’s ability to fight cancer, thereby increasing the risk of cancer-related mortality in individuals21,35. Inflammation is a significant factor in cancer development, and periodontitis, being a chronic inflammatory condition, may promote cancer development through the release of inflammatory mediators, thereby increasing cancer-related mortality36,37. The association between periodontitis and cancer mortality in individuals with depression may be influenced by the heightened systemic inflammation and immune dysregulation commonly observed in depression38,39. Depression is known to exacerbate inflammatory responses, which could amplify the effects of periodontitis on cancer risk40. Moreover, individuals with depression often exhibit lifestyle factors such as poor oral hygiene, smoking, and an unhealthy diet, which are shared risk factors for both periodontitis and cancer32. These factors may have a more pronounced impact on individuals with depression due to their already compromised health status.

Periodontitis may influence mortality in individuals with depression through mechanisms involving systemic inflammation, such as WBC and CRP41,42. Although previous studies have shown a positive correlation between depression and systemic inflammatory markers32,41,42, our findings suggest that WBC and CRP do not significantly mediate the association between periodontitis and cancer-related mortality in individuals with depression. This may be due to the lack of specificity of WBC/ CRP in reflecting relevant systemic inflammatory processes32. Future research should explore other inflammatory markers or pathways, such as cortisol32, which may better capture the relationship between periodontitis and long-term health outcomes in this population.

Periodontitis and depression may share some risk factors, such as unhealthy lifestyles or genetic factors, which could increase the risk of patients developing cancer simultaneously. Treatment for periodontitis may affect the immune system or other bodily systems of patients with depression, making them more susceptible to developing cancer, or the treatment itself may have some side effects that increase the risk of cancer occurrence. Overall, these explanations may not be independent but rather the result of interactions among multiple factors. Current studies still have no sufficient information, further investigation involving larger, multicenter populations with extended follow-up periods may elucidate potential underlying associations.

However, our study has some limitations worth noting. Firstly, the small sample size, particularly the limited number of observed cause-specific death outcomes, reduced the confidence of our conclusions and constrained further correlation analyses. Secondly, data on periodontitis and depression were collected concurrently at baseline, possibly failing to accurately reflect causal effects. Thirdly, unlike previous findings, regression, and RCS analyses of average PPD as exposures did not yield similar conclusions to those of periodontitis. It remains uncertain whether this disparity arises from inadequate participant numbers leading to ambiguous correlations or genuine variations in the impact of average CAL/ PDD on mortality associated with periodontitis in participants with depression. Fourthly, there’s inconsistency in depression definition; MDE by DSM-III was used from 1988 to 1994, whereas MDD by DSM-IV was used from 1999 to 2004 and 2009 to 2014, affecting result reliability. Fifthly, only two sites per tooth was used to define the periodontal status and the different periodontal probe in different period, potentially leading to measurement bias and underestimation of the prevalence, and the severity of moderate-to-severe periodontitis. Finally, due to the survival information being the only follow-up data available in this cohort, we were unable to investigate the impact of changes in periodontal status on outcomes.

In conclusion, this study revealed an obvious association between moderate-to-severe periodontitis and increased cancer mortality risk in a representative sample of U.S. adults with depression, with mortality risk escalating alongside periodontitis severity. By uncovering this association, our study emphasizes the potential benefits of preventive dental care and periodontal treatment in mitigating cancer-related mortality risk in individuals with depression.

Materials and methods

Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines for cohort studies was adhered in this cohort study. Details of materials and methods are presented in Supplementary file 1.

Study population

The National Health and Nutrition Examination Survey (NHANES) is designed to monitor the health and nutritional status of the noninstitutionalized US population43. This survey employs a stratified, multistage probability design to recruit a representative sample of the US population. For this study, data was obtained from three periods (1988–1994, 1999–2004, and 2009–2014) as periodontal measurements and mental health data were only collected during these periods concurrently. Participants aged over 30 years with diagnosed depression who provided periodontal measurement data were included in this study23. Exclusions comprised pregnant and lactating participants (n = 16), as well as those unable to provide follow-up information (n = 4). A total of 1,189 participants met the inclusion criteria for this study. The data extraction process is illustrated in Supplementary Fig. 1 (All supplementary tables and figures were provided in Supplementary file 2).

Assessments mental health

Major depressive episode (MDE) and Major depressive disorder (MDD) were regarded as the exposures in this study32,44. Given that distinct mental health questionnaires were administered during the three periods, diagnoses were determined based on the questionnaire results from each respective period. And ensured that the assessment adhered to the diagnostic criteria outlined in the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM-III or DSM-IV)45–47:1988–1994: lifetime MDE (diagnostic variable: MQPDEP, DSM-III)

1999–2004: MDD (diagnostic variable: CIQMDEP, DSM-IV)

2009–2014: MDD assessment by the Patient Health Questionnaire (PHQ-9 score > 9, diagnostic variable: DPQ 010–0090, DSM-IV).

Assessment of oral examination

Periodontitis was defined in accordance with the criteria of partial mouth examination. Which provided by the Centers for Disease Control and Prevention, in partnership with the American Academy of Periodontology (CDC-AAP)48. To ensure consistency in diagnostic criteria, participants underwent random selection for checking clinical attachment loss (CAL) and periodontal probing depth (PPD) in one maxillary quadrant and one mandibular quadrant. The measurement sites were specifically designated as the mesial buccal and mid buccal sites. Referring to previous studies, participants were categorized into two groups: those with moderate-to-severe periodontitis as the exposed and unexposed part was those with no/mild periodontitis47,49–51. Moderate-to-severe periodontitis was defined as having at least one interproximal site with a CAL of ≥ 4 mm, or at least one interproximal site with a PPD of ≥ 5 mm, on the same/ different sites. The average CAL and PPD of each participant were calculated for comparison of periodontal status47,49.

Ascertainment of participants mortality

Mortality information was acquired from the National Center for Health Statistics. Baseline was defined as the time of participants' periodontal examinations52,53. Person-years were calculated starting from the day of the oral examination and ending on the day of death, loss to follow-up, or December 31, 2019, whichever came first52,53. The ICD-10 was utilized to ascertain the causes of death, with appropriate ICD-10 codes selected for calculating mortality, encompassing cancer and cardiovascular disease (CVD)52,53.

Assessment of covariates

Directed acyclic graph (DAG) was employed to select the covariates (Supplementary Fig. 2)54,55, and nine covariates were included: age, gender, race, socioeconomic status (SES), marital status, smoking, alcohol intake (drinking status), physical activity, and nutritional status (body mass index, BMI). Additionally, further adjustments were made for comorbidities (hypertension, hyperlipidemia, diabetes) and three cohort periods (1988 – 1994, 1999 – 2004, and 2009 – 2014). Latent class analysis was employed to integrate the income, education level, occupation, and insurance into a categorical variable with three levels representing SES. (Supplementary Table 1, Supplementary Fig. 3) ref52,54,56,57.

Statistical analysis

Following NHANES analytical guidelines, statistical analysis was conducted considering complex sampling designs, which included weights, clustering, and stratification52,53,57. To address disparities between different periodontal statuses (no/mild or moderate-to-severe periodontitis) in population, student’s t-tests were utilized for continuous covariates and χ2 tests for categorical covariates52,53,57. Kaplan Meier (KM) curve was employed to detected potential mortality differences between two periodontal status groups. Additionally, cumulative incidence function (CIF) was utilized to depict variation in mortality over time among the two periodontal status groups58. Total person-years were calculated without weighting, and the median follow-up was determined using weighted reverse KM survival curves. The association between moderate-to-severe periodontitis and all-cause mortality in depressed participants was assessed using Cox proportional risk models59. Competing risk models were utilized to evaluate the association between periodontitis and cause-specific mortality. The Weibull accelerated failure time (AFT) models was employed to assess the impact of periodontitis on the survival time of participants with depression 60. Proportional risk has been tested by Schoenfeld residuals. 4 models were established in this study: Model 0, univariate regression analysis; Model 1, including age, SES, race, marital status, and gender; Model 2, incorporating alcohol intake, physical activity, smoking, and nutritional status (BMI); and Model 3, adding hypertension, hyperlipidemia, diabetes, and cohort periods. Details regarding the missing rate and multiple imputation methods of covariates are provided in Supplementary Table 2 ref23,52. If significant differences in mortality were observed in the association regression analysis, AFT and Cox proportional risk models were used to establish the mediation models, the “mediation” package was employed for conducting these mediation analyses. Weighted cumulative incidence data were utilized to calculate the adjusted absolute risk differences for 5- and 10 year periods23,61. Stratified analyses were conducted, with participants grouped by age (regroup as young, < 45 years, or old, ≥ 45 years) and gender. Periodontal status was categorized by periodontitis severity to assess potential association between severity of periodontitis and all kinds of mortality in participants with depression23.

For comparison, further analysis was conducted on the results of average CAL/ PPD. Initially, the association between average CAL/ PPD and all kinds of mortality rates in depressed participants was explored. Additionally, average CAL and PPD were categorized into quartiles (quartile 1—4) based on the complex sample, with first quartile of four as the reference, to investigate the relationship between quartiles of average CAL/ PPD and all kinds of mortality, trend tests were performed49. Restricted cubic spline (RCS) was employed to detected potential dose–response relationships between average CAL/ PPD and all kinds of mortality. Nonlinear tests were conducted using likelihood ratio tests. Stratified analyses involved RCS grouping by age and gender.

Sensitivity analyses included the following: (1) To minimize potential bias, participants with less than follow-up (< 2 years) were excluded (n = 27); (2) To avoid the influence of existing serious diseases, excluded participants with CVD/ cancer (n = 2008); (3) Add an analysis was conducted without multiple imputation; (4) Participants with missing information for any covariates were excluded from statistical analysis (n = 185); (5) Participants from NHANES III (MDE) were excluded (n = 277), and only the association between moderate-to-severe periodontitis and all kinds of mortality in participants with MDD was analyzed. (6) Univariable Cox regression analyses was conducted in NHANES III and NHANES 2009–2014; (7) Excluded deaths due to accidents and other causes that may not directly related to periodontitis (n = 52). P < 0.05 was considered as statistical really significance and statistical analysis used R software (version 4.3.1, Austria).

Supplementary Information

Supplementary Information 1.

Supplementary Information 2.

Supplementary Information

The online version contains supplementary material available at 10.1038/s41598-024-72297-z.

Acknowledgements

The authors appreciate Prof. Hao Xu's guidance on the direction of this study related to periodontitis. We are grateful to the participants and to the people involved in the National Health and Nutrition Examination Survey study.

Author contributions

YH. Z.: Data curation, formal analysis, investigation, methodology, software, visualization, and writing; WQ. L.: Data curation, formal analysis, investigation, methodology, software, visualization, and writing, Supervision, conceptualization, review & editing; L. L.: Resources, project administration, and review & editing; SF. L.: Review, supervision & validation; XZ. C.: Review, supervision & validation; HB. L: Review, supervision & validation.

Funding

Liaoning Provincial Applied Basic Research Program Project [2023JH2/101300042]; National Natural Science Foundation of China [grant number 81970942].

Data availability

The data and code that support the findings of this study are available from https://github.com/leescu/PD-MDD_Cohort.

Competing interests

The authors declare no competing interests.

Ethical approval

The study was conducted in accordance with the Declaration of Helsinki and approved by the National Center for Health Statistics (NCHS) Research Ethics Review Board (ERB) Approval. (https://www.cdc.gov/nchs/nhanes/irba98.htm).

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References

1. Marx W Major depressive disorder Nat. Rev. Dis. Primers 2023 10.1038/s41572-023-00454-1 37620370
Marx, W. et al. Major depressive disorder. Nat. Rev. Dis. Primers10.1038/s41572-023-00454-1 (2023).37620370
2. Neuteboom D Accelerated intermittent theta burst stimulation in major depressive disorder: A systematic review Psychiatr. Res. 2023 327 115429 10.1016/j.psychres.2023.115429
Neuteboom, D. et al. Accelerated intermittent theta burst stimulation in major depressive disorder: A systematic review. Psychiatr. Res. 327, 115429. 10.1016/j.psychres.2023.115429 (2023).
3. Cui LL Major depressive disorder: Hypothesis, mechanism, prevention and treatment Signal Transduct. Target. Therapy 2024 10.1038/s41392-024-01738-y
Cui, L. L. et al. Major depressive disorder: Hypothesis, mechanism, prevention and treatment. Signal Transduct. Target. Therapy10.1038/s41392-024-01738-y (2024).
4. Malhi GS Mann JJ Depression Lancet 2018 392 2299 2312 10.1016/s0140-6736(18)31948-2 30396512
Malhi, G. S. & Mann, J. J. Depression. Lancet 392, 2299–2312. 10.1016/s0140-6736(18)31948-2 (2018).30396512
5. Surtees PG Depression and ischemic heart disease mortality: Evidence from the EPIC-Norfolk United Kingdom prospective cohort study Am. J. Psychiatr. 2008 165 515 523 10.1176/appi.ajp.2007.07061018 18245176
Surtees, P. G. et al. Depression and ischemic heart disease mortality: Evidence from the EPIC-Norfolk United Kingdom prospective cohort study. Am. J. Psychiatr. 165, 515–523. 10.1176/appi.ajp.2007.07061018 (2008).18245176
6. Harshfield EL Association between depressive symptoms and incident cardiovascular diseases JAMA-J. Am. Med. Assoc. 2020 324 2396 2405 10.1001/jama.2020.23068
Harshfield, E. L. et al. Association between depressive symptoms and incident cardiovascular diseases. JAMA-J. Am. Med. Assoc. 324, 2396–2405. 10.1001/jama.2020.23068 (2020).
7. Berk M Comorbidity between major depressive disorder and physical diseases: A comprehensive review of epidemiology, mechanisms and management World Psychiatr. 2023 22 366 387 10.1002/wps.21110
Berk, M. et al. Comorbidity between major depressive disorder and physical diseases: A comprehensive review of epidemiology, mechanisms and management. World Psychiatr. 22, 366–387. 10.1002/wps.21110 (2023).
8. Meng RW Association of depression with all-cause and cardiovascular disease mortality among adults in China Jama Network Open 2020 10.1001/jamanetworkopen.2019.21043 33141158
Meng, R. W. et al. Association of depression with all-cause and cardiovascular disease mortality among adults in China. Jama Network Open10.1001/jamanetworkopen.2019.21043 (2020).33141158
9. Gilman SE Depression and mortality in a longitudinal study: 1952–2011 Can. Med. Assoc. J. 2017 189 E1304 E1310 10.1503/cmaj.170125 29061855
Gilman, S. E. et al. Depression and mortality in a longitudinal study: 1952–2011. Can. Med. Assoc. J. 189, E1304–E1310. 10.1503/cmaj.170125 (2017).29061855
10. Correll CU Prevalence, incidence and mortality from cardiovascular disease in patients with pooled and specific severe mental illness: A large-scale meta-analysis of 3,211,768 patients and 113,383,368 controls World Psychiatr. 2017 16 163 180 10.1002/wps.20420
Correll, C. U. et al. Prevalence, incidence and mortality from cardiovascular disease in patients with pooled and specific severe mental illness: A large-scale meta-analysis of 3,211,768 patients and 113,383,368 controls. World Psychiatr. 16, 163–180. 10.1002/wps.20420 (2017).
11. Hjorthoj C Association between alcohol and substance use disorders and all-cause and cause-specific mortality in schizophrenia, bipolar disorder, and unipolar depression: A nationwide, prospective, register-based study Lancet Psychiatr. 2015 2 801 808 10.1016/s2215-0366(15)00207-2
Hjorthoj, C. et al. Association between alcohol and substance use disorders and all-cause and cause-specific mortality in schizophrenia, bipolar disorder, and unipolar depression: A nationwide, prospective, register-based study. Lancet Psychiatr. 2, 801–808. 10.1016/s2215-0366(15)00207-2 (2015).
12. Lundberg J Determinants and outcomes of suicidal behavior among patients with major depressive disorder JAMA Psychiatr. 2023 80 1218 1225 10.1001/jamapsychiatry.2023.2833
Lundberg, J. et al. Determinants and outcomes of suicidal behavior among patients with major depressive disorder. JAMA Psychiatr. 80, 1218–1225. 10.1001/jamapsychiatry.2023.2833 (2023).
13. Wang W Association of dietary overall antioxidant intake with all-cause and cause-specific mortality among adults with depression: Evidence from NHANES 2005–2018 Food Funct. 2024 15 4603 4613 10.1039/d4fo00236a 38590241
Wang, W. et al. Association of dietary overall antioxidant intake with all-cause and cause-specific mortality among adults with depression: Evidence from NHANES 2005–2018. Food Funct. 15, 4603–4613. 10.1039/d4fo00236a (2024).38590241
14. Hajishengallis G Chavakis T Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities Nat. Rev. Immunol. 2021 21 426 440 10.1038/s41577-020-00488-6 33510490
Hajishengallis, G. & Chavakis, T. Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities. Nat. Rev. Immunol. 21, 426–440. 10.1038/s41577-020-00488-6 (2021).33510490
15. Dempsey LA Defective fibrolysis in periodontitis Nat. Immunol. 2022 23 150 150 10.1038/s41590-022-01133-1 35105988
Dempsey, L. A. Defective fibrolysis in periodontitis. Nat. Immunol. 23, 150–150. 10.1038/s41590-022-01133-1 (2022).35105988
16. Hajishengallis G Interconnection of periodontal disease and comorbidities: Evidence, mechanisms, and implications Periodontology 2022 2000 89 9 18 10.1111/prd.12430
Hajishengallis, G. Interconnection of periodontal disease and comorbidities: Evidence, mechanisms, and implications. Periodontology 2000(89), 9–18. 10.1111/prd.12430 (2022).
17. Li WQ Is periodontal disease a risk indicator for colorectal cancer? A systematic review and meta-analysis J. Clin. Periodontol. 2021 48 336 347 10.1111/jcpe.13402 33179280
Li, W. Q. et al. Is periodontal disease a risk indicator for colorectal cancer? A systematic review and meta-analysis. J. Clin. Periodontol. 48, 336–347. 10.1111/jcpe.13402 (2021).33179280
18. Wu YZ The interaction between the nervous system and the stomatognathic system: From development to diseases Int. J. Oral Sci. 2023 10.1038/s41368-023-00241-4 37696827
Wu, Y. Z. et al. The interaction between the nervous system and the stomatognathic system: From development to diseases. Int. J. Oral Sci.10.1038/s41368-023-00241-4 (2023).37696827
19. Solis ACD Evaluation of periodontitis in hospital outpatients with major depressive disorder. A focus on gingival and circulating cytokines Brain Behav. Immun. 2016 53 49 53 10.1016/j.bbi.2015.11.014 26616397
Solis, A. C. D. et al. Evaluation of periodontitis in hospital outpatients with major depressive disorder. A focus on gingival and circulating cytokines. Brain Behav. Immun. 53, 49–53. 10.1016/j.bbi.2015.11.014 (2016).26616397
20. Sung CE Periodontitis, <i>Helicobacter pylori</i> infection, and gastrointestinal tract cancer mortality J. Clin. Periodontol. 2022 49 210 220 10.1111/jcpe.13590 34961943
Sung, C. E. et al. Periodontitis, <i>Helicobacter pylori</i> infection, and gastrointestinal tract cancer mortality. J. Clin. Periodontol. 49, 210–220. 10.1111/jcpe.13590 (2022).34961943
21. Pink C Periodontitis and systemic inflammation as independent and interacting risk factors for mortality: Evidence from a prospective cohort study Bmc Med. 2023 10.1186/s12916-023-03139-4 37953258
Pink, C. et al. Periodontitis and systemic inflammation as independent and interacting risk factors for mortality: Evidence from a prospective cohort study. Bmc Med.10.1186/s12916-023-03139-4 (2023).37953258
22. Liu Y Does periodontitis affect the association of biological aging with mortality? J. Dental Res. 2023 102 909 918 10.1177/00220345231179117
Liu, Y. et al. Does periodontitis affect the association of biological aging with mortality?. J. Dental Res. 102, 909–918. 10.1177/00220345231179117 (2023).
23. Li WQ Periodontitis and the risk of all-cause and cause-specific mortality among US adults with diabetes: A population-based cohort study J. Clin. Periodontol. 2024 51 288 298 10.1111/jcpe.13901 37967814
Li, W. Q. et al. Periodontitis and the risk of all-cause and cause-specific mortality among US adults with diabetes: A population-based cohort study. J. Clin. Periodontol. 51, 288–298. 10.1111/jcpe.13901 (2024).37967814
24. Dominy SS Porphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors Sci. Adv. 2019 10.1126/sciadv.aau3333 30746447
Dominy, S. S. et al. Porphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors. Sci. Adv.10.1126/sciadv.aau3333 (2019).30746447
25. Wang RPH Ho YS Leung WK Goto T Chang RCC Systemic inflammation linking chronic periodontitis to cognitive decline Brain Behav. Immunity 2019 81 63 73 10.1016/j.bbi.2019.07.002
Wang, R. P. H., Ho, Y. S., Leung, W. K., Goto, T. & Chang, R. C. C. Systemic inflammation linking chronic periodontitis to cognitive decline. Brain Behav. Immunity 81, 63–73. 10.1016/j.bbi.2019.07.002 (2019).
26. Bai XB Oral pathogens exacerbate Parkinson’s disease by promoting Th1 cell infiltration in mice Microbiome 2023 10.1186/s40168-023-01685-w 37978405
Bai, X. B. et al. Oral pathogens exacerbate Parkinson’s disease by promoting Th1 cell infiltration in mice. Microbiome10.1186/s40168-023-01685-w (2023).37978405
27. Li X Kiprowska M Kansara T Kansara P Li P Neuroinflammation: A distal consequence of periodontitis J. Dental Res. 2022 101 1441 1449 10.1177/00220345221102084
Li, X., Kiprowska, M., Kansara, T., Kansara, P. & Li, P. Neuroinflammation: A distal consequence of periodontitis. J. Dental Res. 101, 1441–1449. 10.1177/00220345221102084 (2022).
28. Warren KR Role of chronic stress and depression in periodontal diseases Periodontology 2014 2000 64 127 138 10.1111/prd.12036
Warren, K. R. et al. Role of chronic stress and depression in periodontal diseases. Periodontology 2000(64), 127–138. 10.1111/prd.12036 (2014).
29. Martín-Hernández D Neuroinflammation related to the blood-brain barrier and sphingosine-1-phosphate in a pre-clinical model of periodontal diseases and depression in rats J. Clin. Periodontol. 2023 50 642 656 10.1111/jcpe.13780 36644813
Martín-Hernández, D. et al. Neuroinflammation related to the blood-brain barrier and sphingosine-1-phosphate in a pre-clinical model of periodontal diseases and depression in rats. J. Clin. Periodontol. 50, 642–656. 10.1111/jcpe.13780 (2023).36644813
30. Sari A Kokacya MH Ide M Periodontal conditions and association of periodontitis with oral-health-related quality of life in patients experiencing different episodes of bipolar disorder compared with healthy controls J. Clin. Periodontol. 2024 51 274 287 10.1111/jcpe.13897 37963629
Sari, A., Kokacya, M. H. & Ide, M. Periodontal conditions and association of periodontitis with oral-health-related quality of life in patients experiencing different episodes of bipolar disorder compared with healthy controls. J. Clin. Periodontol. 51, 274–287. 10.1111/jcpe.13897 (2024).37963629
31. Solis ACO Marques AH Pannuti CM Lotufo RFM Lotufo-Neto F Evaluation of periodontitis in hospital outpatients with major depressive disorder J. Periodontal Res. 2014 49 77 84 10.1111/jre.12082 23586804
Solis, A. C. O., Marques, A. H., Pannuti, C. M., Lotufo, R. F. M. & Lotufo-Neto, F. Evaluation of periodontitis in hospital outpatients with major depressive disorder. J. Periodontal Res. 49, 77–84. 10.1111/jre.12082 (2014).23586804
32. Nascimento GG Is there an association between depression and periodontitis? A birth cohort study J. Clin. Periodontol. 2019 46 31 39 10.1111/jcpe.13039 30499588
Nascimento, G. G. et al. Is there an association between depression and periodontitis? A birth cohort study. J. Clin. Periodontol. 46, 31–39. 10.1111/jcpe.13039 (2019).30499588
33. Saletu A Controlled clinical and psychometric studies on the relation between periodontitis and depressive mood J. Clin. Periodontol. 2005 32 1219 1225 10.1111/j.1600-051X.2005.00855.x 16268998
Saletu, A. et al. Controlled clinical and psychometric studies on the relation between periodontitis and depressive mood. J. Clin. Periodontol. 32, 1219–1225. 10.1111/j.1600-051X.2005.00855.x (2005).16268998
34. Zheng DX Periodontal disease and emotional disorders: A meta-analysis J. Clin. Periodontol. 2021 48 180 204 10.1111/jcpe.13395 33103263
Zheng, D. X. et al. Periodontal disease and emotional disorders: A meta-analysis. J. Clin. Periodontol. 48, 180–204. 10.1111/jcpe.13395 (2021).33103263
35. Tonetti MS Treatment of periodontitis and endothelial function N. Engl. J. Med. 2007 356 911 920 10.1056/NEJMoa063186 17329698
Tonetti, M. S. et al. Treatment of periodontitis and endothelial function. N. Engl. J. Med. 356, 911–920. 10.1056/NEJMoa063186 (2007).17329698
36. Coussens LM Werb Z Inflammation and cancer Nature 2002 420 860 867 10.1038/nature01322 12490959
Coussens, L. M. & Werb, Z. Inflammation and cancer. Nature 420, 860–867. 10.1038/nature01322 (2002).12490959
37. Chen X Kang R Kroemer G Tang DL Broadening horizons: the role of ferroptosis in cancer Nat. Rev. Clin. Oncol. 2021 18 280 296 10.1038/s41571-020-00462-0 33514910
Chen, X., Kang, R., Kroemer, G. & Tang, D. L. Broadening horizons: the role of ferroptosis in cancer. Nat. Rev. Clin. Oncol. 18, 280–296. 10.1038/s41571-020-00462-0 (2021).33514910
38. Kronsten VT Tranah TH Pariante C Shawcross DL Gut-derived systemic inflammation as a driver of depression in chronic liver disease J. Hepatol. 2022 76 665 680 10.1016/j.jhep.2021.11.008 34800610
Kronsten, V. T., Tranah, T. H., Pariante, C. & Shawcross, D. L. Gut-derived systemic inflammation as a driver of depression in chronic liver disease. J. Hepatol. 76, 665–680. 10.1016/j.jhep.2021.11.008 (2022).34800610
39. Sominsky L Pre-pregnancy obesity is associated with greater systemic inflammation and increased risk of antenatal depression Brain Behav. Immun. 2023 113 189 202 10.1016/j.bbi.2023.07.005 37437818
Sominsky, L. et al. Pre-pregnancy obesity is associated with greater systemic inflammation and increased risk of antenatal depression. Brain Behav. Immun. 113, 189–202. 10.1016/j.bbi.2023.07.005 (2023).37437818
40. Normann SJ Cornelius J Concurrent depression of tumor macrophage infiltration and systemic inflammation by progressive cancer growth Cancer Res. 1978 38 3453 3459 99232
Normann, S. J. & Cornelius, J. Concurrent depression of tumor macrophage infiltration and systemic inflammation by progressive cancer growth. Cancer Res. 38, 3453–3459 (1978).99232
41. Muñoz Aguilera E Is systemic inflammation a missing link between periodontitis and hypertension? Results from two large population-based surveys J. Intern. Med. 2021 289 532 546 10.1111/joim.13180 32969093
Muñoz Aguilera, E. et al. Is systemic inflammation a missing link between periodontitis and hypertension? Results from two large population-based surveys. J. Intern. Med. 289, 532–546. 10.1111/joim.13180 (2021).32969093
42. Torrungruang K Vathesatogkit P Mahanonda R Thienpramuk L Periodontitis and hypertension are linked through systemic inflammation: A 5 year longitudinal study J. Clin. Periodontol. 2024 51 536 546 10.1111/jcpe.13942 38196116
Torrungruang, K., Vathesatogkit, P., Mahanonda, R. & Thienpramuk, L. Periodontitis and hypertension are linked through systemic inflammation: A 5 year longitudinal study. J. Clin. Periodontol. 51, 536–546. 10.1111/jcpe.13942 (2024).38196116
43. Qiu ZX Associations of serum carotenoids with risk of cardiovascular mortality among individuals with type 2 diabetes: Results from NHANES Diabetes Care 2022 45 1453 1461 10.2337/dc21-2371 35503926
Qiu, Z. X. et al. Associations of serum carotenoids with risk of cardiovascular mortality among individuals with type 2 diabetes: Results from NHANES. Diabetes Care 45, 1453–1461. 10.2337/dc21-2371 (2022).35503926
44. Frank P Association between depression and physical conditions requiring hospitalization JAMA Psychiatr. 2023 80 690 699 10.1001/jamapsychiatry.2023.0777
Frank, P. et al. Association between depression and physical conditions requiring hospitalization. JAMA Psychiatr. 80, 690–699. 10.1001/jamapsychiatry.2023.0777 (2023).
45. Spitzer RL Validation and utility of a self-report version of PRIME-MD—The PHQ primary care study Jama-J. Am. Med.Assoc. 1999 282 1737 1744 10.1001/jama.282.18.1737
Spitzer, R. L. et al. Validation and utility of a self-report version of PRIME-MD—The PHQ primary care study. Jama-J. Am. Med.Assoc. 282, 1737–1744. 10.1001/jama.282.18.1737 (1999).
46. Kessler RC Lifetime and 12 month prevalence of Dsm-Iii-R psychiatric-disorders in the united-states—results from the national-comorbidity-survey Arch. Gen. Psychiatr. 1994 51 8 19 10.1001/archpsyc.1994.03950010008002 8279933
Kessler, R. C. et al. Lifetime and 12 month prevalence of Dsm-Iii-R psychiatric-disorders in the united-states—results from the national-comorbidity-survey. Arch. Gen. Psychiatr. 51, 8–19 (1994).8279933
47. Sheehan DV MINI—: Mini international neuropsychiatric interview—: English version 5.0.0—: DSM-IV J. Clin. Psychiatr. 1998 59 34 57 10.4088/JCP.09m05305whi
Sheehan, D. V. et al. MINI—: Mini international neuropsychiatric interview—: English version 5.0.0—: DSM-IV. J. Clin. Psychiatr. 59, 34–57. 10.4088/JCP.09m05305whi (1998).
48. Eke PI Borgnakke WS Genco RJ Recent epidemiologic trends in periodontitis in the USA Periodontology 2020 2000 82 257 267 10.1111/prd.12323
Eke, P. I., Borgnakke, W. S. & Genco, R. J. Recent epidemiologic trends in periodontitis in the USA. Periodontology 2000(82), 257–267. 10.1111/prd.12323 (2020).
49. Li WQ Associations of periodontitis with risk of all-cause and cause-specific mortality among us adults with chronic kidney disease J. Dent. 2023 10.1016/j.jdent.2023.104712 38072336
Li, W. Q. et al. Associations of periodontitis with risk of all-cause and cause-specific mortality among us adults with chronic kidney disease. J. Dent.10.1016/j.jdent.2023.104712 (2023).38072336
50. Tran DT Assessment of partial-mouth periodontal examination protocols for periodontitis surveillance J. Clin. Periodontol. 2014 41 846 852 10.1111/jcpe.12285 25041094
Tran, D. T. et al. Assessment of partial-mouth periodontal examination protocols for periodontitis surveillance. J. Clin. Periodontol. 41, 846–852. 10.1111/jcpe.12285 (2014).25041094
51. Page RC Eke PI Case definitions for use in population—Based surveillance of periodontitis J. Periodontol. 2007 78 1387 1399 10.1902/jop.2007.060264 17608611
Page, R. C. & Eke, P. I. Case definitions for use in population—Based surveillance of periodontitis. J. Periodontol. 78, 1387–1399. 10.1902/jop.2007.060264 (2007).17608611
52. Zhang YB Associations of healthy lifestyle and socioeconomic status with mortality and incident cardiovascular disease: Two prospective cohort studies Bmj-Br. Med. J. 2021 10.1136/bmj.n604
Zhang, Y. B. et al. Associations of healthy lifestyle and socioeconomic status with mortality and incident cardiovascular disease: Two prospective cohort studies. Bmj-Br. Med. J.10.1136/bmj.n604 (2021).
53. Hicks CW Wang D Matsushita K Windham BG Selvin E Peripheral neuropathy and all-cause and cardiovascular mortality in US adults a prospective cohort study Ann. Intern. Med. 2021 10.7326/m20-1340 33900796
Hicks, C. W., Wang, D., Matsushita, K., Windham, B. G. & Selvin, E. Peripheral neuropathy and all-cause and cardiovascular mortality in US adults a prospective cohort study. Ann. Intern. Med.10.7326/m20-1340 (2021).33900796
54. Wang L Trends in consumption of ultraprocessed foods among US youths aged 2–19 Years, 1999–2018 Jama-J. Am. Med. Assoc. 2021 326 519 530 10.1001/jama.2021.10238
Wang, L. et al. Trends in consumption of ultraprocessed foods among US youths aged 2–19 Years, 1999–2018. Jama-J. Am. Med. Assoc. 326, 519–530. 10.1001/jama.2021.10238 (2021).
55. Ramirez FD Association of Atopic Dermatitis With Sleep Quality in Children Jama Pediatr. 2019 10.1001/jamapediatrics.2019.0025 30830151
Ramirez, F. D. et al. Association of Atopic Dermatitis With Sleep Quality in Children. Jama Pediatr.10.1001/jamapediatrics.2019.0025 (2019).30830151
56. Banach M Association between phenotypic familial hypercholesterolaemia and telomere length in US adults: Results from a multi-ethnic survey Eur. Heart J. 2018 39 3635 3640 10.1093/eurheartj/ehy527 30165413
Banach, M. et al. Association between phenotypic familial hypercholesterolaemia and telomere length in US adults: Results from a multi-ethnic survey. Eur. Heart J. 39, 3635–3640. 10.1093/eurheartj/ehy527 (2018).30165413
57. Chen F Association among dietary supplement use, nutrient intake, and mortality among US adults a cohort study Ann. Intern. Med. 2019 10.7326/m18-2478 31683314
Chen, F. et al. Association among dietary supplement use, nutrient intake, and mortality among US adults a cohort study. Ann. Intern. Med.10.7326/m18-2478 (2019).31683314
58. Fine JP Gray RJ A proportional hazards model for the subdistribution of a competing risk J. Am. Stat. Assoc. 1999 94 496 509 10.2307/2670170
Fine, J. P. & Gray, R. J. A proportional hazards model for the subdistribution of a competing risk. J. Am. Stat. Assoc. 94, 496–509. 10.2307/2670170 (1999).
59. Wolbers M Competing risks analyses: objectives and approaches Eur. Heart J. 2014 35 2936 2941 10.1093/eurheartj/ehu131 24711436
Wolbers, M. et al. Competing risks analyses: objectives and approaches. Eur. Heart J. 35, 2936–2941. 10.1093/eurheartj/ehu131 (2014).24711436
60. Gregson J Nonproportional hazards for time-to-event outcomes in clinical trials <i>JACC</i> review topic of the week J. Am. College Cardiol. 2019 74 2102 2112 10.1016/j.jacc.2019.08.1034
Gregson, J. et al. Nonproportional hazards for time-to-event outcomes in clinical trials <i>JACC</i> review topic of the week. J. Am. College Cardiol. 74, 2102–2112. 10.1016/j.jacc.2019.08.1034 (2019).
61. Weinberg MS Association of BCG vaccine treatment with death and dementia in patients with non-muscle-invasive bladder cancer Jama Netw. Open 2023 10.1001/jamanetworkopen.2023.14336 37204792
Weinberg, M. S. et al. Association of BCG vaccine treatment with death and dementia in patients with non-muscle-invasive bladder cancer. Jama Netw. Open10.1001/jamanetworkopen.2023.14336 (2023).37204792
