Epigenome-wide association study using peripheral blood leukocytes identifies genomic regions associated with periodontal disease and edentulism in the Atherosclerosis Risk in Communities study.

AIM: To investigate individual susceptibility to periodontitis by conducting an epigenome-wide association study using peripheral blood. MATERIALS AND METHODS: We included 1077 African American and 457 European American participants of the Atherosclerosis Risk in Communities (ARIC) study who had completed a dental examination or reported being edentulous at Visit 4 and had available data on DNA methylation from Visit 2 or 3. DNA methylation levels were compared by periodontal disease severity and edentulism through discovery analyses and subsequent testing of individual CpGs. RESULTS: Our discovery analysis replicated findings from a previous study reporting a region in gene ZFP57 (6p22.1) that was significantly hypomethylated in severe periodontal disease compared with no/mild periodontal disease in European American participants. Higher methylation levels in a separate region in an unknown gene (located in Chr10: 743,992-744,958) was associated with significantly higher odds of edentulism compared with no/mild periodontal disease in African American participants. In subsequent CpG testing, four CpGs in a region previously associated with periodontitis located within HOXA4 were significantly hypermethylated in severe periodontal disease compared with no/mild periodontal disease in African American participants (odds ratio per 1 SD increase in methylation level: cg11015251: 1.28 (1.02, 1.61); cg14359292: 1.24 (1.01, 1.54); cg07317062: 1.30 (1.05, 1.61); cg08657492: 1.25 (1.01, 1.55)). CONCLUSIONS: Our study highlights epigenetic variations in ZPF57 and HOXA4 that are significantly and reproducibly associated with periodontitis. Future studies should evaluate gene regulatory mechanisms in the candidate regions of these loci.

The association of clinically determined periodontal disease and edentulism with total cancer mortality: The National Health and Nutrition Examination Survey III.

Increasing evidence supports a positive association between periodontal disease and total cancer risk. We evaluated the association of clinically assessed periodontal disease and a consequence, edentulism with total cancer mortality in participants without a prior cancer diagnosis in a U.S. nationally representative population. Included were 6,034 participants aged ≥40 years without a prior cancer diagnosis who participated in the National Health and Nutrition Examination Survey III. Periodontal health was measured by trained dentists. Cancer deaths (n = 702) were ascertained during a median of 21.3 years of follow-up. Cox proportional hazards regression was used to estimate the association of periodontal disease and edentulism with total cancer mortality using no periodontal disease/dentate as the reference and adjusting for potential demographic, lifestyle including smoking and social factor confounders. Fifteen percent had periodontitis and 17% were edentulous. Periodontitis was not statistically significantly associated with risk of total cancer death after multivariable adjustment. Edentulism was associated with an increased risk of cancer mortality (hazard ratio = 1.50, 95% confidence interval = 1.12-2.00) after multivariable adjustment, including in men and women and in each racial/ethnic group studied. The positive association was observed in overweight/obese participants but not participants with normal body mass index, more strongly in prediabetic/diabetic participants than in participants without diabetes and in ever cigarette smokers but not in never cigarette smokers. In this U.S. nationally representative population, those with edentulism, but not periodontal disease, had a higher risk of total cancer death, especially in those with shared risk factors for periodontal disease and cancer.

Using Patients' Social Network to Improve Compliance to Outpatient Screening Colonoscopy Appointments Among Blacks: A Randomized Clinical Trial.

OBJECTIVES: Patient navigation improves colorectal cancer screening among underserved populations, but limited resources preclude widespread adoption in minority-serving institutions. We evaluated whether a patient's self-selected social contact person can effectively facilitate outpatient screening colonoscopy. METHODS: From September 2014 to March 2017 in an urban tertiary center, 399 black participants scheduled for outpatient screening colonoscopy self-selected a social contact person to be a facilitator and provided the person's phone number. Of these, 201 participants (50.4%) were randomly assigned to the intervention arm for their social contact persons to be engaged by phone. The study was explained to the social contact person with details about colonoscopy screening and bowel preparation process. The social contacts were asked to assist the participants, provide support, and encourage compliance with the procedures. The social contact person was not contacted in the usual care arm, n = 198 (49.6%). We evaluated attendance to the scheduled outpatient colonoscopy and adequacy of bowel preparation. Analysis was performed by intention to treat. RESULTS: The social contact person was reached and agreed to be involved for 130 of the 201 participants (64.7%). No differences were found in the proportion of participants who underwent screening colonoscopy (77.3% vs 77.2%; relative risk = 1.01; 95% confidence interval: 0.91-1.12), but there was a modest increase in the proportion with adequate bowel preparation with social contact involvement (89.1% vs 80.9%; relative risk = 1.10; 95% confidence interval: 1.00-1.21). DISCUSSION: Engaging a patient's social network to serve in the role of a patient navigator did not improve compliance to outpatient screening colonoscopy but modestly improved the adequacy of bowel preparation.

The association between clinically determined periodontal disease and prostate-specific antigen concentration in men without prostate cancer: the 2009-2010 National Health and Nutrition Examination Survey.

PURPOSE: We evaluated the association between clinically assessed periodontal disease and serum prostate-specific antigen (PSA) concentration in men without a prostate cancer diagnosis in a US nationally representative sample of non-institutionalized men. METHODS: Included were 1263 men aged ≥ 40 years who participated in the National Health and Nutrition Examination Survey in 2009-2010. Measurements of periodontal health and tooth count were used to define periodontal disease severity (no, mild, moderate, severe) and edentulism. Linear and logistic regressions were used to estimate the association of periodontal disease severity and edentulism with PSA concentration and elevated PSA, respectively. RESULTS: Adjusting for age and other factors including race, body mass index, and education, the natural logarithm of PSA concentration did not change with increasing severity (mild - 0.20, 95% confidence interval [CI] - 0.34 to - 0.05; moderate - 0.12, 95% CI - 0.26 to 0.01; severe - 0.16, 95% CI - 0.43 to 0.12; edentulism - 0.16, 95% CI - 0.35 to 0.04; P-trend 0.13) compared with dentate men without periodontal disease. Although the multivariable-adjusted ORs of elevated PSA were not statistically significant, participants with more severe periodontal disease were less likely to have PSA > 2.0 and > 2.5 ng/mL, but more likely to have PSA > 4.0 ng/mL, compared to dentate men without periodontal disease. Similar non-significant associations with PSA were observed when comparing edentulous men to dentate men without periodontal disease. CONCLUSIONS: In this US nationally representative sample, men with periodontal disease did not have higher serum PSA and were not more likely to have clinically elevated PSA after taking into account age and other factors, contrary to the hypothesis. This study suggests that periodontal disease does not notably affect the specificity of PSA for prostate cancer screening.

Periodontal and Other Oral Bacteria and Risk of Lung Cancer in the Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: Evidence suggests that periodontal disease is associated with increased lung cancer risk, but whether periodontal pathogens are explanatory is unknown. We prospectively studied associations of prediagnostic circulating antibodies with oral bacteria and of periodontal bacteria in subgingival plaque with lung cancer. METHODS: We included 4,263 cancer-free participants in the Atherosclerosis Risk in Communities study with previously measured serum IgG antibodies to 18 oral bacteria. In 1,287 participants for whom subgingival plaque was collected, counts for 8 periodontal bacteria were previously measured. Incident lung cancers (N = 118) were ascertained through 2015 (median follow-up = 17.5 years). We used Cox regression to estimate multivariable-adjusted associations, including for sums of antibodies to orange (C. rectus, F. nucleatum, P. intermedia, P. micra, and P. nigrescens) and red (P. gingivalis, T. forsythensis, and T. denticola) complex bacteria. RESULTS: Orange complex bacteria antibodies were positively associated with lung cancer [per IQR hazard ratios (HR) = 1.15; 95% confidence intervals (CI), 1.02-1.29], which was stronger in men (HR = 1.27, 95% CI 1.08-1.49), and explained by P. intermedia and P. nigrescens (HR = 1.15; 95% CI, 1.04-1.26). Suggestive positive associations with lung cancer (N = 40) were observed for F. nucleatum, A. actinomycetemcomitans, and P. gingivalis counts. Significant positive associations were found for the count to antibody ratio for P. intermedia and P. gingivalis. CONCLUSIONS: We identified positive associations with lung cancer for oral bacteria, especially orange complex that are moderately pathogenic for periodontal disease. IMPACT: This prospective study supports the need for more research on periodontal bacteria in lung cancer etiology. If associations are supported, this may inform novel lung cancer prevention strategies.

Circulating IgG antibodies to periodontal bacteria and lung cancer risk in the CLUE cohorts.

BACKGROUND: Oral health is a key indicator of overall health, well-being, and quality of life. Several studies have provided new evidence about the role of oral diseases, specifically periodontitis, in generating risk for various forms of cancers, including lung, colorectal, and pancreatic cancers. METHODS: Incident lung cancer cases (n = 192) and matched controls (n = 192) were selected from participants of the CLUE I and CLUE II cohorts. Archived serum samples collected from participants in 1974 (in CLUE I) were analyzed using immunoblotting for immunoglobulin G (IgG) antibody levels to 13 bacteria of the periodontium. Associations between antibody levels and lung cancer were estimated using conditional logistic regression. RESULTS: Most of the periodontal bacterial antibodies measured were inversely associated with lung cancer risk; of these, 3 were statistically significant (Prevotellaintermedia, Actinomyces naeslundii, and Veillonella parvula). A statistically significant positive association was observed for one of the Porphyromonas gingivalis strains after adjusting for P. intermedia. The sum of the logarithm of antibodies against the 13 measured bacteria was inversely associated with risk of lung cancer when the analysis was restricted to a longer follow-up (31-44 years after blood collection, highest vs lowest quartile: odds ratio = 0.26, 95% confidence interval = 0.08 to 0.84). CONCLUSIONS: Findings from this study highlight the complexity of using serum IgG antibodies to periodontal bacteria to identify associations between oral pathogens and risk of lung cancer. The inverse associations observed for antibodies to periodontal bacteria suggest that these may represent markers of immunity that provide some advantage in reducing the development of lung cancer.

Two-Sample Mendelian Randomization Analysis of Associations Between Periodontal Disease and Risk of Cancer.

Background: Observational studies indicate that periodontal disease may increase the risk of colorectal, lung, and pancreatic cancers. Using a 2-sample Mendelian randomization (MR) analysis, we assessed whether a genetic predisposition index for periodontal disease was associated with colorectal, lung, or pancreatic cancer risks. Methods: Our primary instrument included single nucleotide polymorphisms with strong genome-wide association study evidence for associations with chronic, aggressive, and/or severe periodontal disease (rs729876, rs1537415, rs2738058, rs12461706, rs16870060, rs2521634, rs3826782, and rs7762544). We used summary-level genetic data for colorectal cancer (n = 58 131 cases; Genetics and Epidemiology of Colorectal Cancer Consortium, Colon Cancer Family Registry, and Colorectal Transdisciplinary Study), lung cancer (n = 18 082 cases; International Lung Cancer Consortium), and pancreatic cancer (n = 9254 cases; Pancreatic Cancer Consortia). Four MR approaches were employed for this analysis: random-effects inverse-variance weighted (primary analyses), Mendelian Randomization-Pleiotropy RESidual Sum and Outlier, simple median, and weighted median. We conducted secondary analyses to determine if associations varied by cancer subtype (colorectal cancer location, lung cancer histology), sex (colorectal and pancreatic cancers), or smoking history (lung and pancreatic cancer). All statistical tests were 2-sided. Results: The genetic predisposition index for chronic or aggressive periodontitis was statistically significantly associated with a 3% increased risk of colorectal cancer (per unit increase in genetic index of periodontal disease; P = .03), 3% increased risk of colon cancer (P = .02), 4% increased risk of proximal colon cancer (P = .01), and 3% increased risk of colorectal cancer among females (P = .04); however, it was not statistically significantly associated with the risk of lung cancer or pancreatic cancer, overall or within most subgroups. Conclusions: Genetic predisposition to periodontitis may be associated with colorectal cancer risk. Further research should determine whether increased periodontitis prevention and increased cancer surveillance of patients with periodontitis is warranted.

SES and correlated factors do not explain the association between periodontal disease, edentulism, and cancer risk.

PURPOSE: Severe periodontal disease and edentulism have been previously reported to be significantly associated with cancer risk and mortality, including in the Atherosclerosis Risk in Communities study (2018); however, complex sources of confounding by socioeconomic status (SES), and characteristics correlated with SES, could have been present in earlier analyses. METHODS: To capture life course SES and its correlates, we generated a propensity score and included it, along with other potential confounders such as smoking and obesity, into a Cox regression model to examine the association between periodontal disease and cancer risk. In addition, we stratified the model with the propensity score by low and high SES. All statistical tests were two-sided. RESULTS: Compared with our previous study, the associations for severe periodontitis and cancer incidence remained comparable after weighting by the propensity score (e.g., for total cancer: before weighting, hazard ratio = 1.24, 95% confidence interval = 1.07-1.42 vs. after weighting, hazard ratio = 1.23, 95% confidence interval = 1.05-1.44 when comparing severe periodontitis to no or mild periodontitis). Associations were comparable in low and high SES strata and statistically significant among participants with high SES. CONCLUSIONS: Complex sources of confounding by SES and its correlates are unlikely to fully account for the positive associations observed for periodontal disease and edentulism and cancer risk.

Periodontal Disease Assessed Using Clinical Dental Measurements and Cancer Risk in the ARIC Study.

Background: While evidence is increasingly consistent with a positive association between periodontitis and cancer risk, most studies have relied on self-reported periodontitis. In this study, we prospectively evaluated the association of periodontal disease severity with cancer risk in black and white older adults in a cohort study that included a dental examination. Methods: Included were 7466 participants in the Atherosclerosis Risk in Communities study cohort who at visit 4 (1996-1998) reported being edentulous or underwent the dental examination. Probing depth and gingival recession were measured at six sites on all teeth; these measurements were used to define periodontal disease severity. Incident cancers (n = 1648) and cancer deaths (n = 547) were ascertained during a median of 14.7 years of follow-up. All statistical tests were two-sided. Results: An increased risk of total cancer (hazard ratio [HR] = 1.24, 95% confidence interval [CI] = 1.07 to 1.44, Ptrend = .004) was observed for severe periodontitis (>30% of sites with attachment loss >3 mm) compared with no/mild periodontitis (<10% of sites with attachment loss >3 mm), adjusting for smoking and other factors. Strong associations were observed for lung cancer (HR = 2.33, 95% CI = 1.51 to 3.60, Ptrend < .001), and elevated risks were noted for colorectal cancer for severe periodontitis, which were significant among never smokers (HR = 2.12, 95% CI = 1.00 to 4.47). Associations were generally weaker, or not apparent among black participants, except for lung and colorectal cancers, where associations were similar by race. No associations were observed for breast, prostate, or hematopoietic and lymphatic cancer risk. Conclusions: This study provides additional evidence that cancer risk, especially for lung and colorectal cancer, is elevated in individuals with periodontitis. Additional research is needed to understand cancer site-specific and racial differences in findings.