Interaction between Infection of Porphyromonas gingivalis, A Keystone Microbe of Oral Microbiome, and Serum Levels of Lutein/Zeaxanthin Is Associated with Risk for Age-related Macular Degeneration.

Interaction between Infection of Porphyromonas gingivalis, A Keystone Microbe of Oral Microbiome, and Serum Levels of Lutein/Zeaxanthin Is Associated with Risk for Age-related Macular Degeneration. | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Interaction between Infection of Porphyromonas gingivalis, A Keystone Microbe of Oral Microbiome, and Serum Levels of Lutein/Zeaxanthin Is Associated with Risk for Age-related Macular Degeneration. Chung-Jung Chiu, Emily Chiu, Min-Lee Chang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6188207/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 11 Nov, 2025 Read the published version in Scientific Reports → Version 1 posted 12 You are reading this latest preprint version Abstract Porphyromonas gingivalis (P. gingivalis) functions as a catalyst bacterium in the development of periodontitis, and the serum antibody level against P. gingivalis is considered a surrogate marker for the activity level of periodontopathic microbiome. The chronic systemic inflammation induced by P. gingivalis elevates the risk of various systemic and neurodegenerative disorders, including atherosclerosis, diabetes, and Alzheimer’s disease. Although the connection between human microbiome and age-related macular degeneration (AMD) remains relatively unexplored, it is noteworthy that AMD shares risk factors and etiological mechanisms with diseases related to P. gingivalis . To investigate the potential association between periodontopathic microbiome and AMD occurrence, we conducted a candidate microbe approach case-control study. Our hypothesis was tested by examining the correlation between serum P. gingivalis immunoglobulin G (IgG) levels and AMD. Comparing the lowest IgG category (≤ 57 enzyme-linked immunosorbent assay units (EU)) with higher categories revealed escalating risks: the second higher category (58–65 EU) conferred almost a 30% increased risk (odds ratio (OR) = 1.28, 95% confidence interval (CI): 1.17 to 1.4), the third higher category (66–119 EU) conferred nearly a 60% increase (OR = 1.58, 95% CI: 1.46 to 1.72), and the highest category (> 119 EU) conveyed over a two-fold risk (OR = 2.04, 95% CI: 1.62 to 2.58) of early AMD. Aligning with the notion that the microbiome composition is significantly shaped by the host's diet, our analysis indicates that sustaining elevated serum levels of lutein/zeaxanthin (≥ 0.35 µmol/L or ≥ 20 µg/dL) might potentially mitigate the P. gingivalis -related AMD risk by as much as 35% (P for interaction < 0.0001). Although the precise mechanism requires additional exploration, these findings suggest a connection between nutrition and oral microbiome, emphasizing their collective role in maintaining eye health. Health sciences/Risk factors Biological sciences/Microbiology/Biofilms Biological sciences/Microbiology/Communities Health sciences/Diseases/Eye diseases Health sciences/Diseases/Oral diseases microbiota microbiome periodontitis Porphyromonas gingivalis retina age-related macular degeneration epidemiology risk factors lutein zeaxanthin National Health and Nutrition Examination Survey (NHANES) Figures Figure 1 SIGNIFICANCE STATEMENT While our oral microbiome may impact eye health, nutritional factors could play a modulatory role in mitigating the associated risk. INTRODUCTION Mucosal surfaces, including the oral mucosa, harbor a dynamic and intricate microbial community known as the "microbiome," holding significant implications for human health and disease 1 . Periodontal disease, a prevalent disease in human population 2 , 3 , is significantly attributed to Porphyromonas gingivalis (P. gingivalis) 4 , 5 , a gram-negative anaerobe primarily residing in the oral cavity. Colonizing the subgingiva, P. gingivalis contributes to the formation of a destructive biofilm (dental plaque) within a multispecies microbe community, leading to alveolar bone loss 6 . Despite its low abundance, P. gingivalis acts as a catalyst in periodontitis, reshaping the composition of the oral commensal microbiome into a dysbiotic state, accelerating microbiome-mediated bone-destructive periodontitis 7 . Moreover, the chronic trickling of this bacterium into the systemic bloodstream triggers a systemic inflammatory response, elevating levels of various inflammatory mediators 8 . This P. gingivalis -induced systemic inflammation is linked to increased risks of systemic diseases such as atherosclerosis, rheumatoid arthritis, metabolic disorders 4 , 9 – 12 , and neurodegenerative diseases, including cognition impairment and Alzheimer’s disease 13 , 14 . This microbe serves as a vivid example of how the microbiome can impact diverse aspects of human health and disease in locations distant from its original habitat in the body. Significantly, our previous studies indicate that specific patterns of oral microbiome are strongly associated with human health and diseases, with P. gingivalis playing a pivotal role in patterns affecting retinal eye health 15 , 16 . Age-related macular degeneration (AMD), a neurodegenerative disease of the retina causing blindness in individuals aged 65 + 17 , shares risk factors and etiological mechanisms with P. gingivalis -related diseases 18 . Hence, there is a hypothesis that periodontopathic microbiome is linked to the occurrence of AMD. To explore this, a "candidate microbe approach, association study" was conducted, correlating serum P. gingivalis immunoglobulin G (IgG) with AMD in a matched case-control study using data from the Third National Health and Nutrition Examination Survey (NHANES-III), a representative sample of the US population. Additionally, investigations were carried out to determine if modifiable risk factors for AMD could influence the P. gingivalis -related risk. MATERIALS and METHODS Study cohort The Third National Health and Nutrition Examination Survey (NHANES-III) was performed between 1988 and 1994 by the National Center for Health Statistics. It is a cross-sectional nationwide health survey of 33994 non-institutionalized US residents aged 2 months and older using a stratified multistage probability sampling design to sample a representative cohort of the US general population. Case and control definitions During the second phase of NHANES-III enrollment (1991–1994), 9371 persons had serum analysis for immunoglobulin levels of P. gingivalis 19 , with 2925 persons ≥ 55 years of age. Of these, 1933 persons had gradable bilateral fundus photography at the time of the complete examination. We excluded persons with history of diabetes, heart attack, stroke, cancer, and missing covariate information. Races other than non-Hispanic white, non-Hispanic black, Mexican-American and participants on immunomodulatory medications or corticosteroids were also excluded from our study. Among non-smokers, other tobacco product users such as chewing tobacco, cigar, and pipe and cotinine level > 15 ng/ml were also excluded. Among the remaining eligible 1070 persons, 174 persons were identified as early AMD cases and 12 persons as late AMD cases. Early AMD was defined as the presence of either soft drusen (≥ 63 µm, equivalent to Grade 3 drusen in the Wisconsin Age-related Maculopathy Grading System) 20 or any drusen type with areas of depigmentation or hypopigmentation of the retinal pigment epithelium (RPE) without any visibility of choroidal vessels or with increased retinal pigment in the macular area. Late AMD was defined as the presence of signs of exudative macular degeneration or geographic atrophy (sharply delineated roughly round or oval area of apparent absence of the RPE in which choroidal vessels are more visible than in surrounding areas). The intergrader and intragrader Kappa scores ranged from 0.62 to 0.83 for the NHANES-III AMD grading, indicating a good reliability 21 . Among the remaining 884 non-AMD persons, we selected a series of control subjects by a random selection of one-by-one frequency matching in age, sex, and race such that the overall characteristics distributions of the controls resembled the overall characteristics distributions of the cases. Serum P. gingivalis immunoglobulin G Serum P. gingivalis IgG indicates systemic response to this periodontal disease-causing pathogenic bacterium. The antibody measurement in the NHANES-III data set was reported in enzyme-linked immunosorbent assay (ELISA) units (EU) of IgG. The detailed measurement methods are previously described elsewhere (National Center for Health Statistics NHANES III Data Documentation. http://www.cdc.gov/nchs/data/nhanes/nhanes3/depp.pdf ). To examine for possible dose-response relationships of P. gingivalis IgG and AMD risk, we retained the same categorization ranges of P. gingivalis IgG from previous report from the Atherosclerosis Risk in Communities Study (ARIC) 22 , which had similar demographics to the NHANES-III subjects 14 . The report showed a significant ( P < 0.0001) relationship between periodontitis severity and P. gingivalis IgG with a mean P. gingivalis IgG for healthy individuals of 53.8 EU, mild periodontitis 60.9 EU, moderate periodontitis 69.4 EU and severe periodontitis 168.4 EU. The midpoint between each of these P. gingivalis IgG means was used to create cut-off points for the four P. gingivalis IgG groups: ≤57 EU (referent), 58–65 EU, 66–119 EU and > 119 EU (highest). Statistical methods The following were considered as covariates in our analyses: age, sex, race, education level, smoking status, body mass index (BMI, computed from weight and height; Kg/m 2 ), drinking alcohol (at least 12 drinks in the past 12 months), serum levels of C reactive protein (CRP), vitamin C, vitamin E, and lutein/zeaxanthin, and two clinical periodontal measurements (mean number of tooth sites that bled on probing [mBOP] and mean clinical attachment loss [mCAL]). Descriptive statistics for these covariates between cases and controls were calculated. To determine significance of differences, analysis of variance (ANOVA) for comparison of means of continuous variables and chi-square tests for categorical variables were used. We also examined the correlations between serum P. gingivalis IgG and these covariates using Spearman correlation coefficients, Mann-Whitney tests, or Kruskal-Wallis tests, as appropriate. To evaluate the association between P. gingivalis IgG and AMD risk, logistic regression models were fitted by controlling for selected covariates. All analyses were performed using SAS® SURVEYLOGISTIC procedure (version 9.3; SAS Institute Inc, Cary, NC), which takes into account of the complex sampling design used in NHANES-III and yields unbiased standard error (SEM) and confidence interval (CI) estimates. Odds ratios (ORs) were calculated by dividing the odds of AMD among persons in higher categories of serum levels of P. gingivalis IgG by the odds among persons in the lowest category of P. gingivalis IgG. We used P < 0.05 to denote statistical significance and all tests were two-sided. This study involved only the secondary data analysis of existing US national databases that are publicly available and have been de-identified. This research qualified for exemption of institutional review board human subjects approval under 45 CFR 46.101(b) (4) as specified by the Federal Regulations for Protection of Human Research Subjects. Thus, this is an exempt study and there was no need for institutional review board approval from our institutions. This human observational study report was prepared to conform to the STROBE guidelines. RESULTS Since our controls were matched with cases in age, sex, and race, it is not surprising that the distributions of these three covariates were not significantly different between cases and controls (Table 1). Probably due to this matching strategy, the distributions for the other covariates were not significantly different, either. However, serum P. gingivalis IgG categorical distributions showed significantly different ( P <0.0001) between cases and controls, and cases tended to be in the higher IgG categorical levels than controls, and the vice versa. In our bivariate analysis, age ( P =0.007) and serum vitamin C level ( P =0.004) were inversely correlated with serum P. gingivalis IgG level while serum vitamin E level ( P =0.004) was positively correlated (Table 2). Male sex ( P =0.01), non-Hispanic black ( P <0.0001), lower levels of education ( P =0.01), and former smokers ( P =0.001) tended to have higher levels of serum P. gingivalis IgG. However, BMI, alcoholic intake, and serum levels of lutein/zeaxanthin and CRP were not significantly correlated with serum P. gingivalis IgG level. Next, in the logistic analysis evaluating our primary interest of the association between serum P. gingivalis IgG level and risk for AMD, we used a hierarchical strategy in our model construction to examine the confounding effects from the covariates (Table 3). Starting from an age-adjusted model (Model 1), we stepwise included the other covariates; Model 2 additionally adjusted for demographic covariates, including sex, race, BMI and education; Model 3 additionally adjusted for habitual exposures, including smoking history and alcohol intake; Model 4 additionally adjusted for serum levels of nutrient covariates, including vitamin C, vitamin E, lutein/zeaxanthin, and CRP, and Model 5 additionally adjusted for two clinical periodontal measurements (mBOP and mCAL). As shown in Table 3, the OR and 95% CI for each serum P. gingivalis IgG categorical level in every higher hierarchical models were similar with the age-adjusted OR and 95% CI, which showed a significant trend ( P =0.036) of increased risk by increasing serum P. gingivalis IgG level. Overall, compared with the lowest IgG category, the second higher category conferred a 20% increased risk for early AMD, the third higher category conferred a 40%-60%, and the highest (fourth) category conferred an over two-fold of risk. Because including more covariates in the models decreases the statistical power, the trend tests became less significant in higher hierarchical models, however, they were all within marginal significance ( P <0.1). Similar results were noted when including the 12 late AMD cases (see Case and control definitions ) in the analysis. We further tried to evaluate if the effect of serum P. gingivalis IgG level on AMD risk varies by the status of modifiable risk factors for AMD, including smoking status (ever smokers vs. non-smokers), BMI (≥25 vs. <25 or ≥28 vs. <28 or ≥30 vs. <30 Kg/m 2 ), and serum levels (higher vs. lower than the median) of vitamin C (median=39 mmol/L), vitamin E (median=23.5 µmol/L), and lutein/zeaxanthin (mediam=0.35 µmol/L). The results indicated that the P. gingivalis -related AMD risk significantly ( P for interaction<0.0001) varies by serum levels of lutein/zeaxanthin (≥0.35 µmol/L vs. <0.35 µmol/L). Compared subjects in the low serum level of lutein/zeaxanthin with those in the high serum level, there is an up to 35.4% (=(0.65-0.42)/0.65) higher risk of AMD for serum P. gingivalis IgG category 2 (58–65 EU), 32.5% (=(0.80-0.54)/0.80) for category 3, and 26% (=(1-0.74)/1) for category 4 (Figure 1). In other words, higher serum lutein/zeaxanthin levels were protective against P. gingivalis -related AMD risk. DISCUSSION Traditionally, microbiology in the context of human health primarily concentrated on local effects. However, our study has revealed a notable shift in perspective, demonstrating a positive association between the serum signature of P. gingivalis and the risk of AMD. This contributes to the growing body of evidence suggesting that the microbiome within the human body can exert influences on distant tissues and organs. Additionally, aligning with the notion that the microbiome composition is significantly shaped by host's diet, our findings indicate that elevated serum levels of lutein/zeaxanthin offer a protective effect against the P. gingivalis -related AMD risk. To date, only few studies have been published that explores the correlation between periodontitis and AMD 23-25 . Although pooled analysis suggested that periodontitis patients may have a higher risk of AMD 23,24 , bias assessment and power analysis indicated that the association remains debatable 25 . As part of the cross-sectional Finnish national population-based Health 2000 Survey 26 , 1751 individuals aged 30 years or older were included in the study, consisting of 54 individuals with degenerative fundus changes (AMD group) and 1,697 individuals free of AMD (non-AMD group). In their univariate analysis comparing the AMD group with the non-AMD group, Karesvuo et al. identified a significant difference in the proportion of individuals with alveolar bone loss among males and a significant difference in the number of teeth among females. However, likely due to insufficient case numbers and control selection, no significant difference was found between the AMD group and the non-AMD group in terms of the proportion of carriage of salivary periodontopathic bacteria, including P. gingivalis . Following multivariate adjustment for various factors such as age, diabetic status, systolic blood pressure, education, smoking, and the carriage of salivary bacteria, only alveolar bone loss remained significantly associated with the risk of AMD among males. While previous research has proposed infection as a potential risk factor for AMD 27 , and P. gingivalis has been linked to various human neurodegenerative disorders 13,14 , our study is the first to establish a significant relationship between P. gingivalis and AMD. Notably, P. gingivalis is not limited to the oral cavity, as it also inhabits other sites within the human body. The ubiquitously expressed transglutaminase 2 (TG2) plays a crucial role in P. gingivalis adherence to host cells 6 , with periodontitis being its sole known clinical manifestation in situ. Furthermore, P. gingivalis acts as a catalyst in periodontopathic microbiome, and the serum P. gingivalis IgG level has been demonstrated to closely correlate with the severity of periodontitis 7,22 . As a result, the serum P. gingivalis IgG level can function as a surrogate marker for the activity level of periodontopathic microbiome in the oral cavity 4 . In contrast to most pathogenic bacteria that typically induce severe inflammation and outcompete native bacteria, P. gingivalis establishes colonization at low levels and functions as a "catalyst" to foster a pathogenic microbiome (pathobionts). Studies in a murine periodontal model have demonstrated that even at low numbers, the introduction of P. gingivalis into the oral microbiome community significantly accelerates pathological alveolar bone loss 28 . However, since P. gingivalis alone fails to induce periodontitis, the hypothesis arises that P. gingivalis exerts its bone-destructive role in collaboration with other dysbiotic bacteria. Mechanistic investigations indicate that P. gingivalis colonization in the oral cavity disrupts the host immune system and induces changes in the quantity and composition of the oral commensal microbiome. This occurs through the secretion of gingipain, a complement component 5 (C5) convertase-like enzyme. Gingipain generates elevated levels of locally active C5a, leading to C5aR activation, triggering inflammation while simultaneously inhibiting the killing capacity of leukocytes and suppressing the expression of chemokines. Studies further highlight the significance of the complement pathway in P. gingivalis -related pathogenesis, proposing the targeting of C3 as a potential treatment strategy for periodontitis 29 . Interestingly, it is well-documented that the activation of C3 and the generation of excessive quantities of C5a and C5b-C9 play a significant role in the pathogenesis of AMD 30 . While it has been established that the inflammatory and immune response triggered by P. gingivalis has both local and systemic effects 4,9-12 , the impact of gingipain, C5 activation, and the dysbiotic microbiome induced by P. gingivalis on the retina is yet to be determined. If an established etiological relationship between P. gingivalis and AMD is confirmed, AMD could join the ranks of diseases—such as obesity, metabolic disorders, and inflammatory bowel diseases—that have been shown to be transmittable through the transfer of dysbiotic microbiome 31 . In such a scenario, the management of P. gingivalis -related AMD risk could involve the elimination of P. gingivalis from the oral cavity. However, it is worth noting that the composition of the microbiome is highly susceptible to changes influenced by the host microenvironment and diet 32 . Our analysis (Figure 1) also suggests that maintaining a higher serum level of lutein/zeaxanthin (≥0.35 µmol/L or ≥20 µg/dL), possibly through a healthy diet or the use of the Age-Related Eye Disease Study 2 (AREDS2) supplement 33-36 , could help modulate the P. gingivalis -related AMD risk. Although studies have demonstrated that lower serum levels of various carotenoids, including zeaxanthin, increase the risk of periodontitis 37 , and supplemental lutein/zeaxanthin has been shown to be protective against AMD 36 , it remains to be determined if lutein/zeaxanthin has a direct impact on the P. gingivalis -driven microbiome. This study boasts several strengths, including its design as a matched case-control study within a representative cohort of the US population. The standardized collection of risk factor information and the use of photographic grading for maculopathy are additional strengths, aiming to minimize the impact of confounding factors and misclassifications. However, it is important to acknowledge certain limitations. The restricted number of AMD cases in our study resulted in insufficient sample sizes for certain analyses. For instance, in our interaction analyses, we only had a sufficient sample size to assess the relationship with serum levels of lutein/zeaxanthin. The cross-sectional nature of the study also poses a limitation in terms of defining temporality. Nevertheless, it's worth noting that serum P. gingivalis IgG is considered to reflect chronic, intermittent exposure 14 , and the average age of onset for periodontitis is notably younger than that for AMD 2 . Additionally, serum levels of lutein/zeaxanthin are considered to reflect the long-term intake of these nutrients 36 . In conclusion, our study has unveiled a novel association between exposure to P. gingivalis , serum lutein/zeaxanthin levels, and the risk for AMD. Although the intricate mechanisms underlying this relationship require further investigation, our findings have the potential to significantly influence therapeutic and preventive strategies for AMD. This is particularly noteworthy given the high prevalence of P. gingivalis in the human population. Declarations Author Contributions C-J. Chiu, contributed to conception, design, data acquisition, analysis, and interpretation, drafted the manuscript, and critically revised the manuscript; E. Chiu, M-L. Chang contributed to data analysis and interpretation, critically revised the manuscript; All authors gave final approval and agree to be accountable for all aspects of the work. Funding Financial support for this project has been provided by the RO1EY021826 and R21EY028209 from the National Institutes of Health. Declaration of Conflicting Interests The funding sources had no role in the design and conduct of the study; the collection, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript. No authors declare a conflict of interest. Data S haring S tatement The data used in this study is freely available for download by the public at: https://wwwn.cdc.gov/nchs/nhanes/nhanes3/default.aspx. References Darveau, R. P. Periodontitis: a polymicrobial disruption of host homeostasis. Nat Rev Microbiol. 8 , 481-490. (2010). Burt, B. & Research Science and Therapy Committee of the American Academy of Periodontology. Position paper: epidemiology of periodontal diseases. J Periodontol. 76 , 1406-1419. (2005). Chapple, I. L. Time to take periodontitis seriously. BMJ. 348 , :g2645. (2014). Pussinen, P. J. et al. Periodontal pathogen carriage, rather than periodontitis, determines the serum antibody levels. J Clin Periodontol. 38 , 405-411. (2011). Hajishengallis, G., Darveau, R. P. & Curtis, M. A. The keystone-pathogen hypothesis. Nature reviews. Microbiology 10 , 717-725, doi:10.1038/nrmicro2873 (2012). Boisvert, H., Lorand, L. & Duncan, M. J. Transglutaminase 2 is essential for adherence of Porphyromonas gingivalis to host cells. Proc Natl Acad Sci U S A. 111 , 5355-5360. (2014 ). Honda, K. Porphyromonas gingivalis sinks teeth into the oral microbiota and periodontal disease. Cell Host Microbe. 10 , 423-425. (2011). Kamer, A. R. et al. Inflammation and Alzheimer's disease: possible role of periodontal diseases. Alzheimers Dement. 4 , 242-250. (2008 ). Rosenstein, E. D., Greenwald, R. A., Kushner, L. J. & Weissmann, G. Hypothesis: the humoral immune response to oral bacteria provides a stimulus for the development of rheumatoid arthritis. Inflammation. 28 , 311-318. (2004). Kozarov, E. V., Dorn, B. R., Shelburne, C. E., Dunn, W. A. J. & Progulske-Fox, A. Human atherosclerotic plaque contains viable invasive Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis. Arterioscler Thromb Vasc Biol. 25 , e17-18. (2005). Genco, R., Offenbacher, S. & Beck, J. Periodontal disease and cardiovascular disease: epidemiology and possible mechanisms. J Am Dent Assoc. 133 , 14S-22S. (2002). Chapple, I. L., Genco, R. & working group 2 of the joint EFP/AAP workshop. Diabetes and periodontal diseases: consensus report of the Joint EFP/AAP Workshop on Periodontitis and Systemic Diseases. J Periodontol. 84 , S106-112. (2013). Sparks Stein, P. et al. Serum antibodies to periodontal pathogens are a risk factor for Alzheimer's disease. Alzheimers Dement. 8 , 196-203. (2012). Noble, J. M. et al. Periodontitis is associated with cognitive impairment among older adults: analysis of NHANES-III. J Neurol Neurosurg Psychiatry. 80 , 1206-1211. (2009). Chiu, C. J., Chang, M. L. & Taylor, A. Associations between Periodontal Microbiota and Death Rates. Sci Rep. 6 , 35428, doi:doi: 10.1038/srep35428. (2016). Chiu, C. J., Chang, M. L., Kantarci, A., Van Dyke, T. E. & Shi, W. Exposure to Porphyromonas gingivalis and Modifiable Risk Factors Modulate Risk for Early Diabetic Retinopathy. Translational vision science & technology 10 , 23, doi:10.1167/tvst.10.2.23 (2021). Congdon, N. et al. Causes and prevalence of visual impairment among adults in the United States. Arch Ophthalmol 122 , 477-485 (2004). Chiu, C. J. & Taylor, A. Dietary hyperglycemia, glycemic index and metabolic retinal diseases. Prog Retin Eye Res. 30 , 18-53. (2011). Dye, B. A., Choudhary, K., Shea, S. & Papapanou, P. N. Serum antibodies to periodontal pathogens and markers of systemic inflammation. J Clin Periodontol. 32 , 1189-1199. (2005). Klein, R. et al. The Wisconsin age-related maculopathy grading system. Ophthalmology 98 , 1128-1134 (1991). Klein, R. et al. Age-related maculopathy in a multiracial United States population: the National Health and Nutrition Examination Survey III. Ophthalmology. 106 , 1056-1065. (1999). Offenbacher, S. et al. Periodontal disease at the biofilm-gingival interface. J Periodontol. 78 , 1911-1925. (2007 ). Pockpa, Z. A. D. et al. Periodontal Diseases and Age-Related Macular Degeneration: Is There a Link? A Review. The Permanente journal 23 , doi:10.7812/tpp/18.260 (2019). Lv, X., Li, W., Fang, Z., Xue, X. & Pan, C. Periodontal Disease and Age-Related Macular Degeneration: A Meta-Analysis of 112,240 Participants. BioMed research international 2020 , 4753645, doi:10.1155/2020/4753645 (2020). Javed, F., Sculean, A. & Romanos, G. E. Association between age-related macular degeneration and periodontal and peri-implant diseases: a systematic review. Acta Ophthalmol 99 , 351-356, doi:10.1111/aos.14629 (2021). Karesvuo, P. et al. Alveolar bone loss associated with age-related macular degeneration in males. J Periodontol. 84 , 58-67. (2013). Barouch, F. C. & Miller, J. W. The role of inflammation and infection in age-related macular degeneration. . Int Ophthalmol Clin 47 , 185-197. (2007). Hajishengallis, G. et al. Low-abundance biofilm species orchestrates inflammatory periodontal disease through the commensal microbiota and complement. Cell Host Microbe. 10 , 497-506. (2011). Maekawa, T. et al. Genetic and Intervention Studies Implicating Complement C3 as a Major Target for the Treatment of Periodontitis. J Immunol. 192 , 6020-6027. (2014). Ambati, J., Atkinson, J. P. & Gelfand, B. D. Immunology of age-related macular degeneration. Nat Rev Immunol. 13 , 438-451. (2013). Garrett, W. S., Gordon, J. I. & Glimcher, L. H. Homeostasis and inflammation in the intestine. Cell. 140 , 859-870. (2010). Zhang, C. et al. Interactions between gut microbiota, host genetics and diet relevant to development of metabolic syndromes in mice. ISME J. 4 , 232-241. (2010). Chiu, C. J., Klein, R., Milton, R. C., Gensler, G. & Taylor, A. Does eating particular diets alter risk of age-related macular degeneration in users of the Age-Related Eye Disease Study supplements? Br J Ophthalmol. 93 , 1241-1246. (2009). Chiu, C. J., Milton, R. C., Klein, R., Gensler, G. & Taylor, A. Dietary compound score and risk of age-related macular degeneration in the Age-Related Eye Disease Study. Ophthalmology. 116 , 939-946. (2009). Chiu, C. J. et al. The Relationship of Major American Dietary Patterns to Age-related Macular Degeneration. Am J Ophthalmol. 158 , 118-127. (2014). Age-Related Eye Disease Study 2 Research Group. Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA. 309 , 2005-2015. (2013). Linden, G. J. et al. Antioxidants and periodontitis in 60-70-year-old men. J Clin Periodontol. 36 , 843-849. (2009). Tables Table 1. Comparisons in characteristics distributions between cases and frequency-matched controls in age, sex, and race. Characteristics Controls a Cases a P value b N=174 N=174 Age yrs (Mean (SEM)) 68.1 (0.6) 69.3 (0.2) 0.30 Male (N (%)) 67 (46.1) 67 (42.5) 0.09 Race (N (%)) Non-Hispanic white 108 (92.1) 108 (90.6) 0.17 Non-Hispanic black 27 (5.5) 27 (6.4) Mexican-American 39 (2.5) 39 (3.0) BMI Kg/m 2 (Mean (SEM)) 26.7 (0.1) 27.8 (0.3) 0.22 Education (N (%)) 12 yrs 36 (32.9) 40 (34.5) Smoking history (N (%)) Non-smokers 95 (52.1) 95 (51.2) 0.96 Former smokers 50 (38.7) 57 (39.4) Active smokers 29 (9.2) 22 (9.5) At least 12 drinks in the past 12 months No 119 (61.4) 120 (60.5) 0.58 Yes 55 (38.6) 54 (39.5) Serum CRP level mg/dL (Mean (SEM)) 0.4 (0.01) 0.5 (0.004) 0.45 Serum vitamin C mmol/L (Mean (SEM)) 56.8 (0.5) 52.1 (0.8) 0.28 Serum vitamin E µmol/L (Mean (SEM)) 31.9 (0.5) 33.9 (0.2) 0.28 Serum lutein/ zeaxanthin µmol/L (Mean (SEM)) 0.5 (0.01) 0.4 (0.01) 0.19 Porphyromonas gingivalis IgG EU ≤57 EU (N (%)) 10 (8.0) 12 (5.8) 119 EU (N (%)) 35 (12.3) 42 (18.2) a For categorical variables, sample sizes (N) are raw numbers while the percentages (%) are weighted for the sampling design used in the Third National Health and Nutrition Examination Survey (NHANES-III). b Analysis of variance ( ANOVA ) was used for statistical tests of significance for continuous variables while Wald chi-squared test was used for all other categorical measures. Abbreviation: BMI, body mass index; CRP, C reactive protein; IgG, immunoglobulin G ; EU, enzyme-linked immunosorbent assay unit ; SEM, standard error. Table 2. Bivariate associations between serum Porphyromonas gingivalis immunoglobulin G concentrations and covariates. Continuous covariates N Spearman correlation coefficient with P. gingivalis IgG (EU) P value Age yrs 348 -0.145 0.007 BMI Kg/m 2 348 0.068 0.21 Serum CRP level mg/dL 348 0.081 0.13 Serum vitamin C mmol/L 348 -0.153 0.004 Serum vitamin E µmol/L 348 0.154 0.004 Serum lutein/zeaxanthin µmol/L 348 0.006 0.91 Categorical covariates N P. gingivalis IgG (EU), median [IQR] P value a Sex Male 134 80 [66-107] 0.01 Female 214 70 [64-95] Race Non-Hispanic white 216 73 [64-93] <0.0001 Non-Hispanic black 54 102 [76-219] Mexican-American 78 100 [78-174] Education 12 yrs 76 72 [64-91] Smoking history Non-smokers 190 69 [64-96] 0.001 Former smokers 107 82 [68-109] Active smokers 51 70 [67-82] At least 12 drinks in the past 12 months No 239 74 [66-95] 0.51 Yes 109 73 [64-109] Porphyromonas gingivalis IgG category ≤57 EU 22 57 [56-57] 119 EU 77 193 [151-449] a P-values were obtained by Mann-Whitney test for variables with 2 categories, and from Kruskal-Wallis test for variables with 3 or more categories. Abbreviation: BMI, body mass index; CRP, C reactive protein; IgG, immunoglobulin G ; EU, enzyme-linked immunosorbent assay unit ; IQR, inter quartile range. Table 3. Logistic analysis relating serum Porphyromonas gingivalis immunoglobulin G levels to risk for age-related macular degeneration. Serum P. gingivalis IgG level (EU) Adjusted OR (95% CI) a Model 1 Model 2 Model 3 Model 4 Model 5 ≤57 (referent) 1 1 1 1 1 58–65 1.19 (1.05 to 1.35) 1.23 (1.07 to 1.41) 1.24 (1.07 to 1.43) 1.27 (1.16 to 1.38) 1.28 (1.17 to 1.40) 66–118 1.44 (1.31 to 1.58) 1.48 (1.27 to 1.73) 1.51 (1.32 to 1.73) 1.55 (1.42 to 1.68) 1.58 (1.46 to 1.72) >119 2.02 (1.66 to 2.46) 2.07 (1.67 to 2.55) 2.03 (1.52 to 2.72) 2.12 (1.68 to 2.66) 2.04 (1.62 to 2.58) P for trend 0.04 0.05 0.06 0.06 0.09 a Model 1: adjusted for age; Model 2: Model 1 additionally adjusted for sex, race, BMI and education; Model 3: Model 2 additionally adjusted for smoking history and alcohol intake; Model 4: Model 3 additionally adjusted for serum vitamin C, E, lutein/xeaxanthin, and CRP levels; Model 5: Model 4 additionally adjusted for two clinical periodontal measurements, mBOP and mCAL. Abbreviation: OR, odds ratio; CI, confidence interval; CRP, C reactive protein; IgG, immunoglobulin G; EU, enzyme-linked immunosorbent assay unit; mBOP, mean number of tooth sites that bled on probing; mCAL, mean clinical attachment loss. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 11 Nov, 2025 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 05 May, 2025 Reviews received at journal 02 May, 2025 Reviewers agreed at journal 22 Apr, 2025 Reviewers agreed at journal 07 Apr, 2025 Reviews received at journal 07 Apr, 2025 Reviewers agreed at journal 07 Apr, 2025 Reviewers agreed at journal 03 Apr, 2025 Reviewers invited by journal 31 Mar, 2025 Editor assigned by journal 31 Mar, 2025 Editor invited by journal 18 Mar, 2025 Submission checks completed at journal 15 Mar, 2025 First submitted to journal 09 Mar, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6188207","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":439706707,"identity":"12bf5c42-a8ac-4677-b16f-403c3803a0f2","order_by":0,"name":"Chung-Jung Chiu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+klEQVRIiWNgGAWjYDACCRDBA2ayMSQw2ABpxsYDpGhJA2lpIEILA1QLA8NhMAuvFv7ZPWYPv8gczpN3YH724GHbebu17YeBttTYROO05M4Zc2MZnsPFhgfYzA0S224nbzuTCNRyLC23AYcWA4kcM2kJnsOJGxt42CRAWswOALUwNhwmWsu5ZLPzDwlrkfwA1DKfAazlgJ3ZDQK2SNxIK5Nm4ElP3MDMZiaRcC45wewG0JYEPH7hn5G8TfJnj3Xi/PbmZ5I/yuzszc6nP3zwocYGpxYQYObtAboQEiMMiWCVCXiUgwDjjx8MDPJQQ+0JKB4Fo2AUjIIRCADLvl88Btbx6wAAAABJRU5ErkJggg==","orcid":"","institution":"The Forsyth Institute","correspondingAuthor":true,"prefix":"","firstName":"Chung-Jung","middleName":"","lastName":"Chiu","suffix":""},{"id":439706708,"identity":"b157ffc7-a46d-4998-8609-b4dd587463cb","order_by":1,"name":"Emily Chiu","email":"","orcid":"","institution":"The University of Vermont","correspondingAuthor":false,"prefix":"","firstName":"Emily","middleName":"","lastName":"Chiu","suffix":""},{"id":439706709,"identity":"0b967ab8-6101-493f-b392-5c7b52048e11","order_by":2,"name":"Min-Lee Chang","email":"","orcid":"","institution":"Harvard Medical School","correspondingAuthor":false,"prefix":"","firstName":"Min-Lee","middleName":"","lastName":"Chang","suffix":""}],"badges":[],"createdAt":"2025-03-09 10:53:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6188207/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6188207/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-025-14144-3","type":"published","date":"2025-11-11T15:58:10+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":82071595,"identity":"8069c7f9-e9ba-4d36-b790-65d6915f7882","added_by":"auto","created_at":"2025-05-06 13:21:56","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":47557,"visible":true,"origin":"","legend":"\u003cp\u003eThe \u003cem\u003ePorphyromonas gingivalis\u003c/em\u003e-related AMD risk significantly (\u003cem\u003eP\u003c/em\u003e for interaction\u0026lt;0.0001) varies by serum levels of lutein/zeaxanthin (≥0.35 µmol/L vs. \u0026lt;0.35 µmol/L).The four \u003cem\u003eP. gingivalis \u003c/em\u003eIgG groups are ≤57 EU (category 1), 58–65 EU (category 2), 66–119 EU (category 3) and \u0026gt;119 EU (category 4). The ORs (95% CIs) for the four \u003cem\u003eP. gingivalis \u003c/em\u003eIgG groups (from high to low) in the low serum lutein/zeaxanthin category are 1 (referent), 0.80 (0.45 to 1.42), 0.65 (0.40 to 1.07), and 0.43 (0.28 to 0.66), and they are 0.74 (0.48 to 1.15), 0.54 (0.37 to 0.80), 0.42 (0.28 to 0.63), and 0.43 (0.28 to 0.65) in the high serum lutein/zeaxanthin category, respectively.\u003c/p\u003e\n\u003cp\u003eAbbreviation: OR, odds ratio; CI, confidence interval; IgG, immunoglobulin G\u003cem\u003e; EU, \u003c/em\u003eenzyme-linked immunosorbent assay \u003cem\u003eunit\u003c/em\u003e.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6188207/v1/694ec52fa0be1b4321a18929.jpg"},{"id":96105240,"identity":"ef365ba5-dc57-4143-b8bf-8bf8ca513cd5","added_by":"auto","created_at":"2025-11-17 16:10:22","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1213236,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6188207/v1/eeb4c07f-7ec4-49c2-bf07-83c006dcb18e.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Interaction between Infection of Porphyromonas gingivalis, A Keystone Microbe of Oral Microbiome, and Serum Levels of Lutein/Zeaxanthin Is Associated with Risk for Age-related Macular Degeneration.","fulltext":[{"header":"SIGNIFICANCE STATEMENT","content":"\u003cp\u003eWhile our oral microbiome may impact eye health, nutritional factors could play a modulatory role in mitigating the associated risk.\u003c/p\u003e"},{"header":"INTRODUCTION","content":"\u003cp\u003eMucosal surfaces, including the oral mucosa, harbor a dynamic and intricate microbial community known as the \"microbiome,\" holding significant implications for human health and disease \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Periodontal disease, a prevalent disease in human population \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e, is significantly attributed to \u003cem\u003ePorphyromonas gingivalis (P. gingivalis)\u003c/em\u003e \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e, a gram-negative anaerobe primarily residing in the oral cavity. Colonizing the subgingiva, \u003cem\u003eP. gingivalis\u003c/em\u003e contributes to the formation of a destructive biofilm (dental plaque) within a multispecies microbe community, leading to alveolar bone loss \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Despite its low abundance, \u003cem\u003eP. gingivalis\u003c/em\u003e acts as a catalyst in periodontitis, reshaping the composition of the oral commensal microbiome into a dysbiotic state, accelerating microbiome-mediated bone-destructive periodontitis \u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. Moreover, the chronic trickling of this bacterium into the systemic bloodstream triggers a systemic inflammatory response, elevating levels of various inflammatory mediators \u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. This \u003cem\u003eP. gingivalis\u003c/em\u003e-induced systemic inflammation is linked to increased risks of systemic diseases such as atherosclerosis, rheumatoid arthritis, metabolic disorders \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan additionalcitationids=\"CR10 CR11\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e, and neurodegenerative diseases, including cognition impairment and Alzheimer\u0026rsquo;s disease \u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. This microbe serves as a vivid example of how the microbiome can impact diverse aspects of human health and disease in locations distant from its original habitat in the body. Significantly, our previous studies indicate that specific patterns of oral microbiome are strongly associated with human health and diseases, with \u003cem\u003eP. gingivalis\u003c/em\u003e playing a pivotal role in patterns affecting retinal eye health \u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. Age-related macular degeneration (AMD), a neurodegenerative disease of the retina causing blindness in individuals aged 65\u0026thinsp;+\u0026thinsp;\u003csup\u003e17\u003c/sup\u003e, shares risk factors and etiological mechanisms with \u003cem\u003eP. gingivalis\u003c/em\u003e-related diseases \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. Hence, there is a hypothesis that periodontopathic microbiome is linked to the occurrence of AMD. To explore this, a \"candidate microbe approach, association study\" was conducted, correlating serum \u003cem\u003eP. gingivalis\u003c/em\u003e immunoglobulin G (IgG) with AMD in a matched case-control study using data from the Third National Health and Nutrition Examination Survey (NHANES-III), a representative sample of the US population. Additionally, investigations were carried out to determine if modifiable risk factors for AMD could influence the \u003cem\u003eP. gingivalis\u003c/em\u003e-related risk.\u003c/p\u003e"},{"header":"MATERIALS and METHODS","content":" \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy cohort\u003c/h2\u003e \u003cp\u003eThe Third National Health and Nutrition Examination Survey (NHANES-III) was performed between 1988 and 1994 by the National Center for Health Statistics. It is a cross-sectional nationwide health survey of 33994 non-institutionalized US residents aged 2 months and older using a stratified multistage probability sampling design to sample a representative cohort of the US general population.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eCase and control definitions\u003c/h3\u003e\n\u003cp\u003eDuring the second phase of NHANES-III enrollment (1991\u0026ndash;1994), 9371 persons had serum analysis for immunoglobulin levels of \u003cem\u003eP. gingivalis\u003c/em\u003e \u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e, with 2925 persons\u0026thinsp;\u0026ge;\u0026thinsp;55 years of age. Of these, 1933 persons had gradable bilateral fundus photography at the time of the complete examination. We excluded persons with history of diabetes, heart attack, stroke, cancer, and missing covariate information. Races other than non-Hispanic white, non-Hispanic black, Mexican-American and participants on immunomodulatory medications or corticosteroids were also excluded from our study. Among non-smokers, other tobacco product users such as chewing tobacco, cigar, and pipe and cotinine level\u0026thinsp;\u0026gt;\u0026thinsp;15 ng/ml were also excluded. Among the remaining eligible 1070 persons, 174 persons were identified as early AMD cases and 12 persons as late AMD cases. Early AMD was defined as the presence of either soft drusen (\u0026ge;\u0026thinsp;63 \u0026micro;m, equivalent to Grade 3 drusen in the Wisconsin Age-related Maculopathy Grading System) \u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e or any drusen type with areas of depigmentation or hypopigmentation of the retinal pigment epithelium (RPE) without any visibility of choroidal vessels or with increased retinal pigment in the macular area. Late AMD was defined as the presence of signs of exudative macular degeneration or geographic atrophy (sharply delineated roughly round or oval area of apparent absence of the RPE in which choroidal vessels are more visible than in surrounding areas). The intergrader and intragrader Kappa scores ranged from 0.62 to 0.83 for the NHANES-III AMD grading, indicating a good reliability \u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. Among the remaining 884 non-AMD persons, we selected a series of control subjects by a random selection of one-by-one frequency matching in age, sex, and race such that the overall characteristics distributions of the controls resembled the overall characteristics distributions of the cases.\u003c/p\u003e\n\u003ch3\u003eSerum P. gingivalis immunoglobulin G\u003c/h3\u003e\n\u003cp\u003eSerum \u003cem\u003eP. gingivalis\u003c/em\u003e IgG indicates systemic response to this periodontal disease-causing pathogenic bacterium. The antibody measurement in the NHANES-III data set was reported in enzyme-linked immunosorbent assay (ELISA) units (EU) of IgG. The detailed measurement methods are previously described elsewhere (National Center for Health Statistics NHANES III Data Documentation. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.cdc.gov/nchs/data/nhanes/nhanes3/depp.pdf\u003c/span\u003e\u003cspan address=\"http://www.cdc.gov/nchs/data/nhanes/nhanes3/depp.pdf\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). To examine for possible dose-response relationships of \u003cem\u003eP. gingivalis\u003c/em\u003e IgG and AMD risk, we retained the same categorization ranges of \u003cem\u003eP. gingivalis\u003c/em\u003e IgG from previous report from the Atherosclerosis Risk in Communities Study (ARIC) \u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e, which had similar demographics to the NHANES-III subjects \u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. The report showed a significant (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) relationship between periodontitis severity and \u003cem\u003eP. gingivalis\u003c/em\u003e IgG with a mean \u003cem\u003eP. gingivalis\u003c/em\u003e IgG for healthy individuals of 53.8 EU, mild periodontitis 60.9 EU, moderate periodontitis 69.4 EU and severe periodontitis 168.4 EU. The midpoint between each of these \u003cem\u003eP. gingivalis\u003c/em\u003e IgG means was used to create cut-off points for the four \u003cem\u003eP. gingivalis\u003c/em\u003e IgG groups: \u0026le;57 EU (referent), 58\u0026ndash;65 EU, 66\u0026ndash;119 EU and \u0026gt;\u0026thinsp;119 EU (highest).\u003c/p\u003e\n\u003ch3\u003eStatistical methods\u003c/h3\u003e\n\u003cp\u003eThe following were considered as covariates in our analyses: age, sex, race, education level, smoking status, body mass index (BMI, computed from weight and height; Kg/m\u003csup\u003e2\u003c/sup\u003e), drinking alcohol (at least 12 drinks in the past 12 months), serum levels of C reactive protein (CRP), vitamin C, vitamin E, and lutein/zeaxanthin, and two clinical periodontal measurements (mean number of tooth sites that bled on probing [mBOP] and mean clinical attachment loss [mCAL]). Descriptive statistics for these covariates between cases and controls were calculated. To determine significance of differences, analysis of variance (ANOVA) for comparison of means of continuous variables and chi-square tests for categorical variables were used. We also examined the correlations between serum \u003cem\u003eP. gingivalis\u003c/em\u003e IgG and these covariates using Spearman correlation coefficients, Mann-Whitney tests, or Kruskal-Wallis tests, as appropriate.\u003c/p\u003e \u003cp\u003eTo evaluate the association between \u003cem\u003eP. gingivalis\u003c/em\u003e IgG and AMD risk, logistic regression models were fitted by controlling for selected covariates. All analyses were performed using SAS\u0026reg; SURVEYLOGISTIC procedure (version 9.3; SAS Institute Inc, Cary, NC), which takes into account of the complex sampling design used in NHANES-III and yields unbiased standard error (SEM) and confidence interval (CI) estimates. Odds ratios (ORs) were calculated by dividing the odds of AMD among persons in higher categories of serum levels of \u003cem\u003eP. gingivalis\u003c/em\u003e IgG by the odds among persons in the lowest category of \u003cem\u003eP. gingivalis\u003c/em\u003e IgG. We used \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 to denote statistical significance and all tests were two-sided.\u003c/p\u003e \u003cp\u003eThis study involved only the secondary data analysis of existing US national databases that are publicly available and have been de-identified. This research qualified for exemption of institutional review board human subjects approval under 45 CFR 46.101(b) (4) as specified by the Federal Regulations for Protection of Human Research Subjects. Thus, this is an exempt study and there was no need for institutional review board approval from our institutions. This human observational study report was prepared to conform to the STROBE guidelines.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003eSince our controls were matched with cases in age, sex, and race, it is not surprising that the distributions of these three covariates were not significantly different between cases and controls (Table 1). Probably due to this matching strategy, the distributions for the other covariates were not significantly different, either. However, serum\u0026nbsp;\u003cem\u003eP. gingivalis\u0026nbsp;\u003c/em\u003eIgG categorical distributions showed significantly different (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.0001) between cases and controls, and cases tended to be in the higher IgG categorical levels than controls, and the vice versa.\u003c/p\u003e\n\u003cp\u003eIn our bivariate analysis, age (\u003cem\u003eP\u003c/em\u003e=0.007) and serum vitamin C level (\u003cem\u003eP\u003c/em\u003e=0.004) were inversely correlated with serum\u0026nbsp;\u003cem\u003eP. gingivalis\u0026nbsp;\u003c/em\u003eIgG level while serum vitamin E level (\u003cem\u003eP\u003c/em\u003e=0.004) was positively correlated (Table 2). Male sex (\u003cem\u003eP\u003c/em\u003e=0.01), non-Hispanic black (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.0001), lower levels of education (\u003cem\u003eP\u003c/em\u003e=0.01), and former smokers (\u003cem\u003eP\u003c/em\u003e=0.001) tended to have higher levels of serum\u0026nbsp;\u003cem\u003eP. gingivalis\u0026nbsp;\u003c/em\u003eIgG. However,\u0026nbsp;BMI, alcoholic intake, and serum levels of\u0026nbsp;lutein/zeaxanthin\u0026nbsp;and\u0026nbsp;CRP\u0026nbsp;were not significantly correlated with\u0026nbsp;serum\u0026nbsp;\u003cem\u003eP. gingivalis\u0026nbsp;\u003c/em\u003eIgG level.\u003c/p\u003e\n\u003cp\u003eNext, in the logistic analysis evaluating our primary interest of the association between serum\u0026nbsp;\u003cem\u003eP. gingivalis\u0026nbsp;\u003c/em\u003eIgG level and risk for AMD, we used a hierarchical strategy in our model construction to examine the confounding effects from the covariates (Table 3). Starting from an age-adjusted model (Model 1), we stepwise included the other covariates; Model 2 additionally adjusted for demographic covariates, including sex, race, BMI and education; Model 3 additionally adjusted for habitual exposures, including smoking history and alcohol intake; Model 4 additionally adjusted for serum levels of nutrient covariates, including vitamin C, vitamin E, lutein/zeaxanthin, and CRP, and Model 5 additionally adjusted for two clinical periodontal measurements (mBOP and mCAL). As shown in Table 3, the OR and 95% CI for each\u0026nbsp;serum\u0026nbsp;\u003cem\u003eP.\u0026nbsp;gingivalis\u0026nbsp;\u003c/em\u003eIgG categorical level\u0026nbsp;in every higher hierarchical models were similar with the age-adjusted OR and 95% CI, which showed a significant trend (\u003cem\u003eP\u003c/em\u003e=0.036) of increased risk by increasing\u0026nbsp;serum\u0026nbsp;\u003cem\u003eP. gingivalis\u0026nbsp;\u003c/em\u003eIgG level. Overall, compared with the lowest IgG category, the second higher category conferred a 20% increased risk for early AMD, the third higher category conferred a 40%-60%, and the highest (fourth) category conferred an over two-fold of risk. Because including more covariates in the models decreases the statistical power, the trend tests became less significant in higher hierarchical models, however, they were all within marginal significance (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.1). Similar results were noted when including the 12 late AMD cases (see\u003cem\u003e\u0026nbsp;Case and control definitions\u003c/em\u003e) in the analysis.\u003c/p\u003e\n\u003cp\u003eWe further tried to evaluate if the effect of serum\u0026nbsp;\u003cem\u003eP. gingivalis\u0026nbsp;\u003c/em\u003eIgG level on AMD risk varies by the status of\u0026nbsp;modifiable risk factors for AMD, including\u0026nbsp;smoking status (ever smokers vs. non-smokers), BMI (\u0026ge;25\u0026nbsp;vs. \u0026lt;25 or\u0026nbsp;\u0026ge;28\u0026nbsp;vs. \u0026lt;28 or\u0026nbsp;\u0026ge;30\u0026nbsp;vs. \u0026lt;30\u0026nbsp;Kg/m\u003csup\u003e2\u003c/sup\u003e), and serum levels (higher vs. lower than the median) of vitamin C (median=39 mmol/L), vitamin E (median=23.5 \u0026micro;mol/L), and\u0026nbsp;lutein/zeaxanthin (mediam=0.35 \u0026micro;mol/L).\u0026nbsp;The results indicated that the\u0026nbsp;\u003cem\u003eP. gingivalis\u003c/em\u003e-related AMD risk\u0026nbsp;significantly (\u003cem\u003eP\u003c/em\u003e for interaction\u0026lt;0.0001) varies by serum levels of\u0026nbsp;lutein/zeaxanthin (\u0026ge;0.35 \u0026micro;mol/L\u0026nbsp;vs. \u0026lt;0.35 \u0026micro;mol/L). Compared subjects in the low\u0026nbsp;serum level of\u0026nbsp;lutein/zeaxanthin with those in the high\u0026nbsp;serum level, there is an up to 35.4% (=(0.65-0.42)/0.65) higher risk of AMD for\u0026nbsp;serum\u0026nbsp;\u003cem\u003eP. gingivalis\u0026nbsp;\u003c/em\u003eIgG category 2\u0026nbsp;(58\u0026ndash;65 EU), 32.5% (=(0.80-0.54)/0.80) for category 3, and 26% (=(1-0.74)/1) for category 4\u0026nbsp;(Figure 1). In other words, higher serum\u0026nbsp;lutein/zeaxanthin levels were protective against\u0026nbsp;\u003cem\u003eP. gingivalis\u003c/em\u003e-related AMD risk.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eTraditionally, microbiology in the context of human health primarily concentrated on local effects. However, our study has revealed a notable shift in perspective, demonstrating a positive association between the serum signature of\u0026nbsp;\u003cem\u003eP. gingivalis\u0026nbsp;\u003c/em\u003eand the risk of AMD. This contributes to the growing body of evidence suggesting that the microbiome within the human body can exert influences on distant tissues and organs. Additionally, aligning with the notion that the microbiome composition is significantly shaped by host\u0026apos;s diet, our findings indicate that elevated serum levels of lutein/zeaxanthin offer a protective effect against the\u0026nbsp;\u003cem\u003eP. gingivalis\u003c/em\u003e-related AMD risk.\u003c/p\u003e\n\u003cp\u003eTo date, only few studies have been published that explores the correlation between periodontitis and AMD \u003csup\u003e23-25\u003c/sup\u003e. Although pooled analysis suggested that periodontitis patients may have a higher risk of AMD \u003csup\u003e23,24\u003c/sup\u003e, bias assessment and power analysis indicated that the association remains debatable \u003csup\u003e25\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eAs part of the cross-sectional Finnish national population-based Health 2000 Survey \u003csup\u003e26\u003c/sup\u003e, 1751 individuals aged 30 years or older were included in the study, consisting of\u0026nbsp;54 individuals with degenerative fundus changes (AMD group) and 1,697 individuals free of AMD (non-AMD group). In their univariate analysis comparing the AMD group with the non-AMD group, Karesvuo et al. identified a significant difference in the proportion of individuals with alveolar bone loss among males and a significant difference in the number of teeth among females. However, likely due to insufficient case numbers and control selection, no significant difference was found between the AMD group and the non-AMD group in terms of the proportion of carriage of salivary periodontopathic bacteria, including \u003cem\u003eP. gingivalis\u003c/em\u003e. Following multivariate adjustment for various factors such as age, diabetic status, systolic blood pressure, education, smoking, and the carriage of salivary bacteria, only alveolar bone loss remained significantly associated with the risk of AMD among males.\u003c/p\u003e\n\u003cp\u003eWhile previous research has proposed infection as a potential risk factor for AMD \u003csup\u003e27\u003c/sup\u003e, and \u003cem\u003eP. gingivalis\u0026nbsp;\u003c/em\u003ehas been linked to various human neurodegenerative disorders \u003csup\u003e13,14\u003c/sup\u003e, our study is the first to establish a significant relationship between \u003cem\u003eP. gingivalis\u0026nbsp;\u003c/em\u003eand AMD. Notably, \u003cem\u003eP. gingivalis\u0026nbsp;\u003c/em\u003eis not limited to the oral cavity, as it also inhabits other sites within the human body. The ubiquitously expressed transglutaminase 2 (TG2) plays a crucial role in \u003cem\u003eP. gingivalis\u003c/em\u003e adherence to host cells \u003csup\u003e6\u003c/sup\u003e, with periodontitis being its sole known clinical manifestation in situ. Furthermore, \u003cem\u003eP. gingivalis\u0026nbsp;\u003c/em\u003eacts as a catalyst in periodontopathic microbiome, and the serum \u003cem\u003eP. gingivalis\u0026nbsp;\u003c/em\u003eIgG level has been demonstrated to closely correlate with the severity of periodontitis \u003csup\u003e7,22\u003c/sup\u003e. As a result, the serum\u0026nbsp;\u003cem\u003eP. gingivalis\u0026nbsp;\u003c/em\u003eIgG level can function as a surrogate marker for the activity level of periodontopathic microbiome\u0026nbsp;in the oral cavity\u0026nbsp;\u003csup\u003e4\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eIn contrast to most pathogenic bacteria that typically induce severe inflammation and outcompete native bacteria, \u003cem\u003eP. gingivalis\u0026nbsp;\u003c/em\u003eestablishes colonization at low levels and functions as a \u0026quot;catalyst\u0026quot; to foster a pathogenic microbiome (pathobionts). Studies in a murine periodontal model have demonstrated that even at low numbers, the introduction of \u003cem\u003eP. gingivalis\u0026nbsp;\u003c/em\u003einto the oral microbiome community significantly accelerates pathological alveolar bone loss \u003csup\u003e28\u003c/sup\u003e. However, since \u003cem\u003eP. gingivalis\u0026nbsp;\u003c/em\u003ealone fails to induce periodontitis, the hypothesis arises that \u003cem\u003eP. gingivalis\u0026nbsp;\u003c/em\u003eexerts its bone-destructive role in collaboration with other dysbiotic bacteria. Mechanistic investigations indicate that \u003cem\u003eP. gingivalis\u0026nbsp;\u003c/em\u003ecolonization in the oral cavity disrupts the host immune system and induces changes in the quantity and composition of the oral commensal microbiome. This occurs through the secretion of gingipain, a complement component 5 (C5) convertase-like enzyme. Gingipain generates elevated levels of locally active C5a, leading to C5aR activation, triggering inflammation while simultaneously inhibiting the killing capacity of leukocytes and suppressing the expression of chemokines. Studies further highlight the significance of the complement pathway in \u003cem\u003eP. gingivalis\u003c/em\u003e-related pathogenesis, proposing the targeting of C3 as a potential treatment strategy for periodontitis \u003csup\u003e29\u003c/sup\u003e. Interestingly, it is well-documented that the activation of C3 and the generation of excessive quantities of C5a and C5b-C9 play a significant role in the pathogenesis of AMD \u003csup\u003e30\u003c/sup\u003e. While it has been established that the inflammatory and immune response triggered by \u003cem\u003eP. gingivalis\u0026nbsp;\u003c/em\u003ehas both local and systemic effects \u003csup\u003e4,9-12\u003c/sup\u003e, the impact of gingipain, C5 activation, and the dysbiotic microbiome induced by \u003cem\u003eP. gingivalis\u0026nbsp;\u003c/em\u003eon the retina is yet to be determined.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIf an established etiological relationship between \u003cem\u003eP. gingivalis\u0026nbsp;\u003c/em\u003eand AMD is confirmed, AMD could join the ranks of diseases\u0026mdash;such as obesity, metabolic disorders, and inflammatory bowel diseases\u0026mdash;that have been shown to be transmittable through the transfer of dysbiotic microbiome\u0026nbsp;\u003csup\u003e31\u003c/sup\u003e. In such a scenario, the management of \u003cem\u003eP. gingivalis\u003c/em\u003e-related AMD risk could involve the elimination of \u003cem\u003eP. gingivalis\u0026nbsp;\u003c/em\u003efrom the oral cavity. However, it is worth noting that the composition of the microbiome\u0026nbsp;is highly susceptible to changes influenced by the host microenvironment and diet\u0026nbsp;\u003csup\u003e32\u003c/sup\u003e. Our analysis (Figure 1) also suggests that maintaining a higher serum level of lutein/zeaxanthin (\u0026ge;0.35 \u0026micro;mol/L or \u0026ge;20 \u0026micro;g/dL), possibly through a healthy diet or the use of the Age-Related Eye Disease Study 2 (AREDS2) supplement\u0026nbsp;\u003csup\u003e33-36\u003c/sup\u003e, could help modulate the \u003cem\u003eP. gingivalis\u003c/em\u003e-related AMD risk. Although studies have demonstrated that lower serum levels of various carotenoids, including zeaxanthin, increase the risk of periodontitis\u0026nbsp;\u003csup\u003e37\u003c/sup\u003e, and supplemental lutein/zeaxanthin has been shown to be protective against AMD\u0026nbsp;\u003csup\u003e36\u003c/sup\u003e, it remains to be determined if lutein/zeaxanthin has a direct impact on the \u003cem\u003eP. gingivalis\u003c/em\u003e-driven microbiome.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis study boasts several strengths, including its design as a matched case-control study within a representative cohort of the US population. The standardized collection of risk factor information and the use of photographic grading for maculopathy are additional strengths, aiming to minimize the impact of confounding factors and misclassifications. However, it is important to acknowledge certain limitations. The restricted number of AMD cases in our study resulted in insufficient sample sizes for certain analyses. For instance, in our interaction analyses, we only had a sufficient sample size to assess the relationship with serum levels of lutein/zeaxanthin. The cross-sectional nature of the study also poses a limitation in terms of defining temporality. Nevertheless, it\u0026apos;s worth noting that serum \u003cem\u003eP. gingivalis\u0026nbsp;\u003c/em\u003eIgG is considered to reflect chronic, intermittent exposure \u003csup\u003e14\u003c/sup\u003e, and the average age of onset for periodontitis is notably younger than that for AMD \u003csup\u003e2\u003c/sup\u003e. Additionally, serum levels of lutein/zeaxanthin are considered to reflect the long-term intake of these nutrients \u003csup\u003e36\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn conclusion, our study has unveiled a novel association between exposure to \u003cem\u003eP. gingivalis\u003c/em\u003e, serum lutein/zeaxanthin levels, and the risk for AMD. Although the intricate mechanisms underlying this relationship require further investigation, our findings have the potential to significantly influence therapeutic and preventive strategies for AMD. This is particularly noteworthy given the high prevalence of \u003cem\u003eP. gingivalis\u0026nbsp;\u003c/em\u003ein the human population.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eC-J. Chiu, contributed to conception, design, data acquisition, analysis, and interpretation, drafted the manuscript, and critically revised the manuscript; E. Chiu, M-L. Chang contributed to data analysis and interpretation, critically revised the manuscript; All authors gave final approval and agree to be accountable for all aspects of the work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFinancial support for this project has been provided by the RO1EY021826 and R21EY028209 from the National Institutes of Health.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of Conflicting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe funding sources had no role in the design and conduct of the study; the collection, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript. No authors declare a conflict of interest.\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eS\u003c/strong\u003e\u003cstrong\u003eharing\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eS\u003c/strong\u003e\u003cstrong\u003etatement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data used in this study is freely available for download by the public at: https://wwwn.cdc.gov/nchs/nhanes/nhanes3/default.aspx.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eDarveau, R. P. Periodontitis: a polymicrobial disruption of host homeostasis. \u003cem\u003eNat Rev Microbiol. \u003c/em\u003e\u003cstrong\u003e8\u003c/strong\u003e, 481-490. (2010).\u003c/li\u003e\n\u003cli\u003eBurt, B. \u0026amp; Research Science and Therapy Committee of the American Academy of Periodontology. Position paper: epidemiology of periodontal diseases. \u003cem\u003eJ Periodontol. \u003c/em\u003e\u003cstrong\u003e76\u003c/strong\u003e, 1406-1419. (2005).\u003c/li\u003e\n\u003cli\u003eChapple, I. L. Time to take periodontitis seriously. \u003cem\u003eBMJ.\u003c/em\u003e \u003cstrong\u003e348\u003c/strong\u003e, :g2645. (2014).\u003c/li\u003e\n\u003cli\u003ePussinen, P. J.\u003cem\u003e et al.\u003c/em\u003e Periodontal pathogen carriage, rather than periodontitis, determines the serum antibody levels. \u003cem\u003eJ Clin Periodontol.\u003c/em\u003e \u003cstrong\u003e38\u003c/strong\u003e, 405-411. (2011).\u003c/li\u003e\n\u003cli\u003eHajishengallis, G., Darveau, R. P. \u0026amp; Curtis, M. A. The keystone-pathogen hypothesis. \u003cem\u003eNature reviews. Microbiology\u003c/em\u003e \u003cstrong\u003e10\u003c/strong\u003e, 717-725, doi:10.1038/nrmicro2873 (2012).\u003c/li\u003e\n\u003cli\u003eBoisvert, H., Lorand, L. \u0026amp; Duncan, M. J. Transglutaminase 2 is essential for adherence of Porphyromonas gingivalis to host cells. \u003cem\u003eProc Natl Acad Sci U S A.\u003c/em\u003e \u003cstrong\u003e111\u003c/strong\u003e, 5355-5360. (2014 ).\u003c/li\u003e\n\u003cli\u003eHonda, K. Porphyromonas gingivalis sinks teeth into the oral microbiota and periodontal disease. \u003cem\u003eCell Host Microbe. \u003c/em\u003e\u003cstrong\u003e10\u003c/strong\u003e, 423-425. (2011).\u003c/li\u003e\n\u003cli\u003eKamer, A. R.\u003cem\u003e et al.\u003c/em\u003e Inflammation and Alzheimer\u0026apos;s disease: possible role of periodontal diseases. \u003cem\u003eAlzheimers Dement. \u003c/em\u003e\u003cstrong\u003e4\u003c/strong\u003e, 242-250. (2008 ).\u003c/li\u003e\n\u003cli\u003eRosenstein, E. D., Greenwald, R. A., Kushner, L. J. \u0026amp; Weissmann, G. Hypothesis: the humoral immune response to oral bacteria provides a stimulus for the development of rheumatoid arthritis. \u003cem\u003eInflammation. \u003c/em\u003e\u003cstrong\u003e28\u003c/strong\u003e, 311-318. (2004).\u003c/li\u003e\n\u003cli\u003eKozarov, E. V., Dorn, B. R., Shelburne, C. E., Dunn, W. A. J. \u0026amp; Progulske-Fox, A. Human atherosclerotic plaque contains viable invasive Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis. \u003cem\u003eArterioscler Thromb Vasc Biol.\u003c/em\u003e \u003cstrong\u003e25\u003c/strong\u003e, e17-18. (2005).\u003c/li\u003e\n\u003cli\u003eGenco, R., Offenbacher, S. \u0026amp; Beck, J. Periodontal disease and cardiovascular disease: epidemiology and possible mechanisms. \u003cem\u003eJ Am Dent Assoc.\u003c/em\u003e \u003cstrong\u003e133\u003c/strong\u003e, 14S-22S. (2002).\u003c/li\u003e\n\u003cli\u003eChapple, I. L., Genco, R. \u0026amp; working group 2 of the joint EFP/AAP workshop. Diabetes and periodontal diseases: consensus report of the Joint EFP/AAP Workshop on Periodontitis and Systemic Diseases. \u003cem\u003eJ Periodontol.\u003c/em\u003e \u003cstrong\u003e84\u003c/strong\u003e, S106-112. (2013).\u003c/li\u003e\n\u003cli\u003eSparks Stein, P.\u003cem\u003e et al.\u003c/em\u003e Serum antibodies to periodontal pathogens are a risk factor for Alzheimer\u0026apos;s disease. \u003cem\u003eAlzheimers Dement.\u003c/em\u003e \u003cstrong\u003e8\u003c/strong\u003e, 196-203. (2012).\u003c/li\u003e\n\u003cli\u003eNoble, J. M.\u003cem\u003e et al.\u003c/em\u003e Periodontitis is associated with cognitive impairment among older adults: analysis of NHANES-III. \u003cem\u003eJ Neurol Neurosurg Psychiatry.\u003c/em\u003e \u003cstrong\u003e80\u003c/strong\u003e, 1206-1211. (2009).\u003c/li\u003e\n\u003cli\u003eChiu, C. J., Chang, M. L. \u0026amp; Taylor, A. Associations between Periodontal Microbiota and Death Rates. \u003cem\u003eSci Rep.\u003c/em\u003e \u003cstrong\u003e6\u003c/strong\u003e, 35428, doi:doi: 10.1038/srep35428. (2016).\u003c/li\u003e\n\u003cli\u003eChiu, C. J., Chang, M. L., Kantarci, A., Van Dyke, T. E. \u0026amp; Shi, W. Exposure to Porphyromonas gingivalis and Modifiable Risk Factors Modulate Risk for Early Diabetic Retinopathy. \u003cem\u003eTranslational vision science \u0026amp; technology\u003c/em\u003e \u003cstrong\u003e10\u003c/strong\u003e, 23, doi:10.1167/tvst.10.2.23 (2021).\u003c/li\u003e\n\u003cli\u003eCongdon, N.\u003cem\u003e et al.\u003c/em\u003e Causes and prevalence of visual impairment among adults in the United States. \u003cem\u003eArch Ophthalmol\u003c/em\u003e \u003cstrong\u003e122\u003c/strong\u003e, 477-485 (2004).\u003c/li\u003e\n\u003cli\u003eChiu, C. J. \u0026amp; Taylor, A. Dietary hyperglycemia, glycemic index and metabolic retinal diseases. \u003cem\u003eProg Retin Eye Res.\u003c/em\u003e \u003cstrong\u003e30\u003c/strong\u003e, 18-53. (2011).\u003c/li\u003e\n\u003cli\u003eDye, B. A., Choudhary, K., Shea, S. \u0026amp; Papapanou, P. N. Serum antibodies to periodontal pathogens and markers of systemic inflammation. \u003cem\u003eJ Clin Periodontol.\u003c/em\u003e \u003cstrong\u003e32\u003c/strong\u003e, 1189-1199. (2005).\u003c/li\u003e\n\u003cli\u003eKlein, R.\u003cem\u003e et al.\u003c/em\u003e The Wisconsin age-related maculopathy grading system. \u003cem\u003eOphthalmology\u003c/em\u003e \u003cstrong\u003e98\u003c/strong\u003e, 1128-1134 (1991).\u003c/li\u003e\n\u003cli\u003eKlein, R.\u003cem\u003e et al.\u003c/em\u003e Age-related maculopathy in a multiracial United States population: the National Health and Nutrition Examination Survey III. \u003cem\u003eOphthalmology.\u003c/em\u003e \u003cstrong\u003e106\u003c/strong\u003e, 1056-1065. (1999).\u003c/li\u003e\n\u003cli\u003eOffenbacher, S.\u003cem\u003e et al.\u003c/em\u003e Periodontal disease at the biofilm-gingival interface. \u003cem\u003eJ Periodontol. \u003c/em\u003e\u003cstrong\u003e78\u003c/strong\u003e, 1911-1925. (2007 ).\u003c/li\u003e\n\u003cli\u003ePockpa, Z. A. D.\u003cem\u003e et al.\u003c/em\u003e Periodontal Diseases and Age-Related Macular Degeneration: Is There a Link? A Review. \u003cem\u003eThe Permanente journal\u003c/em\u003e \u003cstrong\u003e23\u003c/strong\u003e, doi:10.7812/tpp/18.260 (2019).\u003c/li\u003e\n\u003cli\u003eLv, X., Li, W., Fang, Z., Xue, X. \u0026amp; Pan, C. Periodontal Disease and Age-Related Macular Degeneration: A Meta-Analysis of 112,240 Participants. \u003cem\u003eBioMed research international\u003c/em\u003e \u003cstrong\u003e2020\u003c/strong\u003e, 4753645, doi:10.1155/2020/4753645 (2020).\u003c/li\u003e\n\u003cli\u003eJaved, F., Sculean, A. \u0026amp; Romanos, G. E. Association between age-related macular degeneration and periodontal and peri-implant diseases: a systematic review. \u003cem\u003eActa Ophthalmol\u003c/em\u003e \u003cstrong\u003e99\u003c/strong\u003e, 351-356, doi:10.1111/aos.14629 (2021).\u003c/li\u003e\n\u003cli\u003eKaresvuo, P.\u003cem\u003e et al.\u003c/em\u003e Alveolar bone loss associated with age-related macular degeneration in males. \u003cem\u003eJ Periodontol. \u003c/em\u003e\u003cstrong\u003e84\u003c/strong\u003e, 58-67. (2013).\u003c/li\u003e\n\u003cli\u003eBarouch, F. C. \u0026amp; Miller, J. W. The role of inflammation and infection in age-related macular degeneration. . \u003cem\u003eInt Ophthalmol Clin \u003c/em\u003e\u003cstrong\u003e47\u003c/strong\u003e, 185-197. (2007).\u003c/li\u003e\n\u003cli\u003eHajishengallis, G.\u003cem\u003e et al.\u003c/em\u003e Low-abundance biofilm species orchestrates inflammatory periodontal disease through the commensal microbiota and complement. \u003cem\u003eCell Host Microbe.\u003c/em\u003e \u003cstrong\u003e10\u003c/strong\u003e, 497-506. (2011).\u003c/li\u003e\n\u003cli\u003eMaekawa, T.\u003cem\u003e et al.\u003c/em\u003e Genetic and Intervention Studies Implicating Complement C3 as a Major Target for the Treatment of Periodontitis. \u003cem\u003eJ Immunol. \u003c/em\u003e\u003cstrong\u003e192\u003c/strong\u003e, 6020-6027. (2014).\u003c/li\u003e\n\u003cli\u003eAmbati, J., Atkinson, J. P. \u0026amp; Gelfand, B. D. Immunology of age-related macular degeneration. \u003cem\u003eNat Rev Immunol. \u003c/em\u003e\u003cstrong\u003e13\u003c/strong\u003e, 438-451. (2013).\u003c/li\u003e\n\u003cli\u003eGarrett, W. S., Gordon, J. I. \u0026amp; Glimcher, L. H. Homeostasis and inflammation in the intestine. \u003cem\u003eCell. \u003c/em\u003e\u003cstrong\u003e140\u003c/strong\u003e, 859-870. (2010).\u003c/li\u003e\n\u003cli\u003eZhang, C.\u003cem\u003e et al.\u003c/em\u003e Interactions between gut microbiota, host genetics and diet relevant to development of metabolic syndromes in mice. \u003cem\u003eISME J. \u003c/em\u003e\u003cstrong\u003e4\u003c/strong\u003e, 232-241. (2010).\u003c/li\u003e\n\u003cli\u003eChiu, C. J., Klein, R., Milton, R. C., Gensler, G. \u0026amp; Taylor, A. Does eating particular diets alter risk of age-related macular degeneration in users of the Age-Related Eye Disease Study supplements? \u003cem\u003eBr J Ophthalmol. \u003c/em\u003e\u003cstrong\u003e93\u003c/strong\u003e, 1241-1246. (2009).\u003c/li\u003e\n\u003cli\u003eChiu, C. J., Milton, R. C., Klein, R., Gensler, G. \u0026amp; Taylor, A. Dietary compound score and risk of age-related macular degeneration in the Age-Related Eye Disease Study. \u003cem\u003eOphthalmology. \u003c/em\u003e\u003cstrong\u003e116\u003c/strong\u003e, 939-946. (2009).\u003c/li\u003e\n\u003cli\u003eChiu, C. J.\u003cem\u003e et al.\u003c/em\u003e The Relationship of Major American Dietary Patterns to Age-related Macular Degeneration. \u003cem\u003eAm J Ophthalmol. \u003c/em\u003e\u003cstrong\u003e158\u003c/strong\u003e, 118-127. (2014).\u003c/li\u003e\n\u003cli\u003eAge-Related Eye Disease Study 2 Research Group. Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. \u003cem\u003eJAMA. \u003c/em\u003e\u003cstrong\u003e309\u003c/strong\u003e, 2005-2015. (2013).\u003c/li\u003e\n\u003cli\u003eLinden, G. J.\u003cem\u003e et al.\u003c/em\u003e Antioxidants and periodontitis in 60-70-year-old men. \u003cem\u003eJ Clin Periodontol. \u003c/em\u003e\u003cstrong\u003e36\u003c/strong\u003e, 843-849. (2009).\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1.\u003c/strong\u003e Comparisons in characteristics distributions between cases and frequency-matched controls in age, sex, and race.\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eControls\u003c/strong\u003e\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCases\u003c/strong\u003e\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;value\u003c/strong\u003e\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eN=174\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eN=174\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge yrs (Mean (SEM))\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15px;\"\u003e\n \u003cp\u003e68.1 (0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15px;\"\u003e\n \u003cp\u003e69.3 (0.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12px;\"\u003e\n \u003cp\u003e0.30\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMale (N (%))\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15px;\"\u003e\n \u003cp\u003e67 (46.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15px;\"\u003e\n \u003cp\u003e67 (42.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12px;\"\u003e\n \u003cp\u003e0.09\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRace (N (%))\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; \u0026nbsp;Non-Hispanic white\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15px;\"\u003e\n \u003cp\u003e108 (92.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15px;\"\u003e\n \u003cp\u003e108 (90.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"bottom\" style=\"width: 12px;\"\u003e\n \u003cp\u003e0.17\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; \u0026nbsp;Non-Hispanic black\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15px;\"\u003e\n \u003cp\u003e27 (5.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15px;\"\u003e\n \u003cp\u003e27 (6.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; \u0026nbsp;Mexican-American\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15px;\"\u003e\n \u003cp\u003e39 (2.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15px;\"\u003e\n \u003cp\u003e39 (3.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBMI Kg/m\u003csup\u003e2\u003c/sup\u003e (Mean (SEM))\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15px;\"\u003e\n \u003cp\u003e26.7 (0.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15px;\"\u003e\n \u003cp\u003e27.8 (0.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12px;\"\u003e\n \u003cp\u003e0.22\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEducation (N (%))\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; \u0026nbsp;\u0026lt;12 yrs\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e90 (29.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e90 (32.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"bottom\" style=\"width: 12px;\"\u003e\n \u003cp\u003e0.32\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; \u0026nbsp;12 yrs\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e48 (37.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e44 (32.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; \u0026nbsp;\u0026gt;12 yrs\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e36 (32.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e40 (34.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSmoking history (N (%))\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; \u0026nbsp;Non-smokers\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e95 (52.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e95 (51.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"bottom\" style=\"width: 12px;\"\u003e\n \u003cp\u003e0.96\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; \u0026nbsp;Former smokers\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e50 (38.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e57 (39.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; \u0026nbsp;Active smokers\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e29 (9.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e22 (9.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAt least 12 drinks in the past 12 months\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e\u003cem\u003eNo\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e119 (61.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e120 (60.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e0.58\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e\u003cem\u003eYes\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e55 (38.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e54 (39.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSerum CRP level mg/dL (Mean (SEM))\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0.4 (0.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0.5 (0.004)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e0.45\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSerum vitamin C \u0026nbsp;mmol/L (Mean (SEM))\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15px;\"\u003e\n \u003cp\u003e56.8 (0.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15px;\"\u003e\n \u003cp\u003e52.1 (0.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e0.28\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSerum vitamin E \u0026nbsp;\u0026micro;mol/L (Mean (SEM))\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15px;\"\u003e\n \u003cp\u003e31.9 (0.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15px;\"\u003e\n \u003cp\u003e33.9 (0.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e0.28\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSerum lutein/ zeaxanthin \u0026nbsp;\u0026micro;mol/L (Mean (SEM))\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0.5 (0.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0.4 (0.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e0.19\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ePorphyromonas gingivalis\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003eIgG EU\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; \u0026nbsp;\u0026le;57 EU \u0026nbsp; \u0026nbsp; (N (%))\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e10 (8.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e12 (5.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" valign=\"bottom\" style=\"width: 12px;\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; \u0026nbsp;58-65 EU \u0026nbsp; \u0026nbsp; (N (%))\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e34 (21.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e25 (18.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; \u0026nbsp;66-119 EU \u0026nbsp; \u0026nbsp; (N (%))\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e95 (58.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e95 (57.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 56px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp; \u0026nbsp;\u0026gt;119 EU \u0026nbsp; \u0026nbsp; (N (%))\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e35 (12.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e42 (18.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003csup\u003ea\u0026nbsp;\u003c/sup\u003eFor categorical variables, sample sizes (N) are raw numbers while the percentages (%) are weighted for the sampling design used in the Third National Health and Nutrition Examination Survey (NHANES-III).\u003c/p\u003e\n\u003cp\u003e\u003csup\u003eb\u0026nbsp;\u003c/sup\u003eAnalysis of variance (\u003cem\u003eANOVA\u003c/em\u003e) was used for statistical tests of significance for continuous variables while Wald chi-squared test was used for all other categorical measures.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAbbreviation: BMI, body mass index; CRP, C reactive protein; IgG, immunoglobulin G\u003cem\u003e; EU,\u0026nbsp;\u003c/em\u003eenzyme-linked immunosorbent assay\u0026nbsp;\u003cem\u003eunit\u003c/em\u003e; SEM, standard error.\u003cbr\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2.\u003c/strong\u003e Bivariate associations between serum \u003cem\u003ePorphyromonas gingivalis\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/em\u003eimmunoglobulin G concentrations and covariates.\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eContinuous covariates\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eN\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSpearman correlation coefficient with \u003cem\u003eP. gingivalis\u0026nbsp;\u003c/em\u003eIgG (EU)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge yrs\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e348\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003e-0.145\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e0.007\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBMI Kg/m\u003csup\u003e2\u003c/sup\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e348\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003e0.068\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e0.21\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSerum CRP level mg/dL\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e348\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003e0.081\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e0.13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSerum vitamin C \u0026nbsp;mmol/L\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e348\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003e-0.153\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSerum vitamin E \u0026nbsp;\u0026micro;mol/L\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e348\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003e0.154\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSerum lutein/zeaxanthin \u0026nbsp;\u0026micro;mol/L\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e348\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003e0.006\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e0.91\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCategorical covariates\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eN\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP. gingivalis\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003eIgG (EU), median [IQR]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;value\u003c/strong\u003e\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSex\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 237px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMale\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 51px;\"\u003e\n \u003cp\u003e134\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 237px;\"\u003e\n \u003cp\u003e80 [66-107]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 79px;\"\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFemale\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 51px;\"\u003e\n \u003cp\u003e214\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 237px;\"\u003e\n \u003cp\u003e70 [64-95]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRace\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 237px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp; \u0026nbsp;Non-Hispanic white\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 51px;\"\u003e\n \u003cp\u003e216\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 237px;\"\u003e\n \u003cp\u003e73 [64-93]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp; \u0026nbsp;Non-Hispanic black\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 51px;\"\u003e\n \u003cp\u003e54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 237px;\"\u003e\n \u003cp\u003e102 [76-219]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp; \u0026nbsp;Mexican-American\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 51px;\"\u003e\n \u003cp\u003e78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 237px;\"\u003e\n \u003cp\u003e100 [78-174]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEducation\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 237px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp; \u0026nbsp;\u0026lt;12 yrs\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 51px;\"\u003e\n \u003cp\u003e180\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 237px;\"\u003e\n \u003cp\u003e76 [65-114]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 79px;\"\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp; \u0026nbsp;12 yrs\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 51px;\"\u003e\n \u003cp\u003e92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 237px;\"\u003e\n \u003cp\u003e74 [65-87]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp; \u0026nbsp;\u0026gt;12 yrs\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 51px;\"\u003e\n \u003cp\u003e76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 237px;\"\u003e\n \u003cp\u003e72 [64-91]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSmoking history\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp; \u0026nbsp;Non-smokers\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 51px;\"\u003e\n \u003cp\u003e190\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 237px;\"\u003e\n \u003cp\u003e69 [64-96]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 79px;\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp; \u0026nbsp;Former smokers\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 51px;\"\u003e\n \u003cp\u003e107\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 237px;\"\u003e\n \u003cp\u003e82 [68-109]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp; \u0026nbsp;Active smokers\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 51px;\"\u003e\n \u003cp\u003e51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 237px;\"\u003e\n \u003cp\u003e70 [67-82]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAt least 12 drinks in the past 12 months\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 237px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eNo\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 51px;\"\u003e\n \u003cp\u003e239\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 237px;\"\u003e\n \u003cp\u003e74 [66-95]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 79px;\"\u003e\n \u003cp\u003e0.51\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eYes\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 51px;\"\u003e\n \u003cp\u003e109\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 237px;\"\u003e\n \u003cp\u003e73 [64-109]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ePorphyromonas gingivalis\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003eIgG category\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 51px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 237px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp; \u0026nbsp;\u0026le;57 EU\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 51px;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 237px;\"\u003e\n \u003cp\u003e57 [56-57]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp; \u0026nbsp;58-65 EU\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 51px;\"\u003e\n \u003cp\u003e59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 237px;\"\u003e\n \u003cp\u003e62 [61-64]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp; \u0026nbsp;66-119 EU\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 51px;\"\u003e\n \u003cp\u003e190\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 237px;\"\u003e\n \u003cp\u003e77 [70-91]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp; \u0026nbsp;\u0026gt;119 EU \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 51px;\"\u003e\n \u003cp\u003e77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 237px;\"\u003e\n \u003cp\u003e193 [151-449]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003csup\u003ea\u0026nbsp;\u003c/sup\u003eP-values were obtained by Mann-Whitney test for variables with 2 categories, and from Kruskal-Wallis test for variables with 3 or more categories.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAbbreviation: BMI, body mass index; CRP, C reactive protein; IgG, immunoglobulin G\u003cem\u003e; EU,\u0026nbsp;\u003c/em\u003eenzyme-linked immunosorbent assay \u003cem\u003eunit\u003c/em\u003e; IQR, inter quartile range.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3.\u0026nbsp;\u003c/strong\u003eLogistic analysis relating serum \u003cem\u003ePorphyromonas gingivalis\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/em\u003eimmunoglobulin G levels to risk for age-related macular degeneration.\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"105%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSerum \u003cem\u003eP. gingivalis\u0026nbsp;\u003c/em\u003eIgG level (EU)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"5\" valign=\"top\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAdjusted OR (95% CI)\u003c/strong\u003e\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eModel 1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eModel 2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eModel 3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eModel 4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eModel 5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026le;57 (referent)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e58\u0026ndash;65\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e1.19 (1.05 to 1.35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e1.23 (1.07 to 1.41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e1.24 (1.07 to 1.43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e1.27 (1.16 to 1.38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e1.28 (1.17 to 1.40)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e66\u0026ndash;118\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e1.44 (1.31 to 1.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e1.48 (1.27 to 1.73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e1.51 (1.32 to 1.73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e1.55 (1.42 to 1.68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e1.58 (1.46 to 1.72)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026gt;119\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e2.02 (1.66 to 2.46)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e2.07 (1.67 to 2.55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e2.03 (1.52 to 2.72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e2.12 (1.68 to 2.66)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e2.04 (1.62 to 2.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 20px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;for trend\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 15px;\"\u003e\n \u003cp\u003e0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 16px;\"\u003e\n \u003cp\u003e0.09\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003csup\u003ea\u0026nbsp;\u003c/sup\u003eModel 1: adjusted for age; Model 2: Model 1 additionally adjusted for sex, race, BMI and education; Model 3: Model 2 additionally adjusted for smoking history and alcohol intake; Model 4: Model 3 additionally adjusted for serum vitamin C, E, lutein/xeaxanthin, and CRP levels; Model 5: Model 4 additionally adjusted for two clinical periodontal measurements, mBOP and mCAL.\u003c/p\u003e\n\u003cp\u003eAbbreviation: OR, odds ratio; CI, confidence interval; CRP, C reactive protein; IgG, immunoglobulin G;\u003cem\u003e\u0026nbsp;EU,\u0026nbsp;\u003c/em\u003eenzyme-linked immunosorbent assay \u003cem\u003eunit;\u0026nbsp;\u003c/em\u003emBOP, mean number of tooth sites that bled on probing; mCAL, mean clinical attachment loss.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"microbiota, microbiome, periodontitis, Porphyromonas gingivalis, retina, age-related macular degeneration, epidemiology, risk factors, lutein, zeaxanthin, National Health and Nutrition Examination Survey (NHANES)","lastPublishedDoi":"10.21203/rs.3.rs-6188207/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6188207/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e \u003cem\u003ePorphyromonas gingivalis (P. gingivalis)\u003c/em\u003e functions as a catalyst bacterium in the development of periodontitis, and the serum antibody level against \u003cem\u003eP. gingivalis\u003c/em\u003e is considered a surrogate marker for the activity level of periodontopathic microbiome. The chronic systemic inflammation induced by \u003cem\u003eP. gingivalis\u003c/em\u003e elevates the risk of various systemic and neurodegenerative disorders, including atherosclerosis, diabetes, and Alzheimer\u0026rsquo;s disease. Although the connection between human microbiome and age-related macular degeneration (AMD) remains relatively unexplored, it is noteworthy that AMD shares risk factors and etiological mechanisms with diseases related to \u003cem\u003eP. gingivalis\u003c/em\u003e. To investigate the potential association between periodontopathic microbiome and AMD occurrence, we conducted a candidate microbe approach case-control study. Our hypothesis was tested by examining the correlation between serum \u003cem\u003eP. gingivalis\u003c/em\u003e immunoglobulin G (IgG) levels and AMD. Comparing the lowest IgG category (\u0026le;\u0026thinsp;57 enzyme-linked immunosorbent assay units (EU)) with higher categories revealed escalating risks: the second higher category (58\u0026ndash;65 EU) conferred almost a 30% increased risk (odds ratio (OR)\u0026thinsp;=\u0026thinsp;1.28, 95% confidence interval (CI): 1.17 to 1.4), the third higher category (66\u0026ndash;119 EU) conferred nearly a 60% increase (OR\u0026thinsp;=\u0026thinsp;1.58, 95% CI: 1.46 to 1.72), and the highest category (\u0026gt;\u0026thinsp;119 EU) conveyed over a two-fold risk (OR\u0026thinsp;=\u0026thinsp;2.04, 95% CI: 1.62 to 2.58) of early AMD. Aligning with the notion that the microbiome composition is significantly shaped by the host's diet, our analysis indicates that sustaining elevated serum levels of lutein/zeaxanthin (\u0026ge;\u0026thinsp;0.35 \u0026micro;mol/L or \u0026ge;\u0026thinsp;20 \u0026micro;g/dL) might potentially mitigate the \u003cem\u003eP. gingivalis\u003c/em\u003e-related AMD risk by as much as 35% (P for interaction\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). Although the precise mechanism requires additional exploration, these findings suggest a connection between nutrition and oral microbiome, emphasizing their collective role in maintaining eye health.\u003c/p\u003e","manuscriptTitle":"Interaction between Infection of Porphyromonas gingivalis, A Keystone Microbe of Oral Microbiome, and Serum Levels of Lutein/Zeaxanthin Is Associated with Risk for Age-related Macular Degeneration.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-06 13:21:52","doi":"10.21203/rs.3.rs-6188207/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-05-05T07:33:38+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-02T15:49:05+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"102010976106680899037271560860269247153","date":"2025-04-22T16:20:13+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"238206621773831114485250259163800462531","date":"2025-04-07T18:46:06+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-07T16:39:06+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"14240567421198333921478424376439350068","date":"2025-04-07T14:48:53+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"26565351283501801554657941313703046532","date":"2025-04-03T18:54:27+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-03-31T14:05:41+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-03-31T13:09:35+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-03-18T04:58:52+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-03-15T05:29:14+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-03-09T10:38:26+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b8b29a34-aa85-4608-b547-f716604086af","owner":[],"postedDate":"May 6th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":46811338,"name":"Health sciences/Risk factors"},{"id":46811339,"name":"Biological sciences/Microbiology/Biofilms"},{"id":46811340,"name":"Biological sciences/Microbiology/Communities"},{"id":46811341,"name":"Health sciences/Diseases/Eye diseases"},{"id":46811342,"name":"Health sciences/Diseases/Oral diseases"}],"tags":[],"updatedAt":"2025-11-17T16:06:01+00:00","versionOfRecord":{"articleIdentity":"rs-6188207","link":"https://doi.org/10.1038/s41598-025-14144-3","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2025-11-11 15:58:10","publishedOnDateReadable":"November 11th, 2025"},"versionCreatedAt":"2025-05-06 13:21:52","video":"","vorDoi":"10.1038/s41598-025-14144-3","vorDoiUrl":"https://doi.org/10.1038/s41598-025-14144-3","workflowStages":[]},"version":"v1","identity":"rs-6188207","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6188207","identity":"rs-6188207","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}