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Inflammation plays a central role in many diseases of aging, and genetic differences in the inflammatory response appear to influence different disease courses among individuals. Variations in the genes for the family of interleukin 1 (IL-1) proteins are inherited together in a small set of patterns and provide an example of the role of inflammatory genetics as a modifier of diseases of aging. The IL-1 genetic variations are associated with variation in both the inflammatory response and the clinical presentation of a range of diseases, including coronary artery disease, Alzheimer disease, gastric cancer, and periodontitis. This growing understanding of the role of genetic variation in inflammation and chronic disease presents opportunities to identify healthy persons who are at increased risk of disease and to potentially modify the trajectory of disease to prolong healthy aging. Nutrition represents one of the promising approaches to modulation of the risk of diseases of aging because of the effects of certain nutrients on gene expression. One of the most practical applications of nutritional modulation of chronic disease may be nutrients that regulate the expression of key inflammatory genes. [ABSTRACT FROM AUTHOR]

Focused Clinical Question: What are the fundamental debates and questions related to the newly developed two-vector system for classification of periodontal diseases that have emerged as to how to accurately assign, stage, and grade periodontitis cases? The aim of the present manuscript is to demonstrate the essential thought processes that are needed in utilizing the new periodontitis classification system to diagnose two gray zone cases., Summary: Clinical case 1 includes an 83-year-old male diagnosed with periodontitis and classified as Stage III Generalized Grade B periodontitis, while clinical case 2, a 73-year-old male was classified as presenting Stage IV Generalized Grade B periodontitis. Although clinical and radiographic evaluations revealed similarities between the cases, the thought process that includes clinical judgment is described to guide a more accurate diagnosis following the guidelines of the new classification system., Conclusion: The two cases demonstrated here offer an opportunity for clinicians to recognize the essential role of sound clinical judgment in certain cases when applying the new periodontal disease classification system and also clarify questions emerging from implementing this classification system., (© 2020 American Academy of Periodontology.)

Rationale: The endemic of peri-implantitis affects over 25% of dental implants. Current treatment depends on empirical patient and site-based stratifications and lacks a consistent risk grading system. Methods: We investigated a unique cohort of peri-implantitis patients undergoing regenerative therapy with comprehensive clinical, immune, and microbial profiling. We utilized a robust outlier-resistant machine learning algorithm for immune deconvolution. Results: Unsupervised clustering identified risk groups with distinct immune profiles, microbial colonization dynamics, and regenerative outcomes. Low-risk patients exhibited elevated M1/M2-like macrophage ratios and lower B-cell infiltration. The low-risk immune profile was characterized by enhanced complement signaling and higher levels of Th1 and Th17 cytokines. Fusobacterium nucleatum and Prevotella intermedia were significantly enriched in high-risk individuals. Although surgery reduced microbial burden at the peri-implant interface in all groups, only low-risk individuals exhibited suppression of keystone pathogen re-colonization. Conclusion: Peri-implant immune microenvironment shapes microbial composition and the course of regeneration. Immune signatures show untapped potential in improving the risk-grading for peri-implantitis., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Chronic inflammation has emerged as a key factor that contributes to some common chronic diseases and reduces lifespan. Studies have identified multiple types of chronic inflammation ranging from autoimmune disease, which attacks specific tissues, to autoinflammatory diseases, which cause low-grade systemic inflammation and contribute to several common chronic diseases. This article highlights new perspectives on the role of chronic inflammation in cardiovascular disease (CVD). Such information is being leveraged to develop new treatment strategies for CVD and may inform how periodontal disease influences CVD., (© 2020 American Academy of Periodontology.)

Background: Successful dissemination of the new classification of periodontitis is facilitated by emphasis on the basic ground rules, clarification of ambiguities, and identification of "gray zones" where thoughtful application of the guidelines by an informed, experienced clinician is paramount to arrive at a correct Stage and Grade., Methods: Highlighted ground rules are (1) Stage is a patient-based, not a tooth-based concept, therefore, a single Stage is assigned per patient; (2) Stage can shift upward over time, if the periodontal status deteriorates, but the initially assigned Stage is retained even after improvement post-therapy; (3) the complexity factors that determine Stage must be evaluated collectively, not in isolation, to arrive at a clinically meaningful assessment; (4) a single Grade is assigned to a patient based on a deliberate evaluation of the "biological fabric" of the case, in terms of history of/risk for further progression, interplay of risk factors, and the two-way effects of periodontitis or its treatment on general health; (v) shift of Grade over time is possible towards either direction, after thorough, collective, evaluation of changes in the above parameters. Exemplified gray zones include a radiographically intact patient with minimal attachment loss in older age; presence of "frank" periodontitis affecting a single tooth; and assessment of factors that do/do not lead to increased complexity of therapy., Conclusion: Differentiating between Stage I/II versus Stage III/IV periodontitis is relatively uncomplicated; further distinction between Stages and correct assignment of Grade requires nuanced, thorough interpretation of a broad array of findings by a knowledgeable clinician., (© 2019 American Academy of Periodontology.)

Biologically guided implant therapy is based on the new periodontitis classification system recently released by the American Academy of Periodontology and the European Federation of Periodontology that uses staging and grading for the diagnosis of periodontitis. This paper proposes that periodontitis staging and grading should be used in dental implant therapy as a means to ensure maximum conservation of teeth and maximum preservation of alveolar bone. These biologic principles should guide the treatment planning process and supersede a mechanically based, restoratively driven rationale that should be secondary to the biologic principles of conservation and preservation but part of the collaborative treatment planning process. And treatment alternatives throughout the patient's lifetime should be provided for in case of prosthesis loss due to peri-implantitis. The use of grading will help with recognition of systemic aspects that can have a negative impact., (© 2018 American Academy of Periodontology.)

Key breakthroughs in our understanding of the etiology and principles of predictable treatment of patients with chronic periodontitis first emerged in the late 1960s and carried on into the mid-1980s. Unfortunately, some generalizations of the evidence led many to believe that periodontitis was a predictable result of exposure to bacterial plaque accumulations over time. For a brief period, the initial plaque concept was translated by some to implicate specific bacterial infections, with both concepts (plaque exposure and specific infection) being false assumptions that led to clinical outcomes which were frustrating to both the clinician and the patient. The primary misconceptions were that every individual was equally susceptible to periodontitis, that disease severity was a simple function of magnitude of bacterial exposure over time, and that all patients would respond predictably if treated based on the key principles of bacterial reduction and regular maintenance care. We now know that although bacteria are an essential initiating factor, the clinical severity of periodontitis is a complex multifactorial host response to the microbial challenge. The complexity comes from the permutations of different factors that may interact to alter a single individual's host response to challenge, inflammation resolution and repair, and overall outcome to therapy. Fortunately, although there are many permutations that may influence host response and repair, the pathophysiology of chronic periodontitis is generally limited to mild periodontitis with isolated moderate disease in most individuals. However, approximately 20%-25% of individuals will develop generalized severe periodontitis and probably require more intensive bacterial reduction and different approaches to host modulation of the inflammatory outcomes. This latter group may also have serious systemic implications of their periodontitis. The time appears to be appropriate to use what we know and currently understand to change our approach to clinical care. Our goal would be to increase our likelihood of identifying those patients who have a more biologically disruptive response combined with a more impactful microbial dysbiosis. Current evidence, albeit limited, indicates that for those individuals we should prevent and treat more intensively. This paper discusses what we know and how we might use that information to start individualizing risk and treat some of our patients in a more targeted manner. In my opinion, we are further along than many realize, but we have a great lack of prospective clinical evidence that must be accumulated while we continue to unravel the contributions of specific mechanisms., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

A new periodontitis classification scheme has been adopted, in which forms of the disease previously recognized as "chronic" or "aggressive" are now grouped under a single category ("periodontitis") and are further characterized based on a multi-dimensional staging and grading system. Staging is largely dependent upon the severity of disease at presentation as well as on the complexity of disease management, while grading provides supplemental information about biological features of the disease including a history-based analysis of the rate of periodontitis progression; assessment of the risk for further progression; analysis of possible poor outcomes of treatment; and assessment of the risk that the disease or its treatment may negatively affect the general health of the patient. Necrotizing periodontal diseases, whose characteristic clinical phenotype includes typical features (papilla necrosis, bleeding, and pain) and are associated with host immune response impairments, remain a distinct periodontitis category. Endodontic-periodontal lesions, defined by a pathological communication between the pulpal and periodontal tissues at a given tooth, occur in either an acute or a chronic form, and are classified according to signs and symptoms that have direct impact on their prognosis and treatment. Periodontal abscesses are defined as acute lesions characterized by localized accumulation of pus within the gingival wall of the periodontal pocket/sulcus, rapid tissue destruction and are associated with risk for systemic dissemination., (© 2018 American Academy of Periodontology and European Federation of Periodontology.)

Background: Authors were assigned the task to develop case definitions for periodontitis in the context of the 2017 World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions. The aim of this manuscript is to review evidence and rationale for a revision of the current classification, to provide a framework for case definition that fully implicates state-of-the-art knowledge and can be adapted as new evidence emerges, and to suggest a case definition system that can be implemented in clinical practice, research and epidemiologic surveillance., Methods: Evidence gathered in four commissioned reviews was analyzed and interpreted with special emphasis to changes with regards to the understanding available prior to the 1999 classification. Authors analyzed case definition systems employed for a variety of chronic diseases and identified key criteria for a classification/case definition of periodontitis., Results: The manuscript discusses the merits of a periodontitis case definition system based on Staging and Grading and proposes a case definition framework. Stage I to IV of periodontitis is defined based on severity (primarily periodontal breakdown with reference to root length and periodontitis-associated tooth loss), complexity of management (pocket depth, infrabony defects, furcation involvement, tooth hypermobility, masticatory dysfunction) and additionally described as extent (localized or generalized). Grade of periodontitis is estimated with direct or indirect evidence of progression rate in three categories: slow, moderate and rapid progression (Grade A-C). Risk factor analysis is used as grade modifier., Conclusions: The paper describes a simple matrix based on stage and grade to appropriately define periodontitis in an individual patient. The proposed case definition extends beyond description based on severity to include characterization of biological features of the disease and represents a first step towards adoption of precision medicine concepts to the management of periodontitis. It also provides the necessary framework for introduction of biomarkers in diagnosis and prognosis., (© 2018 American Academy of Periodontology and European Federation of Periodontology.)

A classification scheme for periodontal and peri-implant diseases and conditions is necessary for clinicians to properly diagnose and treat patients as well as for scientists to investigate etiology, pathogenesis, natural history, and treatment of the diseases and conditions. This paper summarizes the proceedings of the World Workshop on the Classification of Periodontal and Peri-implant Diseases and Conditions. The workshop was co-sponsored by the American Academy of Periodontology (AAP) and the European Federation of Periodontology (EFP) and included expert participants from all over the world. Planning for the conference, which was held in Chicago on November 9 to 11, 2017, began in early 2015. An organizing committee from the AAP and EFP commissioned 19 review papers and four consensus reports covering relevant areas in periodontology and implant dentistry. The authors were charged with updating the 1999 classification of periodontal diseases and conditions and developing a similar scheme for peri-implant diseases and conditions. Reviewers and workgroups were also asked to establish pertinent case definitions and to provide diagnostic criteria to aid clinicians in the use of the new classification. All findings and recommendations of the workshop were agreed to by consensus. This introductory paper presents an overview for the new classification of periodontal and peri-implant diseases and conditions, along with a condensed scheme for each of four workgroup sections, but readers are directed to the pertinent consensus reports and review papers for a thorough discussion of the rationale, criteria, and interpretation of the proposed classification. Changes to the 1999 classification are highlighted and discussed. Although the intent of the workshop was to base classification on the strongest available scientific evidence, lower level evidence and expert opinion were inevitably used whenever sufficient research data were unavailable. The scope of this workshop was to align and update the classification scheme to the current understanding of periodontal and peri-implant diseases and conditions. This introductory overview presents the schematic tables for the new classification of periodontal and peri-implant diseases and conditions and briefly highlights changes made to the 1999 classification. It cannot present the wealth of information included in the reviews, case definition papers, and consensus reports that has guided the development of the new classification, and reference to the consensus and case definition papers is necessary to provide a thorough understanding of its use for either case management or scientific investigation. Therefore, it is strongly recommended that the reader use this overview as an introduction to these subjects. Accessing this publication online will allow the reader to use the links in this overview and the tables to view the source papers (Table )., (© 2018 American Academy of Periodontology and European Federation of Periodontology.)

Background: Lipoprotein(a) [Lp(a)] is a genetic risk factor for cardiovascular disease (CVD), and proinflammatory interleukin-1 (IL-1) genotypes may influence Lp(a)-mediated CVD events. The genotype IL-1(+) is associated with higher rates of inflammation than IL-1(-) genotype. Targeting IL-1β was recently shown to decrease CVD events independent of low-density lipoprotein-cholesterol levels., Objective: The objective of the study is to assess the modulatory effect of IL-1 genotypes on risk mediated by Lp(a) METHODS: We assessed whether IL-1 genotypes modulate the effect of Lp(a) on major adverse cardiovascular events (cardiovascular death, myocardial infarction, and stroke/transient ischemic attack) and angiographically determined coronary artery disease (CAD). IL-1 genotypes and Lp(a) were measured in 603 patients without diabetes mellitus undergoing angiography. Major adverse cardiovascular events and CAD were assessed over a median of 45 months., Results: In multivariable-adjusted analysis, Lp(a) was associated with major adverse cardiovascular events (hazard ratio [HR] [95% confidence interval {CI}]: 2.95 [1.16-7.54], P = .023) and CAD (odds ratio [OR] [95% CI]: 1.84 [1.12-3.03], P = .016) comparing quartile 4 vs quartile 1. In Cox regression analysis, IL-1(+) patients with Lp(a) above the median (>9.2 mg/dL) had a worse event-free cumulative survival (HR [95% CI]: 3.59 [1.07-12.03], P = .039) compared to IL-1(-) patients with Lp(a) below the median. In IL-1(+) patients aged ≤60 years, Lp(a) was also associated with angiographically determined CAD (OR [95% CI]: 2.90 [1.07-7.86], P = .036) comparing quartile 4 vs quartile 1 but not IL-1(-) patients., Conclusion: Proinflammatory IL-1(+) genotypes modulate the risk of Lp(a) long-term CVD events and CAD. These data suggest that the dual genetic contributions of elevated Lp(a) levels and IL-1(+) genotypes may identify younger subjects at particularly high risk for CVD events., (Copyright © 2017 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Approximately 40 years ago periodontists began systematically developing the evidence to treat predictably and prevent gingivitis and periodontitis. More recently, periodontists have been among a small group of skilled dental-implant surgeons leading that revolution in dentistry. Today, much of the mild/localized moderate periodontitis is not treated by periodontists, and an increasing number of implants are placed by dentists with limited surgical training. The current field of periodontics includes a broad range of surgical skills and technologies to regenerate predictably destroyed tissues and manage complex interdisciplinary treatment that may, in some way, involve the tissues that support teeth and implants. In addition, periodontal researchers have shown that moderate-to-severe periodontitis increases the systemic inflammatory burden and transient bacteremias that result in a significant independent role for periodontitis in multiple systemic diseases. Although many periodontists have very advanced practices that incorporate certain aspects of the current and near-future dimensions of periodontics, the innovations and technologies have not yet fully integrated throughout the specialty. It is an appropriate time to ask the question: Quo vadis? Which paths have the potential to deliver great value to our patients and to the health-care system? And who will be our patients in the near future? We propose some key capabilities, knowledge and clinical applications. Perhaps most importantly, we propose new partnerships. Much of the vision centers around the application of special diagnostic technologies and surgical skills to help our dental colleagues better manage complex dental and periodontal cases and to deliver on the promise of reducing systemic inflammation sufficiently to enhance medical management of certain chronic diseases and reduce preterm births. The specialty has always been about retaining teeth in good health and in recent years has focused on controlling oral inflammation to enhance systemic health. We already have several of the key principles, concepts and technologies that are likely to define the role of periodontics in the evolving health-care delivery system. Perhaps it is time to define the mission and start moving toward the future periodontics., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: There is disagreement as to whether patient stratification by a combination of diabetes, smoking, and genetic test results is useful for informing the frequency of dental prophylaxes., Methods: The authors appeal to basic tenets of clinical study design and statistical analysis of clinical investigations, and highlight how secondary ad hoc analyses, such as those of Diehl and colleagues, are frequently underpowered and inconclusive. They also provide evidence from numerous studies supporting the use of genetics to identify risk., Results: The authors believe the conclusions reached from their original analyses are valid and the analyses of Diehl and colleagues serve to simply reinforce the authors' specific intent of avoiding such underpowered analyses altogether with the Michigan Personalized Prevention Study., Conclusions: Until full genome sequencing in many people with highly specified disease phenotypes is feasible, experimental approaches based on biological findings and hypothesis testing should not be summarily discounted., Practical Implications: Stratification of patients to provide "personalized" treatment remains an important, yet elusive, goal. The current debate serves to highlight the need for large, clinical utility studies that can adequately determine how phenotypic and genotypic data can be best used to improve oral health in the US population., (Copyright © 2015 American Dental Association. Published by Elsevier Inc. All rights reserved.)

Like other healthcare professionals, dentists are in a position to not only treat but also prevent chronic diseases using individualized treatment plans that address disease risk and preventive measures that can be initiated prior to the appearance of symptoms. Such measures start with assessment of risk based on the patient's past history of disease and risk factors.

Dental care costs in the United States exceed $100 billion annually. Personalized medicine efforts in dentistry are driven by potentially compelling clinical utility and cost-effectiveness prospects in the major diseases of periodontitis, caries, and oral cancers. This review discusses progress and challenges identifying genetic markers and showing clinical utility in dentistry. Genome-wide association studies (GWAS) of chronic periodontitis (CP) identified no significant variants, but CDKN2BAS variants on chromosome 9 were significantly associated with aggressive periodontitis. Stratifying patients by interleukin (IL)-1 gene variants, smoking and diabetes differentiated CP prevention outcomes. Dental caries' GWAS identified significant signals in LYZL2, AJAp1, and KPNA4; and efforts are ongoing to identify genetic factors for multiple caries phenotypes. Trials of molecularly targeted therapies are in progress for oral, head, and neck squamous cell carcinomas (OHNSCC) and results have been promising but limited in their effectiveness. Current opportunities and challenges for molecular targeting for OHNSCC are discussed., (© 2014 The Authors. Clinical Genetics published by John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: The aim of this study was to assess the influence of pro-inflammatory interleukin (IL)-1 genotype status on the risk for coronary artery disease (CAD), defined as >50% diameter stenosis, and cardiovascular events mediated by oxidized phospholipids (OxPLs) and lipoprotein (Lp) (a)., Background: OxPLs are pro-inflammatory, circulate on Lp(a), and mediate CAD. Genetic variations in the IL-1 region are associated with increased inflammatory mediators., Methods: IL-1 genotypes, OxPL on apolipoprotein B-100 (OxPL/apoB), and Lp(a) levels were measured in 499 patients undergoing coronary angiography. The composite genotype termed IL-1(+) was defined by 3 single-nucleotide polymorphisms in the IL-1 gene cluster associated with higher levels of pro-inflammatory cytokines. All other IL-1 genotypes were termed IL-1(-)., Results: Among IL-1(+) patients, the highest quartile of OxPL/apoB was significantly associated with a higher risk for CAD compared with the lowest quartile (odds ratio [OR]: 2.84; p = 0.001). This effect was accentuated in patients age ≤60 years (OR: 7.03; p < 0.001). In IL-1(-) patients, OxPL/apoB levels showed no association with CAD. The interaction was significant for OxPL/apoB (OR: 1.99; p = 0.004) and Lp(a) (OR: 1.96; p < 0.001) in the IL-1(+) group versus the IL-1(-) group in patients age ≤60 years but not in those age >60 years. In IL-1(+) patients age ≤60 years, after adjustment for established risk factors, high-sensitivity C-reactive protein, and Lp(a), OxPL/apoB remained an independent predictor of CAD. IL-1(+) patients above the median OxPL/apoB presented to the cardiac catheterization laboratory a mean of 3.9 years earlier (p = 0.002) and had worse 4-year event-free survival (death, myocardial infarction, stroke, and need for revascularization) compared with other groups (p = 0.006)., Conclusions: Our study suggests that IL-1 genotype status can stratify population risk for CAD and cardiovascular events mediated by OxPL. These data suggest a clinically relevant biological link between pro-inflammatory IL-1 genotype, oxidation of phospholipids, Lp(a), and genetic predisposition to CAD and cardiovascular events., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Prevention reduces tooth loss, but little evidence supports biannual preventive care for all adults. We used risk-based approaches to test tooth loss association with 1 vs. 2 annual preventive visits in high-risk (HiR) and low-risk (LoR) patients. Insurance claims for 16 years for 5,117 adults were evaluated retrospectively for tooth extraction events. Patients were classified as HiR for progressive periodontitis if they had ≥ 1 of the risk factors (RFs) smoking, diabetes, interleukin-1 genotype; or as LoR if no RFs. LoR event rates were 13.8% and 16.4% for 2 or 1 annual preventive visits (absolute risk reduction, 2.6%; 95%CI, 0.5% to 5.8%; p = .092). HiR event rates were 16.9% and 22.1% for 2 and 1 preventive visits (absolute risk reduction, 5.2%; 95%CI, 1.8% to 8.4%; p = .002). Increasing RFs increased events (p < .001). Oral health care costs were not increased by any single RF, regardless of prevention frequency (p > .41), but multiple RFs increased costs vs. no (p < .001) or 1 RF (p = .001). For LoR individuals, the association between preventive dental visits and tooth loss was not significantly different whether the frequency was once or twice annually. A personalized medicine approach combining gene biomarkers with conventional risk factors to stratify populations may be useful in resource allocation for preventive dentistry (ClinicalTrials.gov, NCT01584479).

Objective: Within the interleukin-1 (IL-1) cytokine family, IL-1 receptor antagonist (IL1RN) gene variants have been associated with radiological severity of knee osteoarthritis (OA) in cross-sectional studies. The present study tested the relation between IL1RN gene variants and progression of knee OA assessed radiographically by change in Kellgren-Lawrence (KL) score over time., Design: 1153 Caucasian adults (age range: 44-89) from the Johnson County Osteoarthritis Project were evaluated for unequivocal radiographic evidence of knee OA at baseline, defined as KL score ≥2, and were re-examined after 4-11 years for radiographic changes typical of OA progression. IL1RN gene variants were tested for association with OA progression and for potential interaction with body mass index (BMI). Other IL-1 gene variations were tested for association with OA progression as a secondary objective., Results: Of 154 subjects with OA at baseline, 88 showed progression at follow-up. Seven IL1RN single nucleotide polymorphisms (SNPs) and one IL-1 receptor SNP were associated with progression. Four IL1RN haplotypes, each occurring in >5% of this population, showed different relationships with progression, including one (rs315931/rs4251961/rs2637988/rs3181052/rs1794066/rs419598/rs380092/rs579543/rs315952/rs9005/rs315943/rs1374281; ACAGATACTGCC) associated with increased progression [odds ratio (OR) 1.91 (95%CI 1.16-3.15); P = 0.012]. Haplotypes associated with progression by KL score were also associated with categorical change in joint space narrowing. BMI was associated with OA progression in subjects carrying a specific IL1RN haplotype, but not in subjects without that haplotype., Conclusion: A significantly greater likelihood of radiological progression of knee OA was associated with a commonly occurring IL1RN haplotype that could be tagged by three IL1RN SNPs (rs419598, rs9005, rs315943). Interactions were also observed between IL1RN gene variants and BMI relative to OA progression. This suggests that IL1RN gene markers may be useful in stratifying patients for medical management and drug development., (Copyright © 2013 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Background: Interleukin-1 (IL-1) gene polymorphisms have been associated with increased levels of inflammatory mediators and several inflammatory diseases. Periodontitis is a bacterially induced chronic inflammatory disease that destroys the connective tissues and bone that support the teeth, affects substantial numbers of adults, and has been implicated as a contributing factor in systemic diseases. IL-1 gene polymorphisms, most prominently IL1A (-889), IL1A (+4845), and IL1B (+3954), have been associated with chronic periodontitis (CP) in whites. Since the first report, ≥125 studies have examined IL-1 gene variation in relation to periodontal disease. These studies have produced mixed findings in diverse periodontal phenotypes and in different ethnic groups. One previous meta-analysis has been published on this topic and supported an association between IL-1 genes and periodontitis, but considerable doubt remains about the patient populations in which the association may be of clinical relevance., Methods: A systematic review and meta-analysis was conducted in an attempt to clarify whether IL-1 gene variants were associated with well-defined clinical phenotypes of CP in white patients. Study inclusion criteria focused on the analytic framework originally proposed for the IL-1 genetic effect in which overexpression of inflammatory mediators is hypothesized to result in more severe periodontitis in response to a bacterial challenge., Results: Twenty-seven studies were included in the qualitative analysis. Nineteen studies yielded significant associations between carriage of the minor IL-1 alleles and periodontitis. The meta-analysis, based on 13 qualifying studies, found significant effects for the two individual gene variations (IL1A odds ratio [OR] = 1.48; IL1B OR = 1.54) and for a composite genotype that combines minor alleles at each locus (OR = 1.51). Statistically significant heterogeneity was found that could not be explained, but there was no indication of publication bias., Conclusion: This review and meta-analysis show that IL1A and IL1B genetic variations are significant contributors to CP in whites.

Human differences in disease phenotype and treatment responses are well documented. Technological advances now allow healthcare providers to improve the prevention and treatment of chronic diseases by stratifying patient populations. Although personalized medicine has great promise, it has, so far, been primarily applied in oncology. Wider adoption requires changes in the healthcare system and in clinical decision-making, and early applications of personalized medicine appear to require strong clinical utility and sufficient value to drive adoption. Personalized medicine is likely to enter dentistry as patients start to demand it and as new drugs are developed for pathways common to oral diseases.

Background: The aim of this human investigation is to explore the relationship of gingivitis with salivary biomarkers, periodontal pathogens, and interleukin (IL)-1 polymorphism after a transient inflammatory burden., Methods: Thirty healthy human participants were randomized by IL-1 genotype status to control for potential influences of this particular single nucleotide polymorphism on the inflammatory profile. Oral hygiene practices ceased for 21 days to induce gingivitis (induction), after which home care was reinstated until 35 days (resolution). Clinical parameters included plaque (PI) and gingival (GI) indices and papillary bleeding score (PBS). Levels and proportions of 40 subgingival bacteria were determined using checkerboard DNA-DNA hybridization. Saliva was analyzed using a multiplex protein array for 30 biomarkers associated with host defense, inflammation, tissue destruction, and angiogenesis., Results: Mean PI, GI, and PBS values were significantly increased during induction and decreased during resolution as measured at 35 days (P <0.01), although no differences were observed between IL-1 groups. Participants were stratified as either "high" or "low" responders based on inflammatory response (high: GI >1.5; low: GI ≤1.5). Baseline levels of salivary IL-6 and IL-8 demonstrated the highest ability to discriminate between high and low responders (area under the curve [AUC] of 0.81 and 0.72, respectively). Salivary biomarkers, matrix metalloproteinases (MMPs), and bacterial biofilm were combined to generate receiver operating characteristic curves. High levels of IL-6 and MMP-1 at baseline demonstrated the strongest ability to predict high responders (AUC of 0.89; odds ratio of 17.0; 95% confidence interval, 1.7 to 171.7)., Conclusion: In this proof-of-concept investigation, we identified specific biomarker and microbial signatures that are associated with gingival inflammation (ClinicalTrials.gov number NCT00980525).

Background: A lack of biomarkers that identify patients at risk for severe osteoarthritis (OA) complicates development of disease-modifying OA drugs., Objective: To determine whether inflammatory genetic markers could stratify patients with knee OA into high and low risk for destructive disease., Methods: Genotype associations with knee OA severity were assessed in two Caucasian populations. Fifteen single nucleotide polymorphisms (SNPs) in six inflammatory genes were evaluated for association with radiographic severity and with synovial fluid mediators in a subset of the patients., Results: Interleukin 1 receptor antagonist (IL1RN) SNPs (rs419598, rs315952 and rs9005) predicted Kellgren-Lawrence scores independently in each population. One IL1RN haplotype was associated with lower odds of radiographic severity (OR=0.15; 95% CI 0.065 to 0.349; p<0.0001), greater joint space width and lower synovial fluid cytokine levels. Carriage of the IL1RN haplotype influenced the age relationship with severity., Conclusion: IL1RN polymorphisms reproducibly contribute to disease severity in knee OA and may be useful biomarkers for patient selection in disease-modifying OA drug trials.

Chronic adult periodontitis is a bacterially induced chronic inflammatory disease that destroys the connective tissue and bone that support teeth. Concepts of the specific mechanisms involved in the disease have evolved with new technologies and knowledge. Histopathologic observations of diseased human tissues were used previously to speculate on the causes of periodontitis and to describe models of pathogenesis. Experimental evidence later emerged to implicate bacterial plaque deposits as the primary factor initiating periodontitis. At the same time, specific bacteria and immunoinflammatory mechanisms were differentially implicated in the disease. In the mid-1990s, early insights about complex diseases, such as periodontitis, led to new conceptual models of the pathogenesis of periodontitis. Those models included the bacterial activation of immunoinflammatory mechanisms, some of which targeted control of the bacterial challenge and others that had adverse effects on bone and connective tissue remodeling. Such models also acknowledged that different environmental and genetic factors modified the clinical phenotype of periodontal disease. However, the models did not capture the dynamic nature of the biochemical processes, i.e., that innate differences among individuals and changes in environmental factors may accelerate biochemical changes or dampen that shift. With emerging genomic, proteomic, and metabolomic data and systems biology tools for interpreting data, it is now possible to begin describing the basic elements of a new model of pathogenesis. Such a model incorporates gene, protein, and metabolite data into dynamic biologic networks that include disease-initiating and -resolving mechanisms. This type of model has a multilevel framework in which the biochemical networks that are regulated by innate and environmental factors can be described and the interrelatedness of networks can be captured. New models in the next few years will be merely frameworks for integrating key knowledge as it becomes available from the "-omics" technologies. However, it is possible to describe some of the key elements of the new models and discuss distinctions between the new and older models. It is hoped that improved conceptual models of pathogenesis will assist in focusing new research and speed the translation of new data into practical applications.

The concept of inflammation has a long history. Although an inflammatory response to injury or another trigger is necessary, chronic diseases, such as coronary heart disease and diabetes, may develop because of unchecked inflammatory responses that have maladapted over decades. For example, the earliest changes in atherosclerosis occur in the endothelium, leading to a cascade of inflammatory responses, such as accumulation of monocytes and T cells, migration of leukocytes into the intima, monocyte differentiation and proliferation, and lesion and fibrous cap development. Inflammatory markers, such as C-reactive protein, may allow clinical insight into these decades-long processes, adding value to predictive measures of disease outcomes. Anti-inflammatory factors, such as adiponectin, may provide further understanding of the inflammatory pathways involved. Greater understanding of the complex pathways involved in inflammation may provide alternative therapeutic strategies to combat inflammation and chronic diseases potentially arising from it.

Interleukin-1beta (IL-1beta) activates inflammatory mediator cascades and has been implicated in the pathogenesis of several diseases. Single nucleotide polymorphisms (SNPs) of the IL1B promoter have been associated with various inflammatory diseases. We recently reported that IL1B gene transcription was influenced by four promoter SNPs, and that individual SNP function in vitro was governed by haplotype context. In the present study we tested the in vivo relevance of this observation by comparing IL1B promoter haplotype-pairs with IL-1beta protein levels in 900 gingival tissue fluid samples. Three SNPs (-511, -1464, -3737) defined four IL1B promoter haplotypes that occurred in the study population and could be assigned unambiguously to each chromosome. The four haplotypes defined ten haplotype-pairs of which four pairs, representing 57% of the population, were associated with 28-52% higher IL-1beta protein levels in vivo. Two of these pairs, characterized by homozygosity for the common allele at -3737, were also associated with raised serum levels of C-reactive protein (p = 0.02). We validated these findings in stimulated peripheral blood mononuclear cells (PBMCs) from a separate population (N = 70). PBMCs with IL1B haplotype-pairs associated with higher in vivo levels of IL-1beta produced 86-287% more IL-1beta in vitro than the reference group. We believe that this is the first demonstration of a relationship between in vivo levels of an inflammatory mediator and gene promoter haplotypes on both chromosomes. These findings may apply to other inducible genes and could provide a logical framework for exploring disease risk related to genetic variability in pathogenic mediators.