Family History of MI, Smoking, and Risk of Periodontal Disease.

Periodontal disease (PD) shares common risk factors with cardiovascular disease. Our hypothesis was that having a family history of myocardial infarction (FamHxMI) may be a novel risk factor for PD. Risk assessment based on FamHxMI, conditional on smoking status, was examined given the strong influence of smoking on PD. Exploratory analysis with inflammatory biomarkers and genetic determinants was conducted to understand potential mechanistic links. The Women's Genome Health Study (WGHS) is a prospective cohort of US female health care professionals who provided blood samples at baseline in the Women's Health Study, a 2 × 2 factorial clinical trial investigating vitamin E and aspirin in the prevention of cardiovascular disease and cancer. PD was ascertained via self-report over 12 y of follow-up. Prevalence (3,442 cases), incidence (1,365 cases), and survival analysis of PD were investigated for associations of FamHxMI as well as in strata of FamHxMI by smoking. Kruskal-Wallis, chi-square tests, multivariate regression, and Cox proportional hazard models were used for the analyses. In the WGHS, women with FamHxMI showed higher risk of ever having PD. A particularly high-risk group of having both FamHxMI and smoking at baseline was highlighted in the prevalence and risk of developing PD. PD risk increased according to the following strata: no FamHxMI and nonsmokers (reference), FamHxMI and nonsmokers (hazard ratio [HR] = 1.2, 95% CI = 1.0 to 1.5), smokers without FamHxMI (HR = 1.3, 95% CI = 1.2 to 1.5), and smokers with FamHxMI (HR = 1.5, 95% CI = 1.2 to 1.8). An independent analysis by the dental Atherosclerosis Risk in Communities study ( N = 5,552) identified more severe periodontitis cases among participants in the high-risk group (smokers with FamHxMI). Further examination of interactions among inflammatory biomarkers or genetic exploration with FamHxMI did not explain the risk increase of PD associated with FamHxMI in the WGHS. Future efforts based on an integrative-omics approach may facilitate validation of these findings and suggest a mechanistic link between PD and FamHxMI.

Association of interleukin-1 gene variations with moderate to severe chronic periodontitis in multiple ethnicities.

BACKGROUND AND OBJECTIVE: Genetic markers associated with disease are often non-functional and generally tag one or more functional "causative" variants in linkage disequilibrium. Markers may not show tight linkage to the causative variants across multiple ethnicities due to evolutionary divergence, and therefore may not be informative across different population groups. Validated markers of disease suggest causative variants exist in the gene and, if the causative variants can be identified, it is reasonable to hypothesize that such variants will be informative across diverse populations. The aim of this study was to test that hypothesis using functional Interleukin-1 (IL-1) gene variations across multiple ethnic populations to replace the non-functional markers originally associated with chronic adult periodontitis in Caucasians. MATERIAL AND METHODS: Adult chronic periodontitis cases and controls from four ethnic groups (Caucasians, African Americans, Hispanics and Asians) were recruited in the USA, Chile and China. Genotypes of IL1B gene single nucleotide polymorphisms (SNPs), including three functional SNPs (rs16944, rs1143623, rs4848306) in the promoter and one intronic SNP (rs1143633), were determined using a single base extension method or TaqMan 5' nuclease assay. Logistic regression and other statistical analyses were used to examine the association between moderate to severe periodontitis and IL1B gene variations, including SNPs, haplotypes and composite genotypes. Genotype patterns associated with disease in the discovery study were then evaluated in independent validation studies. RESULTS: Significant associations were identified in the discovery study, consisting of Caucasians and African Americans, between moderate to severe adult chronic periodontitis and functional variations in the IL1B gene, including a pattern of four IL1B SNPs (OR = 1.87, p < 0.0001). The association between the disease and this IL1B composite genotype pattern was validated in two additional studies consisting of Hispanics (OR = 1.95, p = 0.04) or Asians (OR = 3.27, p = 0.01). A meta-analysis of the three populations supported the association between the IL-1 genotype pattern and moderate to severe periodontitis (OR 1.95; p < 0.001). Our analysis also demonstrated that IL1B gene variations had added value to conventional risk factors in predicting chronic periodontitis. CONCLUSION: This study validated the influence of IL-1 genetic factors on the severity of chronic periodontitis in four different ethnicities.

Clinical application of genetics to guide prevention and treatment of oral diseases.

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.

Patient stratification for preventive care in dentistry.

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).

IL-1 receptor antagonist gene as a predictive biomarker of progression of knee osteoarthritis in a population cohort.

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.

Personalized medicine: will dentistry ride the wave or watch from the beach?

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.

A review of electronic interventions for prevention and treatment of overweight and obesity in young people.

The objective of this systematic review is to provide a qualitative comparison of interactive electronic media interventions for the prevention or treatment of obesity and/or obesity-related behaviours in children and adolescents. Literature searches of 12 databases from the earliest publication date until March 2010 were conducted. Twenty-four studies in which children and/or adolescents interacted with electronic interventions delivered as adjunct or sole interventions for the prevention or treatment of obesity and/or obesity-related behaviours met the inclusion criteria. Fifteen focussed on obesity prevention and nine on treatment interventions. The average study quality design score was 45%. Most studies demonstrated some form of significant outcome (e.g. reported changes in dietary and/or physical activity behaviours) in participants receiving interactive electronic interventions, with 11 out of 15 studies leading to positive changes in measured or reported adiposity outcomes. In 87% of studies, the effects of interactive electronic interventions were not separately evaluated from other intervention components. These results should be viewed with caution because of the overall poor quality of the studies. Studies were mostly conducted in the USA, largely in minority populations, and the direct transferability of interventions to other populations is unclear. Further high quality research is needed in this area to accurately inform the evidence base.

Patients are not equally susceptible to periodontitis: does this change dental practice and the dental curriculum?

In the 1960s and 1970s, data became available indicating that most of the adult population had periodontal disease and that effective bacterial removal prevented and treated periodontitis. This information led to a systematic approach to the management of periodontal disease and influenced teaching of periodontics in dental schools. We now know that most adults have only gingivitis and very mild localized periodontitis. A small percentage, albeit representing substantial numbers, of adults have generalized severe periodontitis. We also recognize that a few currently known and measurable risk factors, including diabetes, smoking, and genetics, can identify the patients who are at risk for the severe generalized cases that require extensive therapy and intensive prevention, as well as patients at risk for a less-predictable response to treatment. This review will discuss the evidence that supports the change in our knowledge and understanding of periodontal disease. The question now becomes at what point, and how, do we integrate this new knowledge into the dental curriculum?

Candidate genes as potential links between periodontal and cardiovascular diseases.

Recent epidemiological associations between periodontal disease and cardiovascular disease have led to a search for biological mechanisms that explain the associations. Genetic factors that influence biological processes involved in both diseases represent one of the potential mechanisms that may link periodontitis and cardiovascular disease. At present, several candidate genes have been investigated in one of the diseases but not the other. Although there are limited data to support a specific candidate gene as the explanation for observed associations between the 2 diseases, a few candidates look promising. One candidate that influences inflammation, interleukin-1 gene polymorphisms, has been associated with periodontal disease and cardiovascular disease. This review will consider biological mechanisms and genes that may be reasonable candidates for an etiological mechanism that influences the clinical characteristics of both periodontal disease and cardiovascular disease.

Effect of the interleukin-1 genotype on monocyte IL-1beta expression in subjects with adult periodontitis.

An association has been reported between polymorphisms in the genes encoding IL-1alpha (-889) and IL-1beta (+3953) (periodontitis susceptibility trait, PST), and an increased severity of periodontitis (18). The IL-1beta polymorphism was reported to correlate with increased IL-1beta expression by monocytes in response to bacterial stimulants. In the present study, we determined if PST positive subjects with periodontitis exhibit elevated production of IL-1beta, compared to PST negative periodontitis patients. Peripheral blood monocytes were obtained from 10 PST+ and 10 PST- age- and disease-balanced subjects with adult forms of periodontitis. Monocytes were cultured with a panel of bacterial stimulants, including Escherichia coli and Porphyromonas gingivalis LPS, and whole formalinized periodontal pathogens P. gingivalis, Bacteroides forsythus and Prevotella intermedia, and health-associated organisms Veillonella parvula and Streptococcus sanguis. Our results demonstrate that monocytes from PST+ and PST- patients showed no significant differences in IL-1beta production in response to any stimulant tested. In addition, the periodontal pathogens P. gingivalis, B. forsythus and P. intermedia failed to stimulate higher IL-1beta responses compared to health-associated species V. parvula and S. sanguis. A marked interindividual variation in production of IL-1beta was seen, with high, low and intermediate responders present in both PST+ and PST- groups. We conclude that genetic loci other than the PST polymorphisms are also important regulators of monocyte IL-1 responses.

Genetic polymorphisms of the IL-1alpha and IL-1beta genes in African-American LJP patients and an African-American control population.

BACKGROUND: A functional polymorphism of the interleukin-1 beta (IL-1beta) gene has been proposed to be a risk factor for periodontitis. In adult forms of periodontitis, non-smokers of northern European heritage carrying the "2" allele of the IL-1alpha-889 and the IL-1beta +3953 RFLPs in either the heterozygous or the homozygous state at both loci were observed to have a greater risk for developing severe periodontitis. Studies of early-onset periodontitis (EOP) found that allele "1" of both IL-1alpha-889 and IL-1beta +3953 was transmitted more frequently with the EOP phenotype. The purpose of the present study was to determine the prevalence of the IL-1alpha and IL-1beta genotype polymorphisms in an African-American (AA) control population and in 37 African-Americans with localized juvenile periodontitis (LJP). METHODS: The IL-1alpha +4845 and IL-1beta +3953 loci were genotyped by PCR amplification, followed by restriction enzyme digestion and gel electrophoresis. The IL-1alpha +4845 locus, in linkage disequilibrium (>99%) with IL-1alpha-889, was genotyped because it is technically easier. Data were analyzed using r x c contingency tables. RESULTS: The IL-1beta +3953 allele "1" was carried by >99% of the AA control population and by 100% of the AA LJP group, with most individuals being homozygous 1,1. The prevalence of the composite genotype with at least one allele "2" at each of the IL-1beta +3953 and IL-1alpha +4845 loci was 14% (AA control group) and 8% (AA LJP group). CONCLUSIONS: Given the high frequency of the IL-1beta allele "1" in the African-American population, it would appear that knowledge of this +3953 polymorphism would provide little diagnostic or predictive information for LJP.

Effect of interleukin-1 gene polymorphisms on gingival inflammation assessed by bleeding on probing in a periodontal maintenance population.

Bleeding on probing (BOP) is the most significant clinical parameter for the assessment of periodontal inflammation. The aim of this prospective longitudinal trial was to study the association between allelic variants of the IL-1 gene complex and gingival inflammation. Three hundred and twenty-three randomly selected periodontal maintenance patients (64.4% females) received a periodontal examination that included probing depth measurements and BOP at each of 4 supportive periodontal therapy (SPT) appointments. A blood sample taken from each subject was analysed for the presence of specific allotypes of the IL-1 gene complex. Two polymorphisms located at +4845 bp in the IL-1 alpha region and at +3954 bp in the IL-1 beta region were evaluated by a polymerase chain reaction method; 35.3% of the examined subjects were positive for specific combinations of allotypes of the IL-1 gene complex previously associated with an increased risk for severe periodontitis. The population consisted of 90 current smokers and 94 former smokers. An analysis of the association between the IL-1 genotype and BOP in the whole population (including smokers) did not reach statistical significance because of the overriding effect of smoking. A subset analysis of the 139 never smokers indicated that genotype positive patients had a significantly elevated chance of presenting an increase in the BOP% over a 4-appointment recall period (p = 0.03) after correcting for oral hygiene. In fact, patients who were genotype-negative had a 50% smaller chance of showing increases in BOP% during SPT. A further analysis explored the relationship between the genotype and the level of BOP% at the most recent recall visit. A generalized linear model showed a statistically significant effect of the genotype status after correcting for plaque accumulation and prevalence of residual pockets (> or = 5 mm). Genotype-negative subjects had significantly lower BOP% (p = 0.0097). It is concluded that the increased BOP prevalence and incidence observed in IL-1 genotype-positive subjects indicates that some individuals have a genetically determined hyper-inflammatory response that is expressed in the clinical response of the periodontal tissues.

Interleukin-1 genetic association with periodontitis in clinical practice.

BACKGROUND: Periodontitis is a bacterial disease modified by multiple risk factors. The pro-inflammatory cytokine interleukin- (IL-1) is a key regulator of the host responses to microbial infection and a major modulator of extracellular matrix catabolism and bone resorption. It has been reported that variations in the IL-1 gene cluster on chromosome 2 are associated with increased susceptibility to severe adult periodontitis. METHODS: The present study evaluated the association between a composite IL-1 genotype, including allele 2 at each of two loci (IL-1A +4845 plus IL- B +3954), and a broad spectrum of periodontally healthy to diseased patients in a population that is typically encountered in a dental practice setting. Ninety patients, non-smokers or former smokers with less than 10 pack-year (pk/yr) history, were recruited from a private dental practice. The major outcome variable was bone loss determined by computerized linear measurements of radiographs. Genotypes were analyzed from finger-stick blood samples using previously reported methods. RESULTS: Multivariate logistic regression models demonstrated that patient age, former smoking history, and the IL-1 genotype were significantly associated with severity of adult periodontitis. For non-smokers or former light smokers (<5 pk/yr), IL-1 genotype positives were at increased odds ratio of having moderate to severe periodontal disease of 3.75 (95% CI: 1.04-13.50) to 5.27 (95% CI: 1.23-22.70), depending on ethnicity, compared to IL-1 genotype negatives. Former moderate smokers (>5 pk/yr and <10 pk/yr) who were IL-1 genotype negative were at increased odds ratio of having moderate to severe periodontal disease of 7.43 (95% CI: 1.20-46.20) compared to non-smokers or former light smokers who were IL-1 genotype negative. In addition, past smoking history was also a significant effect modifier as demonstrated by the statistically significant interaction between past smoking history status and IL-1 genotype status. CONCLUSIONS: This study demonstrates that the composite IL-1 genotype is significantly associated with the severity of adult periodontitis. It also confirmed that both IL-1 genotyping and smoking history provide objective risk factors for periodontal disease in a private practice environment.

Is periodontitis genetic? The answer may be Yes!

Specific bacteria cause periodontitis by activating immuno-inflammatory responses in the tissues. There are certain risk factors that significantly affect the disease process by altering the immuno-inflammatory response and increasing the likelihood of severe periodontitis. These risk factors are smoking, diabetes, IL-1 genotype, and perhaps others. Today about 20 percent of the population smokes at a level that should make a difference relative to periodontitis. About 30 to 33 percent of the Caucasian population is IL-1 genotype positive. There are compelling reasons to look at these risk factors in your practice to help formulate a complete treatment plan for your patients.

The influence of interleukin gene polymorphism on expression of interleukin-1beta and tumor necrosis factor-alpha in periodontal tissue and gingival crevicular fluid.

BACKGROUND: A specific composite genotype of the polymorphic interleukin-1 (IL-1) gene cluster has recently been associated with severe periodontitis. One polymorphism of the composite periodontitis-associated genotype (PAG) has been functionally linked with expression of high levels of IL-1. The purpose of this study was to test whether gingival crevicular fluid (GCF) levels of IL-1beta and tumor necrosis factor-alpha (TNFalpha), and gingival tissue levels of IL-1alpha, IL-1beta, and TNFalpha correlate with PAG, and to examine the effect of conservative periodontal therapy on these levels. METHODS: Twenty-two adults with moderate to advanced periodontal disease were enrolled. Polymerase chain reaction amplification and restriction enzymes were used to identify specific polymorphisms from peripheral blood samples. GCF samples were collected at baseline and 3 weeks following conservative treatment and analyzed by ELISA for IL-1beta and TNFalpha. An interproximal gingival biopsy was collected at baseline and follow-up and analyzed for IL-1alpha, IL-1beta, and TNFalpha by ELISA. RESULTS: The genotyping identified 7 as PAG(+) and 15 as PAG(-). The 2 groups were comparable in terms of existing periodontitis and age. In shallow sites (<4 mm), total IL-1beta in GCF was 2.5 times higher for PAG(+) patients prior to treatment (P=0.03), and 2.2 times higher after treatment (P=0.04), while differences were less apparent in deeper sites. Following treatment, a reduction in IL-1beta concentration in GCF was seen for PAG(-) but not for PAG(+) patients. While not statistically significant, a trend was observed in mean tissue levels of IL-1beta which were 3.6 times higher in PAG(+) versus PAG(-) patients (P=0.09). CONCLUSIONS: These data suggest that PAG(+) patients may demonstrate phenotypic differences as indicated by elevated levels of IL-1beta in GCF.

Host modulation as a therapeutic strategy in the treatment of periodontal disease.

Specific microorganisms initiate the immunoinflammatory processes that destroy tissue in periodontitis. Recent work has demonstrated, in addition to bacterial control, that modulation of the host immunoinflammatory response is also capable of controlling periodontitis. Matrix metalloproteinases (MMPs) destroy collagen and other matrix components, and the osteoclastic bone remodeling determines the periodontal bone response to a bacterial challenge. Other components of the biology, including cytokines and prostanoids, regulate MMPs and bone remodeling and are also involved in regulating the production of defensive elements, such as antibody. Agents directed at blocking MMPs or osteoclastic activity are effective in reducing periodontitis. Agents that inhibit prostaglandin E2 and selective blockage of specific cytokines have also been effective. Improved knowledge of bacterium-host interactions and of the processes leading to tissue destruction will help to identify targets for host modulation to reduce periodontitis in selected situations.

Interleukin-1 genotypes and the association between periodontitis and cardiovascular disease.

An epidemiological association between periodontitis and cardiovascular disease has been reported in multiple studies. Various mechanisms have been proposed as potential explanations for this association, including a common factor that predisposes certain individuals to a hyper-responsive inflammatory response. Variations in the genes that regulate the interleukin-1 (IL-1) response have been associated with both periodontal disease and cardiovascular disease. New data indicate that one pattern of IL-1 genetic polymorphisms, characterized by the IL-1A (+4845) and IL-1B (+3954) markers, is associated with periodontitis but not certain measures of atherosclerosis. Another IL-1 genetic pattern, characterized by the IL-1B (-511) and IL-1RN (+2018) markers, is associated with atherosclerotic plaque formation, as measured by angiography and arterial wall thickness, but not periodontitis. These two patterns also have different functional implications relative to IL-1 biological activity. Studies of IL-1 gene polymorphisms, atherosclerotic plaque instability and cardiovascular clinical events are in progress. Hypothetical models are presented to explain how IL-1 genetic factors may be involved in cardiovascular disease.

Genetic variations in cytokine expression: a risk factor for severity of adult periodontitis.

Periodontitis is a collection of chronic inflammatory diseases that are caused by specific bacteria. The bacteria activate inflammatory mechanisms in the periodontal tissues that destroy collagen and bone that support the teeth. Although bacteria are essential for the initiation of periodontitis, the quantity and types of bacteria have not been sufficient to explain the differences in disease severity. In recent years, it has become evident that for many common chronic diseases, there are modifying factors that do not cause the disease but rather amplify some disease mechanisms to make the clinical condition more severe. There are now data to suggest that a few factors which amplify the inflammatory process make people susceptible to an increased severity of periodontitis. Studies of untreated disease in Sri Lanka identified 3 patterns of disease progression. Studies in twins suggested that part of the clinical characteristics of periodontitis may be explained by genetic factors, but previous attempts to identify genetic markers for periodontitis have been unsuccessful Some genetic variations (polymorphisms) are commonly found in our population and represent a mechanism by which individuals may exhibit variations within the range of what is considered biologically normal. Since certain cytokines are key regulators of the inflammatory response and are important in periodontitis, we investigated the relationship between genetic variations associated with cytokine production and periodontitis severity. There are several polymorphisms in the cluster of genes that influence IL-1 biological activity. In recent clinical trials, two of these polymorphisms, when found together, have been associated with a significant increase in the risk for severe generalized periodontitis. Genetic association with periodontitis was evident only when smokers were excluded from the analysis, confirming the importance of smoking, and suggesting that both smoking and the IL- I genotype are independent factors in severe periodontitis. It is notable that 1 polymorphism associated with severe periodontitis in our study is also known to correlate with a 2- to 4-fold increase in IL-1 beta production. These findings are consistent with the current model of how genetic factors influence common chronic diseases. If we apply this model to periodontitis, it would involve the following: 1) a disease-initiating factor that would undoubtedly be specific bacteria such as Porphyromonas gingivalis, Actinobacillus actinomycetemcomitans. and Bacteroides forsythus: and 2) modifiers of disease mechanisms that account for the clinical severity, including smoking, the IL-I genotype, certain systemic diseases, and psychosocial stress. The association of the IL-I genotype with severe periodontitis is consistent with several lines of periodontal research. Several studies have suggested there is a substantial genetic influence in periodontal disease. Although specific genetic markers have been identified in the uncommon juvenile forms of periodontitis, previous studies of specific genetic markers in adults with periodontitis have not been encouraging. Many investigators have, however, demonstrated a role for IL-1 in the initiation and progression of periodontitis. For example, IL-1 activates the degradation of the extracellular matrix and bone of the periodontal tissues, and elevated tissue or gingival fluid levels of IL-1 beta have been repeatedly associated with periodontitis. In addition, IL-1 is a strong enhancer of tissue levels of PGE2 and TNF-alpha. The association of severe periodontitis with smoking and the IL-1 genotype suggest a role for these factors in the pathogenesis of periodontitis. The finding that host modifying factors are associated with severe periodontitis suggest a biological mechanism by which some individuals, if challenged by bacterial accumulations, may have a more vigorous immunoinflammatory response, leading to more severe clinical disease. (ABSTRACT