Influence of Obesity on Periodontitis Progression Is Conditional on Interleukin-1 Inflammatory Genetic Variation.

BACKGROUND: This study evaluates whether specific patterns of interleukin (IL)-1 gene variants, known to affect periodontitis severity, influence the previously reported association between obesity and subsequent periodontitis progression in a longitudinal database. The study population included 292 men (aged 29 to 64 years at entry) from the Veterans Affairs Dental Longitudinal Study from whom DNA and dental and anthropometric endpoints were collected during multiple examinations (approximately every 3 years for up to 27 years). METHODS: Key variables assessed included: 1) periodontitis; 2) body mass index; 3) waist circumference to height (WHTR) ratio for central adiposity; 4) age; 5) smoking; 6) glucose tolerance; and 7) two previously reported versions of IL-1 genetic patterns associated with periodontitis severity and progression. Disease progression was determined using predefined criteria that used a combination of change in classification of disease severity based on alveolar bone loss and tooth loss during follow-up. Extended Cox regression analyses were used to estimate hazards of experiencing periodontal disease progression with or without adjustments for appropriate covariates. RESULTS: In hazard ratio analyses, men with WHTR >50% at baseline and positive for either IL-1 genotype version were at significantly higher risk (two-fold) for disease progression (P for interaction = 0.04). Participants positive for IL-1 genotype version 2 exhibited earlier progression (fewer years from baseline to first incidence of progression) than those who were negative (P = 0.02, adjusted for age and smoking). CONCLUSION: In this longitudinally monitored male population, observed effect of baseline central adiposity on future periodontitis progression is conditional on proinflammatory IL-1 genetic variations.

Radiographic severity of knee osteoarthritis is conditional on interleukin 1 receptor antagonist gene variations.

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.

IL1B gene promoter haplotype pairs predict clinical levels of interleukin-1beta and C-reactive protein.

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.

Impact of IL-1 genotype and smoking status on the prognosis of osseointegrated implants.

AIM: This study evaluated the impact of the IL-1 genotype and smoking status on the prognosis and development of complications of osseointegrated implants. MATERIAL AND METHODS: The clinical charts of 180 consecutively admitted patients were analyzed with respect to the occurrence of biological complications in conjunction with oral implants. Biologic complications were defined as clinical conditions with suppuration from the peri-implant sulcus, development of a fistula or peri-implantitis with radiologic bone loss. All patients had received one or more ITI dental implants, which had been in function for at least 8 (range: 8-15) years. This patient population had received 292 implants. From these, 51 implants in 34 patients showed late (infectious) biologic complications, and 241 implants had survived without any biologic complications at all. RESULTS: Of the 180 patients, 53 were smokers, who were subdivided in a series of classes according to their intensity of smoking and 127 were never smokers. Sixty-four of 180 (36%) patients tested positive for the IL-1 genotype polymorphism. This prevalence corresponds to previous reports for the prevalence of European descent populations. The results for the non-smoking group indicated no significant correlation between implant complications and a positive IL-1 genotype. However, there was a clear association for heavy smokers between a positive IL-1 genotype and implant complications. 6 of 12 or half of the heavy smokers and IL-1 genotype-positive patients had either an implant failure, i.e. loss of implant, or a biologic complication during the follow-up period. CONCLUSIONS: These findings have led to the conclusion that there is a synergistic effect between a positive IL-1 genotype and smoking that puts dental implants at a significantly higher risk of developing biologic complications during function.

Association between interleukin-1 genotype and periodontal disease in a diabetic population.

BACKGROUND: Recently, it has become evident that for many common chronic diseases, modifying factors amplify disease mechanisms to make the clinical condition more severe. The aims of this report were 1) to investigate the prevalence of periodontitis in a diabetic population, 2) to evaluate the association of periodontitis with metabolic control, and 3) to evaluate periodontitis in diabetics with different interleukin (IL)-1 genotypes. METHODS: One hundred diabetic patients were screened. Type and duration of diabetes, level of control (glycosylated hemoglobin), and demographic data were recorded. Periodontal disease was defined as two or more teeth with clinical attachment loss (CAL) > or = 5 mm. Poorly controlled diabetes was defined as glycosylated hemoglobin values > 8%. Finger-stick blood samples were collected and analyzed for genotyping of IL-1A (+4845), IL-1B (+3954), IL-1B (-511), and IL-1RN (+2018) polymorphisms. RESULTS: Among the diabetic patients in the study, 66% showed periodontal destruction, and 43% of those could be characterized as severe. The prevalence of severe attachment loss increased with decreasing control of diabetes. Only the IL-1B (-511) genotype was found to be associated with periodontal disease in the African American patients (P<0.05). The frequency of allele 1 was 0.77 in periodontitis affected versus 0.33 in healthy African American diabetics. A borderline significant association between IL-1B (+3954) and periodontal disease also was noted in Caribbean periodontal patients (P=0.06); however, the allele 2 frequency in this population was only 10%. CONCLUSIONS: These data confirm the high prevalence and severity of periodontitis in the diabetic population, and support the association between poor glycemic control and periodontal disease. The low prevalence of some of the IL-1 gene polymorphisms in the ethnic groups included in this study limits the validity of conclusions on genotype associations with clinical findings, but there was a trend suggesting that allele 1 at IL-1B (-511) and IL-1B (+3954) was overrepresented among diabetics with periodontal disease.