Comparison of interleukin-1 genotypes in two populations with aggressive periodontitis

The genetic association of interleukin-1 (IL-1) with periodontitis has been investigated in different populations. Failure to detect an association with IL-1 genotypes in European Caucasians with aggressive periodontitis (AGP) has recently been reported. No data from Central American Hispanics are available. The purpose of this explorative study was to study the association between IL-1 genotypes and AGP in two populations. Ninety-one subjects, 28 North European patients and 33 controls together with 16 Central American patients and 14 controls were included in the study according to validated radiographic and clinical criteria. Two polymorphisms, IL-1alpha G(+4845)-T and IL-1beta C(+3954)-T were analysed by means of polymerase chain reaction-restriction fragment length polymorphism. The association between presence of specific genotypes and disease status was estimated by the odds ratio. A logistic regression was also used in order to investigate whether the occurrence of the disease depends upon the combination of the IL-1A and IL-1B alleles in the population. A similar distribution of genotypes between patients and controls in both populations was detected. The frequency of allele 1 of the IL-1A gene was higher in patients of both populations compared with controls, however, no statistical significant differences were found between patients and controls.     

Association of interleukin-1 gene polymorphisms with early-onset periodontitis

Background, aims: Early onset periodontal diseases (EOP) are a group of inflammatory disorders characterised by a rapid rate of periodontal tissue destruction, in young individuals who are otherwise healthy. There is now substantial evidence to suggest that genetic factors play a rôle in the pathogenesis of EOP but the precise nature of these factors remains unclear. Polymorphisms in cytokine genes which may underpin inter‐individual differences in cytokine synthesis and secretion have been associated with other diseases which have an inflammatory pathogenesis, including chronic adult periodontal disease (CAPD). Method: We therefore investigated the frequency of polymorphisms in the genes encoding interleukin‐1β (IL‐1β) and its receptor antagonist (IL‐1RA) in 70 EOP patients, including a subgroup of 21 localised EOP (L‐EOP) patients and 72 periodontally healthy controls. All subjects were of Caucasian heritage and systemically healthy. A single nucleotide polymorphism (SNP) in exon 5 of the IL‐1β gene (IL‐1β⁺³⁹⁵³) was analysed by amplifying the polymorphic region using PCR, followed by restriction digestion with Taq1 and gel electrophoresis. Results: The frequency of IL‐1β genotypes homozygous for allele 1 (corresponding to the presence of a restriction site) of the IL‐1β⁺³⁹⁵³ SNP was found to be significantly increased in EOP patients (χ² test, p=0.025). Upon stratification for smoking status a significant difference was found in the IL‐1β genotype distribution between EOP smokers compared to control smokers (F‐exact test, p=0.02), but not between EOP non‐smokers and control non‐smokers. The IL‐1β 1/1 genotype occurred at a higher frequency in EOP smokers (odds ratio=4.9) compared to control smokers. A variable number tandem repeat polymorphism (VNTR) in intron 2 of the IL‐1RA gene was analysed by amplifying the polymorphic region using PCR and fragment size analysis by gel electrophoresis. There was no evidence for an association of an IL‐1RA genotype with EOP. However the combination of IL‐1β allele 1 and IL‐1RA allele 1 (corresponding to 4 repeats) was associated with EOP (Clump, p=0.01). Conclusions: These findings suggest that an IL‐1β genotype in combination with smoking, and a combined IL‐1β and IL‐1RA genotype are risk factors for EOP and support a role for genetic and environmental factors in susceptibility to EOP.     

Association of interleukin-1 receptor antagonist gene polymorphisms with early onset periodontitis in Japanese

BACKGROUND/AIMS: Early onset periodontitis (EOP), newly 'aggressive periodontitis', is considered to have genetic basis, which have not been clearly defined. The interleukin-1 (IL-1) gene cluster polymorphism as one of genetic factors may influence the expression of several chronic inflammatory diseases. The aim of this study is to investigate the frequency of single nucleotide polymorphisms (SNPs) in the genes encoding IL-1alpha, IL-1beta and a variable number of tandem repeat (VNTR) polymorphisms in the IL-1 receptor antagonist gene (IL-1RN) in 47 generalized EOP (G-EOP) patients and 97 periodontally healthy controls. MATERIAL AND METHODS: All subjects were of Japanese descent and systemically healthy. They were identified according to established clinical criteria. SNPs in the IL-1alpha (+ 4845) and IL-1beta (- 511, + 3954) genes were analyzed by amplifying the polymorphic region using polymerase chain reaction (PCR), followed by restriction-enzyme digestion and agarose gel electrophoresis. IL-1RN (VNTR) polymorphisms were then detected by PCR amplification and fragment size analysis. RESULTS: There was no significant difference in the IL-alpha (+ 4845) and IL-1beta (- 511, + 3954) genotypes and allele frequencies between G-EOP patients and healthy controls. However, the frequency of IL-1RN (VNTR) polymorphic alleles was found to be significantly increased in G-EOP patients (chi2 test, P = 0.007; odds ratio = 3.40). Additionally, the carriage rate of IL-1RN (VNTR) polymorphisms was significantly higher in G-EOP patients than in healthy controls (chi2 test, P = 0.005; odds ratio = 3.81). CONCLUSION: These findings suggest that IL-1RN (VNTR) polymorphisms are associated with G-EOP in Japanese.     

影响早发性牙周炎易感性的相关免疫因素

宿主免疫功能在早发性牙周炎(early-onset periodontitis,EOP)发病中的作用一直备受关注。近年许多研究发现EOP常呈家族性发病，且多数患者对细菌感染有异常的外周血中性粒细胞或单核细胞反应。但与疾病相关的宿主易感因素的研究仍众说纷纭，本文就影响EOP易感性的宿主遗传免疫特质的各方面研究进展进行综述。     

Interleukin-4 polymorphisms in early onset periodontitis

BACKGROUND, AIMS: Periodontitis is the result of a complex interplay between oral bacteria and the host response, often modulated by behavioral factors. Early-onset periodontitis (EOP) is defined by the age of onset, the distribution of lesions and specific microbial pathogens. METHOD: Studies in twins suggested a genetic contribution to the pathogenesis of periodontitis. EOP heritable factors may be related to immune mechanisms which could enhance the pathogenic potential of plaque bacteria in susceptible individuals. Among others, Interleukin 4 (IL-4) is a potent cytokine in the immune response and is a potent down regulator of macrophage function. In the present study, we report a specific genotype of the IL-4 gene, which was detected by specific primers and PCR analysis. RESULTS: In the EOP-group 27.8% were IL-4 promotor- and intron polymorphism positive (PP+ and IP+). None of the age-matched healthy controls or patients with adult periodontitis (n=25) carried the markers. Moreover, serum IL-4 levels of PP+ and IP+ patients were below the detection limit and significantly different (p<0.01) from the IL-4 concentrations of healthy controls and PP- and IP- patients.     

The association of the composite IL-1 genotype with periodontitis progression and/or treatment outcomes: a systematic review

BACKGROUND: Genetically transmitted traits such as cytokine gene polymorphisms may accentuate the host inflammatory response to the bacterial challenge and influence susceptibility to periodontitis. OBJECTIVE: To systematically review the evidence of an association between the interleukin-1 (IL-1) composite genotype, i.e. presence of the allele 2 in the gene clusters IL-1A-889 and in IL-1B +3953, and periodontitis progression and/or treatment outcomes. Material and Methods: Based on the focused question, a search was conducted for longitudinal clinical trials comparing progression of periodontitis and/or treatment outcomes in IL-1 genotype-positive (carrying allele 2) and IL-1 genotype-negative (not carrying allele 2) subjects. A search in the National Library of Medicine computerized bibliographic database MEDLINE and a manual search were performed. Selection of publications, extraction of data and validity assessment were made independently by two reviewers. RESULTS: The search provided 122 titles of which 11 longitudinal publications were included. The heterogeneity of the data prevented the performance of a meta-analysis. While findings from some publications rejected a possible role of IL-1 composite genotype on progression of periodontitis after various therapies, other reported a prognostic value for disease progression of the positive IL-1 genotype status. When assessed on a multivariate risk assessment model, several publications concluded that the assessment of the IL-1 composite genotype in conjunction with other covariates (e.g. smoking and presence of specific bacteria) may provide additional information on disease progression. The small sample size of the available publications, however, requires caution in the interpretation of the results. CONCLUSION: Based on these findings, (i) there is insufficient evidence to establish if a positive IL-1 genotype status contributes to progression of periodontitis and/or treatment outcomes. Therefore, (ii) results obtained with commercially available tests should be interpreted with caution.     

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.     

Prevalence of Porphyromonas gingivalis fimA genotypes in Caucasians

The aim of the present study was to determine the prevalence of Porphyromonas gingivalis fimA genotypes in Caucasian patients with periodontitis. A total of 102 patients harboring P. gingivalis subgingivally were enrolled into the study. Pooled subgingival plaque samples of the six most severely affected sites were taken and analysed by fimA-specific polymerase chain reaction (PCR) and restriction analysis. Moreover, 26 P. gingivalis isolates were analysed by sequence analysis of the fimA gene. Sequence analysis revealed five major fimA genotypes (fimA types I-V) and allowed further subtyping of fimA genotypes II and IV into two subgroups each. The overall prevalences of fimA genotypes as assessed by PCR and restriction analysis among the P. gingivalis-positive patients with periodontitis were: type I, 25.5%; type II, 38.2%; type III, 4.9%; type IV, 18.6%; type V, 3.9%; and non-typable, 6.9%. Two patients were colonized by both type II and type IV, or type III and type IV fimA genotypes, respectively. Patients harboring different fimA genotypes showed no significant difference in severity of periodontal disease, as assessed by pocket probing depth and bleeding on probing following adjustment for smoking habit and age. The results indicate that predominant fimA genotypes in Caucasian periodontitis patients are types I, II, and IV. However, there was no difference in the association of the various fimA genotypes with disease severity.     

Total IgA and Porphyromonas gingivalis-reactive IgA in the saliva of patients with generalised early-onset periodontitis

Generalised early-onset periodontitis (GEOP) is characterized by acute inflammatory bursts, resulting in rapid destruction of the periodontal apparatus in young adults. An impaired host defense seems to play an important role as etiological factor of periodontitis, especially in the development of GEOP. As the gram-negative Porphyromonas gingivalis has been identified as one of the causative anaerobic bacteria, the humoral immune response to this micro-organism is of particular interest in patients with GEOP. To evaluate the local immune status, we measured total and P. gingivalis-reactive salivary IgA in GEOP patients and in age- and gender-matched periodontally normal controls. We found a significantly lower concentration and secretion rate of total salivary IgA in the GEOP group. Although no differences were detected in the concentration or secretion of P. gingivalis-reactive IgA between groups, the specific fraction of P. gingivalis-reactive IgA of the total IgA was significantly higher in the GEOP group. These findings indicate an inhibition of total secretory IgA in GEOP, while the P. gingivalis-reactive humoral immune system in saliva is, however, activated. P. gingivalis seems to selectively activate IgA lymphocyte clones and induces a switch in the fraction of specific IgA.     

Tumoral calcinosis associated with early onset periodontitis

A rare case of tumoral calcinosis (TC) with oral manifestations is presented in a 5-year-old child. The possible correlation between prepubertal periodontitis and TC is suggested and discussed.     

Analysis of genetic polymorphisms at the interleukin-10 and tumour necrosis factor loci in early-onset periodontitis

Early onset periodontitis (EOP) is considered to have a substantial genetic basis, although the gene or genes involved have not been elucidated. The aim of the present study was to investigate possible links between generalized EOP (GEOP) and genes regulating expression of the cytokines tumour necrosis factor (TNF) and interleukin-10 (IL-10). Microsatellite marker DNA sequences corresponding to phenotypic variations in cytokine response were analysed. Genotypic variations in cytokine response have been shown in vitro for TNF and IL-10, and specific alleles are implicated in diseases such as systemic lupus erythmatosus (SLE) and rheumatoid arthritis (RA). Two microsatellites at the IL-10 locus, IL10.R and IL10.G, and 1 microsatellite at the TNF locus, TNFa, were typed for 77 GEOP patients in the West of Scotland. Due to the highly polymorphic nature of the microsatellite loci, a statistical comparison with ethnically matched healthy controls (TNFa, n = 91, IL10.R, n = 94, IL10.G, n = 102) was conducted using a Monte Carlo simulation for each marker. No significant differences were observed for any of the 3 markers, although there were possible indications of trends similar to those observed in SLE for the IL10.G marker. In conclusion, no links were found between GEOP and microsatellites at TNFa, IL10.R or IL10.G loci.     

白细胞介素-10基因型与墨玉县维吾尔族成人慢性牙周炎易患性的相关性研究

目的 探讨白细胞介素-10（IL-10）基因-597（C/A）位点单核苷酸多态性与新疆维吾尔自治区墨玉县维吾尔族成人慢性牙周炎（CP）之间的相关性。方法 随机选取2013年4—5月本课题组对新疆墨玉县维吾尔族成人进行的口腔健康流行病学调查资料及采集的颊黏膜拭子样本共300例,根据纳入排除标准将其分为健康对照组、轻度CP组和中重度CP组,每组各100例。采用四引物等位基因特异性聚合酶链反应扩增法检测受试者IL-10-597位点基因型和等位基因的分布。采用卡方检验、有序多分类Logistic回归等方法进行统计学分析。结果 IL-10-597基因型及等位基因频率在健康对照组、轻度CP、中重度CP组分布的差异均无统计学意义（P>0.05）;抽取样本人群的年龄与CP具有相关性,55~65岁人群患CP的风险是低于35岁人群的25倍（OR=25.56,P<0.001）。结论 IL-10-597（C/A）位点单核苷酸多态性与维吾尔族成人CP的发病风险无明显相关性。     

Neutrophil chemotactic behaviour in patients with early-onset forms of periodontitis

Despite some reports to the contrary, it is generally assumed that early-onset forms of periodontal disease (including both juvenile and rapidly progressive periodontitis) are associated with a defect in neutrophil (PMN) chemotactic behaviour. Using the Boyden chamber technique and N-formyl-methionyl-leucylphenylalanine (FMLP) to assess locomotion by the leading front method, we have failed to show any evidence for such depressed PMN locomotion. Indeed, when PMN chemotaxis and chemokinesis are considered in response to a range of chemoattractant doses our results indicate significant enhancement of all but random locomotion. When taken together with other studies, our results suggest that PMNs from patients with early-onset periodontitis may show abnormal locomotory behaviour which can either be enhanced or reduced in nature. The extent to which these results reflect in vitro methodology in uncertain and, furthermore, their in vivo significance is unclear.     

Association of IL1 gene polymorphisms with chronic periodontitis in Brazilians

Chronic periodontal disease (PD) is an infectious immune-inflammatory illness. Polymorphisms in IL1 genes play a role in inflammatory diseases through the modulation of cytokine levels.

Objective

This study aimed to investigate the association between polymorphisms in the IL1 gene cluster and chronic periodontitis in a Brazilian population.

Design

A sample of 113 subjects over 25 years (mean age 41.2) were grouped into: 44 healthy individuals, 31 subjects with moderate and 38 with severe periodontitis. DNA was obtained through a mouthwash and oral mucosa scraping. PCR-RFLP was used to identify the following polymorphisms: IL1A C − 889T (rs1800587), IL1B C − 511T (rs16944), IL1B C + 3954T (rs11436340), IL1RN intron 2 (rs2234663). Differences in the allele/genotype/haplotype frequencies were assessed by Chi-square test (p < 0.05). The risk associated with alleles, genotypes and haplotypes was calculated as odds ratio (OR) with 95% confidence intervals (CI).

Results

Neither IL1A (C − 889T) nor IL1B (C + 3954T) polymorphisms was associated with chronic PD. Allele T for IL1B (C − 511T) only associated with PD in the group of blacks and mulattos. Moreover, genotype 2/2 for IL1RN (intron 2) was associated with severe PD.

Conclusions

Genotype 2/2 of IL1RN for the whole Brazilian population and allele T of IL1B (C − 511T) in a subgroup of Afro-Americans and mulattos were suggested as putative risk indicators for chronic periodontitis.     

A functional interleukin-1 beta gene polymorphism is associated with chronic periodontitis in a sample of Brazilian individuals

BACKGROUND: Interleukin-1 beta (IL-1 beta) is a potent inflammatory mediator and an important polymorphism in the locus +3954 (C/T) of the human IL1 B gene has been shown to affect the levels of this cytokine. This functional polymorphism has been associated with the establishment of inflammatory diseases, including periodontal disease, in European, Asian and North American populations. OBJECTIVE: The aim of this study was to investigate the association between the IL1 B (+3954) gene polymorphism and the occurrence of different clinical forms of periodontitis in a sample of Brazilian individuals. METHODS: This study employed a cross-sectional design involving individuals from the State of Minas Gerais in the south-eastern region of Brazil. Genomic DNA was obtained from oral swabs of 129 individuals and amplified using the polymerase chain reaction (PCR) with specific primers flanking the locus +3954 of IL1 B. PCR products were submitted to restriction endonuclease digestion and analyzed by polyacrylamide gel electrophoresis, to distinguish alleles T and C of the IL1 B gene, allowing for the determination of the genotypes and detection of the polymorphism. RESULTS AND CONCLUSIONS: The chronic periodontitis group displayed a higher percentage of the T allele (28%) when compared to the aggressive periodontitis group (10.7%, chi(2)=5.24, p=0.02, OR=0.31, CI=0.11--0.88) and to control group (8.7%, chi(2)=7.11, p=0.007, OR=0.24, CI=0.08--0.73). Our data suggested that the polymorphism in the locus +3954 of IL1 B gene could be a risk factor for chronic periodontitis in a sample of Brazilian individuals.     

Possible autosomal-dominant inheritance of prepubertal periodontitis in an extended kindred

Abstract This study presents the clinical findings and the distribution of prepubertal periodontitis in an extended family with high prevalence of this entity. The expression of surface markers and adhesion molecules on peripheral lymphocytes were also studied. Approximately 50% of the children in this family suffered from prepubertal periodontitis. All the affected children were otherwise healthy. 2 identical twins were similarly, but not identically, affected. Detailed laboratory tests and analysis of lymphocyte surface marker expression, including CD 18, were all within the normal levels. Both localized and generalized forms of prepubertal periodontitis were found. The high prevalence of prepubertal periodontitis in the 2 branches of this family, and the fact that identical twins were similarly affected, suggest a strong genetic predisposition for prepubertal periodontitis. The family pedigree is consistent with an autosomal-dominant mode of transmission. The coexistence of localized and generalized forms of the disease in sibs suggests the same genetic etiology for both entities with variability in disease expression. This variability in disease expression is further supported by the fact that 2 identical twins were not identically affected.     

IL-1 genotypes associated with adult severe periodontitis are not associated with generalized early onset periodontitis

J Evid Base Dent Pract 2002;2:60-61     

Interleukin-2 −330 and 166 gene polymorphisms in relation to aggressive or chronic periodontitis and the presence of periodontopathic bacteria

Background and Objective: As a pro‐inflammatory cytokine, interleukin‐2 mediates the activation, growth and differentiation of T and B lymphocytes and natural killer cells. Promoter polymorphisms of the interleukin‐2 gene have been associated with altered interleukin‐2 production or identified as prognostic markers for various infectious diseases. Therefore, the aim of this study was to evaluate two polymorphisms at positions ?330 T/G and 166 G/T in patients with generalized chronic periodontitis (n = 58) or generalized aggressive periodontitis (n = 73) in comparison with periodontitis‐free controls (n = 69). Material and Methods: Both interleukin‐2 polymorphisms were analyzed using the polymerase chain reaction with sequence‐specific primers. Distributions of single alleles, genotypes and haplotypes were calculated using the chi‐square test. Risk factor analyses were carried out by logistic regression with respect to established cofactors for periodontitis. The presence of subgingival bacteria in an individual were analyzed using a molecular biological method (the micro‐Ident^® test). Results: The interleukin‐2 genotype ?330 TG occurred less frequently in patients with chronic periodontitis (25.9% vs. 49.3%). Moreover, this genotype decreased the adjusted odds ratio for chronic periodontitis (odds ratio = 0.394), whereas the interleukin‐2 genotype 166 TT and the haplotype combination interleukin‐2 ?330,166 TT : TT were associated with an increased adjusted odds ratio (odds ratio = 2.82 or 2.97). For the latter interleukin‐2 combination, a positive association for the subgingival presence of Porphyromonas gingivalis (81.3% vs. 59.5%) and bacteria of the ‘red complex’ (78.1% vs. 56.0%) was shown. Conclusion: The interleukin‐2 genotypes ?330 TG and 166 TT, as well as the combination genotype interleukin‐2 TT : TT, could be putative prognostic factors for chronic periodontitis.