The functional effects of the -455G/A polymorphism on the IL-6-induced expression of the beta-fibrinogen gene may be due to linkage disequilibrium with other functional polymorphisms.

Elevated plasma fibrinogen levels have been identified as an independent risk factor for coronary heart diseases, stroke and peripheral artery disease. The -455G/A polymorphism in the promoter region of the beta-fibrinogen gene has been associated with increased plasma fibrinogen levels. However, the functional effect of this polymorphism has been controversial and other polymorphisms in the fibrinogen gene have also been implicated in higher fibrinogen levels. In this study, we evaluated the transcriptional activity of 4 natural haplotypes and 6 artificial haplotypes in the promoter region of the beta-fibrinogen gene. Significantly lower IL-6-induced activity was observed in the -1420A and -148T alleles. In contrast, the -854A allele had significantly higher activity. Artificial haplotypes containing the -1420A, -854A and -148T alleles were also analyzed to confirm individual functional effects. The -1420A and -148T alleles significantly lowered the activities, while the -854A allele significantly raised the activity. From this study we conclude that the -1420G/A, -854G/A and -148C/T polymorphisms in the beta-fibrinogen promoter region are functional polymorphisms while the -455G/A polymorphism may not be a functional one, and that the association of the -455G/A polymorphism with higher fibrinogen levels may actually be due to linkage disequilibrium between the -455G/A polymorphism and other truly functional polymorphisms.

Association of Fcgamma receptor IIa genotype with chronic periodontitis in Caucasians.

BACKGROUND: Functional polymorphisms of immunoglobulin G (IgG) Fc receptors IIIa and IIIb (FcgammaRIIIa and FcgammaRIIIb) have been shown as risk factors for periodontitis. The aim of this study is to examine whether FcgammaRIIa polymorphism is associated with a disease risk as well. METHODS: Baseline periodontal and general health examinations were carried out on 1,221 Caucasian adults. From these, 422 subjects with moderate to severe, or little or no periodontal disease were assigned to two groups according to their mean clinical attachment loss (CAL). Subjects with mean CAL > or = 2.94 mm were diagnosed with chronic periodontitis (n = 213, 62 never-smokers and 151 smokers). Subjects with mean CAL < or = 1.77 mm were considered as having little or no periodontal disease and designated as controls (n = 209, 125 never-smokers and 84 smokers). The FcgammaRIIa genotype for three bi-allelic polymorphisms (FcgammaRIIa-R/ R131, R/H131, and H/H131) was determined by means of allele-specific polymerase chain reactions. RESULTS: The distribution of FcgammaRIIa genotype between the patient and control groups was significantly different, with enrichment of the high ligand-binding genotype FcgammaRIIa-H/H131 in the patients (patients versus controls: 36.6% versus 25.4%; P = 0.04). Multivariate logistic regression model demonstrated that subject age and gender, smoking, and the FcgammaRIIa genotype were significantly associated with severity of chronic periodontitis. For smokers, a significant over-representation of FcgammaRIIa-H/H131 in the patient group compared to the control group (patients versus controls: 35.1% versus 19.0%; P = 0.03). Additionally, smokers with FcgammaRIIa-H/H131 exhibited significantly greater mean CAL (mean +/- SE: 3.44 +/- 0.16 mm) than those with FcgammaRIIa-R/H131 (2.91 +/- 0.14 mm) and R/R131 (2.82 +/- 0.16 mm) (P = 0.04). There was no association between FcgammaRIIa genotype and the disease susceptibility or severity in subjects who had never smoked. CONCLUSIONS: Our results suggest that the FcgammaRIIa-H/H131 genotype may be associated with chronic periodontitis risk (and disease severity) in Caucasian smokers. Further studies with families and studies of mechanisms are necessary to help establish the extent to which this is a genetic determinant of periodontal diseases.

Association of increased levels of fibrinogen and the -455G/A fibrinogen gene polymorphism with chronic periodontitis.

BACKGROUND: Fibrinogen is one of the acute-phase proteins whose levels are elevated during periodontal disease. Recent studies suggest that excessive fibrinogen production might play a role in upregulating host immune responses. In addition, there is a relationship between the -455G/A polymorphism (HaeIII) in the 5' flanking region of the beta-fibrinogen gene promoter and increased fibrinogen levels. In this study, we investigated the distribution of the -455G/A polymorphism and the relationship of this specific genotype to fibrinogen levels in periodontitis patients. METHODS: In order to assess the -455G/A polymorphism, restriction fragment length polymorphism (RFLP) analysis with HaeIII enzyme was performed in the promoter region of the beta-fibrinogen gene. This was carried out on 79 chronic periodontitis patients as compared to 75 periodontally healthy subjects, matched to age, gender, and race. Fibrinogen levels were determined by the radial immunodiffusion assay (RID). RESULTS: The frequency of homozygocity for the rare allele of the beta-fibrinogen gene (H2H2) was 13% for the periodontitis patients and 3% for the control group (P = 0.01). The distributions of H1H1 and H1H2 genotypes were 48% and 39% in the patient group and 70% and 27% in the control group, respectively. Chi-square analysis indicated that the distribution of these genotypes between the 2 groups was significantly different (P = 0.01). Fibrinogen levels were significantly higher in the patient group (2,496.5 mg/l +/- 105) compared to the control group (2,250.0 mg/l +/- 118.3) after adjusting for age, gender, and smoking status (P = 0.04). Consistent with previous reports, in our study population, those subjects with the H2H2 genotype had significantly higher fibrinogen levels (3,005.7 mg/l +/- 182.5) compared to subjects with the H1H1 genotype (2,325.0 mg/l +/- 91.6) or H1H2 genotype (2,438.0 mg/l +/- 117.4) (P = 0.001). Furthermore, the H1H2 and H2H2 genotypes were found at a higher frequency among periodontitis patients than controls. The odds ratios (OR) for these genotypes were 3.26 (95% confidence interval [CI]: 1.25 to 8.53) for the H1H2 genotype and 6.41 (95% CI: 1.15 to 35.83) for the H2H2 genotype as compared to individuals with the H1H1 genotype, after adjusting for age, gender, and smoking status. CONCLUSIONS: The results indicate that a higher percentage of chronic periodontitis patients exhibit genotypes associated with higher plasma fibrinogen levels than healthy individuals. Furthermore, periodontitis patients have significantly higher fibrinogen levels compared to healthy individuals. The presence of H1H2 or H2H2 genotypes as well as elevated fibrinogen levels, in conjunction with other factors, may put individuals at higher risk of having periodontal disease, or may result from periodontal infection-genetic interactions.

Systemic inflammation in cardiovascular and periodontal disease: comparative study.

Epidemiological studies have implicated periodontal disease (PD) as a risk factor for the development of cardiovascular disease (CVD). These studies addressed the premise that local infection may perturb the levels of systemic inflammatory mediators, thereby promoting mechanisms of atherosclerosis. Levels of inflammatory mediators in the sera of subjects with only PD, only CVD, both diseases, or neither condition were compared. Subjects were assessed for levels of C-reactive protein (CRP), serum amyloid A (SAA), ceruloplasmin, alpha(1)-acid-glycoprotein (AAG), alpha(1)-antichymotrypsin (ACT), and the soluble cellular adhesion molecules sICAM-1 and sVCAM by enzyme-linked immunoabsorbent and/or radial immunodiffusion assays. CRP levels in subjects with either condition alone were elevated twofold above subjects with neither disease, whereas a threefold increase was noted in subjects with both diseases (P = 0.0389). Statistically significant increases in SAA and ACT were noted in subjects with both conditions compared to those with one or neither condition (P = 0.0162 and 0.0408, respectively). Ceruloplasmin levels were increased in subjects with only CVD (P = 0.0001). Increases in sVCAM levels were noted in all subjects with CVD (P = 0.0054). No differences in sICAM levels were noted among subject groups. A trend toward higher levels of AAG was noted in subjects with both conditions and for ACT in subjects with only PD. Immunohistochemical examination of endarterectomy specimens of carotid arteries from subjects with atherosclerosis documented SAA and CRP deposition in association with atheromatous lesions. The data support the hypothesis that localized persistent infection may influence systemic levels of inflammatory mediators. Changes in inflammatory mediator levels potentially impact inflammation-associated atherosclerotic processes.

The Molecular Basis for Neutrophil Dysfunction in Early-Onset Periodontitis.

In recent years, much debate has surrounded the neutrophil defects associated with localized juvenile periodontitis (LJP). Controversy exists on the existence of the defect itself, its genetic nature, and the molecular entities and mechanisms which may be involved in such defects and subsequent biological phenomena. This review attempts to summarize neutrophil functions and their role in periodontal diseases, as well as the observed neutrophil defects reported for LJP. J Periodontol 1996;67:345-354.