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RESEARCH REPORT |
1 Departments of Pharmacology,
2 Genetics,
3 Epidemiology, and
4 Periodontology, Ernst Moritz Arndt University, F-Loeffler-Str. 23d, D-17487 Greifswald, Germany;
*corresponding author, meiselp{at}uni-greifswald.de
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS & METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: periodontal diseases • smoking • interleukin-1 • polymorphism • epidemiology
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS & METHODSRESULTSDISCUSSIONREFERENCES |
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Several studies have shown a role for interleukin-1 gene cluster polymorphisms in the risk assessment for periodontal diseases (Kornman et al., 1997; McDevitt et al., 2000; Cullinan et al., 2001). A combined genotype with single nucleotide exchanges in the IL-1A and IL-1B gene was found to be associated with an increased risk of periodontitis. In the original reports, smokers were excluded, and it was hypothesized that smoking could obscure the association of the genetic factor to the disease. Consequently, in later studies, smoking was considered as an exclusion criterion (McDevitt et al. 2000; Cattabriga et al., 2001).
Recently, we reported a study dealing with a possible interaction among the IL-1 genotype, the periodontal phenotype of alveolar bone loss, and smoking (Meisel et al., 2001). This study revealed an obvious over-representation of genotype-positive subjects among patients with severe forms of periodontitis in smokers, but not in non-smokers. Since smoking is one of the main environmental risk factors in periodontal disease, biasing of the results could not be excluded. Moreover, the 154 subjects studied at that time were recruited from the periodontal care unit, and smokers are known to be over-represented in periodontal clinics as compared with the normal population (Haber and Kent, 1992). Thus, there are contradictory results regarding the IL-1 genotype-associated risk of periodontitis with respect to the impact of smoking as an environmental factor.
We have now addressed the association between IL-1 polymorphism and the smoking habit in a broader sense. The SHIP study (Study of Health In Pomerania) is a population-based, cross-sectional survey to describe prevalences and distributions of a broad range of diseases as well as environmental and behavioral risk factors in the northeast German region of Pomerania (John et al., 2001).
The aim of this study was to elucidate the role of the IL-1 polymorphism as a risk factor for periodontal diseases in a randomly selected population. Special attention was paid to the subjects’ smoking history so that the interaction among smoking, genotype, and periodontal disease could be elucidated.
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MATERIALS & METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS & METHODSRESULTSDISCUSSIONREFERENCES |
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Periodontal status was assessed by trained dentists, including probing depth, attachment loss, bleeding on probing, and presence of plaque. The periodontal examination was performed on either the left or right quadrant, and the examination side was changed from subject to subject. All fully erupted teeth were assessed, excluding third molars. A maximum of 14 teeth per subject was examined. Attachment loss and probing depth were assessed with a periodontal probe (PCP 11, Hu-Friedy, Chicago, IL, USA) at mesiobuccal, distobuccal, midbuccal, and midlingual aspects on each selected tooth. The measurements were made in whole millimeters.
Genotyping and Statistics
Of the 1103 Caucasian subjects enrolled, 1085 were successfully genotyped for IL-1 polymorphisms; the remaining refused DNA analyses, or genotyping failed. Genotyping for the mutations of the IL-1 gene cluster was performed at positions IL-1B +3954 and IL-1A -889 according to methods described elsewhere (Meisel et al., 2001). Subjects heterozygous or homozygous with variant alleles 2 at each of the sites analyzed were designated as "genotype-positive". This is the composite genotype suggested to be a susceptibility factor for an enhanced periodontitis risk (Kornman et al., 1997).
To avoid any arbitrarily chosen disease criteria in risk assessment, we used strictly statistical methods to distinguish periodontally "healthy" from "diseased" subjects. Thus, for the extent of attachment loss (percent of sites examined which exceeded 4 mm), quartiles and quintiles were calculated, and subjects in the upper quantiles of distribution were compared with those in the lower quantiles with no or minor attachment loss (as indicated in Fig. 1 and Table 2). Interaction effect of nominal independent on continuous dependent variables (attachment loss, number of teeth) was analyzed by ANOVA.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS & METHODSRESULTSDISCUSSIONREFERENCES |
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).
Crude odds ratios were calculated for the risk of belonging to the groups with an increased extent of periodontal disease. For smokers, IL-1 genotype-positive subjects had an increased risk of a higher proportion of sites with an attachment loss exceeding 4 mm. In contrast, in subjects who never smoked, this association was not detectable (Fig. 1).
Comparing subjects exhibiting a high extent of attachment loss (4th to 5th quintiles of percent attachment loss > 4 mm) with a reference group of those with attachment loss in the lowest quintiles confirmed the observation (Table 2A). Obviously, in these subjects randomly selected from the general population, there exists a significantly increased risk of belonging to the "diseased" group for genotype-positive subjects who are present or former smokers. This is not the case with subjects who never smoked. Analysis by logistic regression including, age, sex, education, and plaque in addition to the IL-1 genotype as independent variables resulted in the odds ratios shown (Table 2B). As expected, the probability of a subject’s belonging to the more affected group decreases when being female, with higher education; it increases with age, plaque extent, smoking, and when being IL-1 genotype-positive. Again, in this analysis, only in smokers was the IL-1 genotype significantly associated with the extent of attachment loss. This association remained significant regardless of the smoking item included in the logistic analysis, namely, subjects smoking currently or subjects who ever smoked regularly, i.e., at least one cigarette per day.
Final state of periodontal diseases is the loss of teeth. Despite the high variability of the number of teeth, further indication came from comparison of the number of remaining teeth with respect to the gene-environmental interaction (Fig. 2). In this cross-sectional study, smoking subjects have lost more teeth than their non-smoking counterparts, regardless of the IL-1 genotype. If IL-1 genotype-positive, however, smokers suffered from an increased rate of tooth loss. This was most obvious with respect to current smokers and is still significant for former and current smokers taken together (see Fig. 2 for significance). There was no age-related bias, since smokers tend to be younger than non-smokers (in this study, median age 48 and 51 yrs, respectively).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS & METHODSRESULTSDISCUSSIONREFERENCES |
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In an earlier study, we have shown that neither the positive genotype for periodontal risk nor the frequency of the allele 2 of the IL-1A or IL-1B genes was found to be correlated with the mean bone loss or any mean clinical parameters (Meisel et al., 2001). However, with respect to the extent of the disease, there was an association of the condition with the positive genotype in smokers but not in non-smokers. Now these results were confirmed by a population-based study without a selection bias. Only in the group of genotype-positive smokers did the odds ratios indicate an increased risk of periodontal disease; moreover, the mean values of periodontal measuring parameters were also increased. These results are quite a contrast to the study presented by Kornman et al. (1997). In their study, smokers were explicitly excluded considering that the smoking-related risk could obscure the polymorphism-related increase in risk. Likewise, an analysis of the association between the IL-1 genotype and bleeding on probing in the whole population (including smokers) did not reach statistical significance because of the overriding effect of smoking (Lang et al., 2000). Thus, it was suggested that both smoking and the IL-I genotype are independent factors in severe periodontitis (Kornman and diGiovine, 1998). The study by McDevitt et al. (2000) suggested an interaction between IL-1 genotype and smoking. Thus, it seems quite reasonable to evaluate possible interactions of both risk factors, smoking and genotype. With respect to tooth survival time, it was demonstrated in a prognostic study that heavy smoking and a positive genotype act as synergistic risk factors for early tooth loss (McGuire and Nunn, 1999). Genotype-positive or -negative non-smokers as well as genotype-negative smokers showed nearly identical tooth survival rates. With respect to the extent of periodontal disease expressed in terms of attachment loss as well as the number of teeth, this interaction between IL-1 genotype and smoking was confirmed by the data presented here. Smoking is the more important risk factor: It increases the risk of periodontitis regardless of the genotype. This risk is further aggravated in subjects being IL-1 genotype-positive. In early-onset periodontitis (EOP), a significant difference was found in the IL-1B genotype distribution between EOP smokers compared with the control group of smokers, but not between EOP non-smokers and control non-smokers (Parkhill et al., 2000).
The interaction of environmental factors with periodontal diseases is poorly understood. With respect to smoking, direct local effects as well as systemic effects can be distinguished. Complex interactions are to be taken into consideration between circulatory and immunological effects exerted by nicotine and toxic effects by arylamines. A synergistic risk pattern may explain the genetic-environmental interaction. Phenotypic differences exist in interleukin levels corresponding to the genotype, and these differences are related to periodontal disease (Engebretson et al., 1999). The positive IL-1 genotype results in enhanced levels of pro-inflammatory cytokines, and an increased formation of interleukins is known to be induced by nicotine and/or bacterial lipopolysaccharides (Wendell and Stein, 2001; Zeidel et al., 2002). These changes may serve as predisposing factors in periodontal disease. Moreover, the IL-1 polymorphisms are highly related to plasma levels of CRP and fibrinogen (Berger et al., 2002). These and other markers of systemic inflammation are influenced by tobacco smoking, possibly by a smoking-induced tissue inflammation (Das, 1985; Fredriksson et al., 2002). In conclusion, synergistic actions of smoking and IL-1-related genetic factors may explain the association of risk factors shown.
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ACKNOWLEDGMENTS |
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Received November 1, 2001; Last revision October 28, 2002; Accepted November 22, 2002
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REFERENCES |
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2 for trend = 5.46 (p = 0.019). (B) Subjects who have never smoked (N = 515).