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The Interleukin-1 Polymorphism, Smoking, and the Risk of Periodontal Disease in the Population-based SHIP Study
1 Departments of Pharmacology, Correspondence: *corresponding author, meiselp{at}uni-greifswald.de
Several studies have shown a role for interleukin-1 gene cluster polymorphisms in the risk assessment for periodontal diseases. In the Study of Health in Pomerania (SHIP), 3148 subjects were randomly selected from the population and assessed for a broad range of diseases and environmental/behavioral risk factors. From the complete study group in the age 40 to 60 years, N = 1085 subjects were genotyped for the interleukin-1 genotype composite polymorphism in relation to periodontal parameters. The study objective was to elucidate the gene-environment interaction between the risk factors smoking and IL-1 polymorphism. An increased risk of periodontal disease was found for IL-1 genotype-positive smokers: odds ratio adjusted for age, sex, education, and plaque OR = 2.50 (95% C.I. 1.21 to 5.13; p = 0.013). This was not the case with subjects who never smoked: OR = 1.09 (0.73-1.62; p = 0.676). These results support the hypothesis of gene-environmental interaction in periodontitis.
Key Words: periodontal diseases • smoking • interleukin-1 • polymorphism • epidemiology
The interleukin-1 family of cytokines has a wide range of activities involved in the genesis and maintenance of inflammatory responses. In periodontal diseases, inflammation and connective tissue destruction are crucial steps in their pathogenesis in which these cytokines are central mediators. Therefore, research efforts focus on the role of these interleukins in the development and course of the condition (Kornman and diGiovine, 1998; Graves, 1999; Boch et al., 2001). 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.
Subjects From a population of 210,000 inhabitants of the German part of Pomerania, we randomly selected 3148 subjects, designated as the SHIP study. From 32 communities in the region, a simple random sample was drawn from residence registries, stratified by gender and age. The design of the study, recruiting of participants, and the scope of this population-based cross-sectional health survey were outlined by John et al. (2001). Participants gave their written informed consent, and the study was approved by the local ethics committee. In this group, the most profound smoking-related differences in periodontal parameters were recognized between ages 40 and 60 yrs. Therefore, all subjects in the age range 40 to 60 yrs (N = 1103) were included in this study. Characteristics of the subjects genotyped, relevant to the objective of the study, are displayed in Table 1  .
Anamnestic and Periodontal Examinations The smoking status and habits of all subjects were assessed by an extensive questionnaire comprised of 31 items concerning present and past quality and quantity of smoking. The items included questions as to whether the subjects had ever used tobacco products, the age at which they started smoking (and, if applicable, ceased smoking), and the frequency and duration of the smoking. In an independent study (N = 335), we proved by cotinine determinations that not more than 2 to 3% of the subjects gave answers inconsistent with their true smoker behavior. Investigations in representative population samples provided evidence that self-reported smoking status is accurate (Caraballo et al., 2001). 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
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
Gene-environmental interactions were calculated from two-by-four contingency tables (Botto and Khoury, 2001). Adjustment for sex, age, plaque, education level, and smoking was carried out by logistic regression analyses (StatView®, SAS, Cary, NC, USA).
The distribution of IL-1-positive composite genotypes among all subjects being between 30% and 40% was found to be in concordance with the frequencies reported in other studies in Caucasians (Papapanou et al., 2001). Subject characteristics revealed only minor differences in periodontal parameters between IL-1-positive and -negative subjects (Table 1  ).
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
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
Since the first report of a relationship between the IL-1 genotype and adult periodontitis (Kornman et al., 1997), this association has been confirmed in numerous other studies, sometimes also with controversial conclusions. McDevitt et al. (2000) demonstrated that patients bearing the positive genotype, when compared with those with the negative genotype, show an increased risk of suffering from moderate and advanced periodontitis. The interleukin-1 genotype exerts a contributing but not exclusive influence on the disease (Diehl et al., 1999). In contrast, contradictory results have been published disputing a role of IL-1 haplotypes in early-onset (Hodge et al., 2001) or adult periodontal diseases (Ehmke et al., 1999). 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.
This work is part of the Community Medicine Research net (CMR) of the University of Greifswald, Germany, funded by the Federal Ministry of Education and Research (grant no. ZZ9603), the Ministry of Cultural Affairs, and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. The CMR gathers several research projects which share data from the population-based Study of Health in Pomerania Received for publication November 1, 2001. Revision received October 28, 2002. Accepted for publication November 22, 2002.
Journal of Dental Research, Vol. 82, No. 3,
189-193 (2003) This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
2 for trend = 5.46 (p = 0.019). (B) Subjects who have never smoked (N = 515).
