Periodontology 2000, Vo. 29, 2002, 177-205 Printed in Denmark, All rights reserved Copyright © Blackwell Munksgaard 2002 PERIODONTOLOGY 2000 Iss 006-6713 Global risk factors and risk indicators for periodontal diseases Jasmm M. ALBANDAR A commendable appreciation of risk factors for de- structive forms of periodontal diseases requires a good understanding of the etiological factors and pathogenesis of these diseases. Periodontal diseases ‘are chronic infectious disorders caused primarily by bacteria. Gingivitis is a nondestructive form of periodontal diseases (158, 179). Experimental gingi- vitis studies (146, 211) provided the first empiric evidence that accumulation of dental plaque bi- ofilms on clean tooth surfaces results in the devel- ‘opment of an inflammatory process encompassing local gingival and periodontal tissues around teeth. Research has also shown that the local inflam- mation will persist as long as the bacterial biofilm is present adjacent to the gingival tissues, and that, the inflammation may resolve subsequent to meticulous removal of the microbial biofilm (211). Hence, chronic gingivitis is a predictable conse- quence of growth of dental plaque biofilms on tooth surfaces adjacent to periodontal tissues. Other nondestructive forms of periodontal dis- eases include infections of nonbacterial origin and noninfectious periodontal diseases (114). ‘The first group includes acute gingival inflammation caused by viruses, such as herpetic gingivostomatitis and HIV infections (42, 49, 112). Non-infectious peri- odontal diseases include gingival inflammation caused by mechanical, thermal, and chemical fac- tors (90, 123). Little is known about the patho- genesis of gingival inflammation caused by viral infections, and the predictability of the tissue re- sponse following these infections is difficult to as- sess. On the other hand, exposure of the gingival tissues to a traumatic agent will invariably result in a local inflammation. Evidence of the existence of risk factors for periodontitis Epidemiological studies show that gingivitis is ubiquitous both in children and adults. Albandar et ail, (13) assessed the prevalence of overt gingival in- flammation in a large group of adolescents without, yup among a larger group examined in the national survey of the oral health of United States children, and found that 82.1% of the subjects had gingival bleeding. Other studies reported similar findings of a very high prevalence of gingivitis in children and adolescents in other parts of the world (23, 88). A high prevalence of gingivitis has also been reported for adults. For instance, it has been estimated that about half of the U. S. adult population have gingival bleeding, sug- gesting that overt gingival inflammation is common periodontitis, who were a suby Studies in animals and humans show that peri- odontitis is preceded by gingivitis (131, 144, 177, 198) and although the accumulation and maturation of a microbial dental plaque biofilm will predictably lead to the development of inflammation in the nearby gingival tissues, the duration of onset (146, 179, 211) and the intensity (18, 175) of the inflammatory pro- cess vary considerably from person to person, as, well as between teeth and tooth sites within the same person. Furthermore, there is evidence that only a subset of individuals and a limited percentage of sites in these individuals will experience severe Joss of periodontal tissue (16, 17, 175). There are data suggesting that only a proportion of individuals and tooth sites with gingival inflam- mation may develop periodontal tissue loss. Albandar 177Albandar ef al. (15) assessed the prevalence of early onset forms] of periodontitis in U.S. adolescents and reported that| in the age groups 13-15years and 16-17years, respec- tively, 0.4% and 0.8% of the children had aggressive (juvenile) periodontitis, and 2.3% aNd 3.2% of the| children had chronic (incidental) periodontitis. Simi- lar results showing a low prevalence of periodonti in children and young adults have also been reported in other populations (22). Hence, most adolescents| and young adults do not develop periodontitis, in| spite of the widespread occurrence of gingival in- flammation in these individuals. risk group comprising 156 young subjects that were examined twice during 6years to study the relation- ship between the presence of overt gingival in- flammation (gingival bleeding) and the occurrence of clinical attachment loss. They found that 9.3% of sites that had gingival bleeding and 0-2mm of attachment loss at baseline showed longitudinal attachment loss of =3mm during 6 years. However, only 4.8% of sites with no gingival bleeding at base- line showed a corresponding attachment loss. Fur- thermore, 11.5% of sites with gingival bleeding at both examinations (baseline and 6years follow up), and 3.2% of sites without gingival bleeding in either of the two examinations showed longitudinal attach- ment loss of =3mm. Hence, 90.7% of sites with gin- gival bleeding at baseline, and 88.5% of sites with gingival bleeding at both examinations did not show clinical attachment loss during the study period. ‘These results showed that there was a significant as sociation between the presence of overt gingivitis and the development and progression of peri odontitis, but also showed that not all sites with gin- gival inflammation developed periodontitis during the 6year su pe proximately 53% of dentate persons, 30-90-years- old, in the USS. had a life-experience periodontal attachment loss of 3mm or more, On the other hand, only 34.5% of these dentate adults had periodontitis, defined as presence of attachment loss of 3mm or more together with a presence of a probing depth of The lower prevalence of periodontitis than gingi- vitis in different age groups, and the significant as- sociation between presence of gingival inflammation and the development and progression of periodontal tissue destruction (16) show that gingival inflam- mation develops into periodontitis in some individ- 178 uals more often than in others. Studies show a sig- nificant variability in the level of periodontitis be- tween different populations (21, 40, 68, 88), and between subgroups of the same population (17, 56).. Furthermore, periodontal tissue loss affects different teeth and sites in the same individual unevenly, as lenced by the significant interindividual and in- traindividual variability in the prevalence and sever- ity of periodontal attachment loss and other par- ameters of periodontal tissue destruction (17, 21, 175, 182). Hence, predisposition to disease pro- gression varies significantly and may be influenced by several factors. Periodontal diseases have previously been per- ceived as continuously progressive disorders, with gingival inflammation unequivocally developing into periodontitis by means of a constantly active disease process leading to a continuous loss of periodontal attachment, and to loss of teeth in due time. How- ever, inferences about the natural history of peri- odontal diseases, anchored in the body of knowledge accumulated during the last few decades, were in- consistent with the traditional concept of disease progression. The work of Lie & coworkers (148) in Sri Lankan tea laborers demonstrated that 8% and 81% of the population had rapid and moderate dis- ease progression, respectively, while 11% showed no disease progression during a 15-year follow up period. Other longitudinal studies in adolescents and adults (5, 6, 8, 39, 57, 89, 93, 183) confirmed the existence of subgroups with various risk predis- position to periodontal disease progression. These and other findings led to the deduction of a new hy- pothesis suggesting that periodontal disease activity is not linearly continuous (5, 219) and that there are factors that affect its predictability, and these ex- posures need to be identified (4), Destructive periodontal diseases are unlike many other chronic inflammatory diseases in that the pres- ence of the infectious agents per sedoes not inevitably lead to the development of periodontal tissues loss which is the hallmark of these diseases. Microbiologi- cal studies show that the oral cavityhasa complex and diverse microbial flora comprising more than 500 di ferent bacterial types (100, 170). It has been suggested that there is a wide diversity in the microbial flora of the oral cavity between persons, and that different in- dividuals tend to maintain a unique flora composition even after antibiotic therapy. It has been argued that this diversity is an indication that periodontal tissue loss may be caused by an array of oral microorgan- isms (170). Although there is strong evidence implic- ‘oorganisms in the etiology of destructiveGlobal risk factors and risk indicators for periodontal diseases periodontal diseases (7, 14, 20, 100, 215, 220), there is alack of correspondence between the somewhat high prevalence of periodontal pathogens and loss of peri- odontal tissue in the affected individuals and tooth sites. Risk vs. association Risk is defined as the probability that an event will Cee re, or SERA aT vidual develops a given disease or experiences a change in health status during a specified interval of time (128). Applied to destructive periodontal dis ‘eases, it is the probability that periodontitis, or a measurable periodontal tissue loss, will take place during a specified period of time. Risk factors may be defined as_distinctive characteristics, or_ex. posures, that increase the probability of developing periodontitis, or lead to a measurable 1 (loss) in the status of the periodontal supporting tissues. be based on an analysis of the temporal relationship between the presence of exposures (potential fac- tors) and the occurrence of tissue loss over a given time period, and this would allow the assessment of Often, the first evidence of the potential existence of risk factors for disease comes from clinicians and researchers who become aware that persons (pa- tients) who develop a disease or condition had dif- ferent characteristics (explanatory variables or en- vironmental exposures) than healthy persons or those with less severe disease (43, 44). In certain, types of exposures, observations and other evidence come from laboratory findings in experimental ani- mals. Based on these observations, scientists de- velop a working hypothesis of a proposed effect of the potential risk factor on the development of the disease or condition, In contrast to clinical sciences, epidemiology is concerned with the occurrence of disease and its risk factors in populations, Hence, a definition of risk groups is pertinent. A periodontal risk group can be defined as a subgroup (of a larger population) whose members, on average, have a higher probability of developing periodontitis and/or loss of periodontal, support, within a given time period, than the re- maining population, Although it is justifiably recognized that prospec tive longitudinal studies, and in particular clinical trials, give the most powerful evidence for the exist fence, and the amount, of risk; in most cases these types of studies are prohibitively unethical, and also very expensive and laborious. For this and other rea- sons, including the length of time needed to assess incidents of new disease, most evidence for the existence of possible risk factors for periodontal dis- eases comes from cross-sectional studies. Although the identification of risk factors for disease, as de- fined above, is unfeasible using cross-sectional studies, when proper study design is employed, such as the use of large representative surveys and the use of cross-sectional and retrospective case-control studies, these studies can provide valuable infor- mation about the presence or absence of an associ- ation between the variables under study and the oc- currence of periodontal diseases. In order to make a distinction between the results of the different types of stu customary to refer to significant ef- fects assessed in cross-sectional studies as associ- ations, whereas effects disclosed using case-control studies and prospective studies have been referred to as risk determinants, risk indicators, or risk markers. Risk assessment Above and beyond the identification of risk factors for periodontal diseases, it is important to assess the periodontal health risk from the presence of these factors and the effect of an increase in their dose. ‘Thete is a considerable variation in the significance of the different factors to the initiation, modulation, and/or prediction of the occurrence and progression of periodontal tissue destruction. In addition, risk assessment may potentially provide profound social, and economical benefits with regard to disease pre- vention and control (222). Among the main measures used to express health risk are absolute risk, relative risk, odds ratio, and attributable risk (80, 136). ‘*_Absolute risk is the probability that an individual all’ develop the disease oveta,specmea Denioao! ime (Fig. 1). + Baal risks the comparison of the health risk between two populations. This measure is com- monplace in prospective and cohort studies and is assessed as the ratio of the disease incidence in these populations. A higher relative risk in these types of studies is often used to suggest a stronger evidence for causation of the outcome measure. It should be noted that relative risk can be measured ‘only when the outcome is dichotomous. * Odds ratio: is an estimate of the relative risk, and is the ratio of the probability of occurrence of the 179Allbandar ourcome + z * a b | atb EXPOSURE o | 4 etd atc b+d Riskofoutome in expored = Rove rok = (sections "arb (RR) ‘tem. mi ‘aviaatiorak = <2 - aS (ar) " aH ‘ianauieren ed renemes) ato (OR) Fig. 1. Risk assessment parameters. event (or developing the disease) to the prob- ability of its nonoccurrence. As this measure uses a backward method of analysis to compute the risk (from outcome to exposure), it is useful studies using a backward research design, includ- ing retrospective and case-control studies. Odds ratios have been commonly used to express risk because they provide a fairly good estimate of the true relative risk of exposure in the target popula- tion, provided that the outcome is rare, © Attributable risk: is also a comparison of the health risk between two populations. However, in contrast to the relative risk, the attributable risk is assessed as the difference in the incidence rates (risk ratios or probabilities) of occurrence of ease between exposed and nonexposed individ- uals (or populations). * Population-attributable risk: (also called attribu- table risk fraction or etiologic fraction) is an ad- ional measure sometimes used to express the ;pact of exposure on outcome (or disease occur- rence) in the target population from which the study sample derives. It measures the proportion of all cases of outcome in the target population that are attributable to exposure, or the pro- portion of cases of outcome that would disappear (change to normal) if exposure in the target popu lation were eliminated. * Prevalence rate ratio: In cross-sectional studies, the selection of groups is by exposure, and the outcome is measured as prevalence rather than incidence. In these studies the prevalence rate ratio is often used as an approximation of the rela- tive risk and is assessed as the ratio of the disease prevalence in the two populations. a 180 Sensitivity and specificity are conceptually different, but statistically related, indices. These indices are useful in the evaluation of a diagnostic test of dis- ease and can be derived from a standard 2x2 table (Fig.2). Sensitivity is the proportion of correctly iden- tified diseased persons, or the proportion of diseased persons who have a positive test. Specificity is the proportion of correctly identified disease-free per- sons, or the proportion of disease-free persons who have a negative test. Clinicians are usually more interested in finding out whether a test result can be used to indicate presence or absence of disease, and how the ex- posure of a person to a risk factor may predict occur- rence of disease. Hence, the predictive value is more relevant in a clinical setting, Positive predictive value is the proportion of persons with a positive test re- sult who have the disease, or the proportion of per- sons with an exposure who may develop the disease. Negative predictive value is the proportion of per- sons with a negative test who are disease-free. Risk factors and risk indicators for periodontal diseases Chronic inflammatory periodontal diseases have several etiological factors for which a plausible bio- DISEASE present absent bs a b atb TEST 1 = c d c+d atc b+d Sensitivity S ate d Spectoty = a Positive predictive value = arb 4 Negative predictive value = ave Fig.2. Calculating the sensitivity and specificity of a diag nostic test.Global risk factors and risk indicators for periodontal diseases logical model of effect exists. As illustrated above, microorganisms in dental plaque biofilms are etio- logical factors essential for the initiation of the in- flammatory process locally at the infection site, and in the absence of these, the inflammatory response does not take place. However, the host response to the presence of bacteria is normally intended to counteract the harmful effect of microorganisms. Hence, an exacerbated or excessive reaction of the host tissue, as well as a lack or deficiency of a suit- able reaction by the host, may also cause or promote host tissue damage. Essentially, each side of this campaign ~ the microorganisms and the host fac- tors ~ includes an array of factors with a range of effects and significance in the process. and to com- plicate this portrait further, there are several other factors that may also contribute to modulate this in- teraction, by either potentiating or decreasing the tissue damage. These latter factors include local fac- tors within the mouth, systemic factors related to the host, and external (environmental) factors. In the listing of factors below, no distinction will be made on whether these factors possess a true risk-modifying effect, or are simply risk indicators. This issue, however, will be revisited later in the dis- cussion. In addition to data from published studies, the text below will include findings from the main, national surveys conducted in the U.S.A. during the last few decades. A description of the methodology and main periodontal findings from these surveys are provided elsewhere (17, 21) Geographic region Different geographic regions normally exhibit con- siderable ifferences in demographic, environmen- tal, and possibly also ecologic characteristics, which may cause significant differences in the occurrence of periodontal diseases between populations in these regions, However, assessment of potential dif- ferences in disease occurrence requires that disease is studied using valid methodology, including rel- evant study design and valid measurement methods. However, this has not always been the case. The epidemiology of periodontal diseases in the ULSA. has been assessed using national surveys em- ploying multistage sampling design, adequate rep- resentation of the target population, and valid meas- urement methods (21). In contrast, there is almost a complete lack of similar surveys in other countries. Often the estimates of disease occurrence in pub- lished studies were biased due to inaccuracies in sampling and/or other study design (124), which makes the comparison of results between different regions in the world rather difficult, if not imposs- ible. Also, in comparing disease occurrence between different parts of the same geographic region, the same principles of representativity and valid meth- odology should be applied. ‘Among the few studies showing that populations from different regions of the world may have differ- ent levels of predisposition to periodontal diseases are the series of studies by Le & coworkers (147, 148) in Sri Lankan tea laborers showing a very prevalence and progression rate of periodontal dis- eases, in contrast to much less disease and a very slow disease progression in Norwegian academics. Obviously, the Sri Lankan tea laborers and the Nor- wegian academics were subpopulations not repre- sentative of their respective populations in Sri Lanka or Norway, respectively. Baelum et al. (38) studied the occurrence of peri- odontal tissue loss in two samples drawn from the Kenyan and Chinese adult populations, and con- cluded that the attachment loss in these two samples ‘was less than that reported previously for subpopu- lations in Sri Lanka and South Pacific islands. They suggested that the periodontal attachment loss pro- files may differ between different populations. How- ever, none of the studies cited above (38, 147, 148) have used a study design that would ensure the selection of study samples representative of their ‘geographic region. In addition, disease definitions, measurement methods, and other important meth- odologies were different. Hence, differences in peri- odontal disease occurrences between these studies may be due to differences in any of a long list of demographic, environmental, and ecologic charac- teristics, some of which may be attributed to the re- gion itself, whereas other may not. Populations from different regions typically differ in ethnicity and other characteristics, such as various degrees of genetic heterogeneity, due to lasting inte- gration/segregation patterns and traditions, and may also show marked demographic and socioeconomic differences. For instance, a genotype that has pre- viously been associated with an increased risk for se- vere periodontitis (131, 161) has recently been shown to be much less prevalent among Chinese persons than Europeans (28). For these and other reasons, itis, difficult to ascertain the proportion of this difference that is attributable to geographic region alone. A more refined analysis is needed to draw an accu- rate conclusion about the differences in disease oc- currence between continents, perhaps in the form of a meta analysis of well designed surveys. However, in 181Albandar view of the lack of such analyzes, examining the re- sults of recent reviews (21, 22, 40, 68, 88, 208) suggests, that the differences in the occurrence of destructive periodontal diseases between countries and sub- populations within these regions may be much larger than the differences between the continents or major regions, Oral hygiene level The role of dental plaque as the principal etiological factor in the development of periodontal diseases, has been shown by Lée & coworkers in the 1960s (146, 211) and as the level of oral hygiene is directly related to the amount of plaque build up on teeth, it is reasonable to predict that the level of oral hy- giene in a population is positively correlated with the prevalence and severity of periodontal diseases. On a population level, several studies have clearly shown that this assumption is valid, In the 1950s, results from epidemiological studies by Lovdal et al (151) and Schei et al. (201) in Norway indicated that ‘groups with poor oral hygiene show a higher preva- lence and severity of periodontal tissue loss than populations with good oral hygiene. In the period 1971-1974, the first National Health and Nutrition Examination Survey (NHANES 1) was conducted in the United States and included a very large sample representative of 194 million noninsti- tutionalized American civilians. In this study, the sta- tus of oral hygiene was assessed by the Simplified Oral Hygiene Index (91) on six teeth per person, and “black males -*-black females » white males white females 3 x 5 3 = 2 e . 2 o 3 aa 2 ee Foi ee g — 3 ° = = 611 1247 18-84 45.64 65-74 Age Fig.3. Oral Hygiene Index, by race, gender, and age. NHANES I, United States 1971-1974 (21). 182 the periodontal status was assessed by the Peri- odontal Index (196) on all teeth present. Although the Russells Periodontal Index has considerable shortcomings in assessing disease prevalence and severity, it does have some value in the identification of risk indicators for advanced disease. One of the important findings of the NHANES I was that the level of oral hygiene in the population was an im- portant risk indicator for the level of periodontiti regardless of age (2). ‘The NHANES I survey also showed that the level of oral hygiene differs significantly by race and gen- der (21), with poorer oral hygiene found in blacks than in whites, and in males than in females (Fig. 3). ‘This may partly explain the higher prevalence and severity of periodontal diseases in blacks and in males. Although the level of oral hygiene is an important risk factor for periodontal diseases in population studies, this parameter shows a much weaker value as a predictor of the future occurrence of periodontal tissue loss when assessed on the person level. Haf- fajee et al, (99) studied the use of clinical parameters including presence of plaque and inflammation (gin- gival redness) as predictors of attachment loss dur- ing one year in 22 subjects. They reported a low sen- sitivity (0.32 for inflammation and 0.42 for plaque) and a relatively high specificity (0.74 for inflam- mation and 0.71 for plaque). Similar findings show- ing a high specificity of absence of gingival bleeding as a predictor of periodontal stability were reported by Lang & coworkers (141). In the beginning of the 1970s, Axelsson and Lindhe initiated a series of prospective controlled studies to assess the effect of adequate oral hygiene procedures on the prevention of periodontal dis- eases and dental caries. Positive results were re- ported from these programs in schoolchildren and adults during the first few years of follow up (29, 30). In addition, a 15-years follow up showed that groups with good oral hygiene had very little change in peri- odontal status compared with the controls (31). These findings are consistent with the results of other studies (99, 141) showing a high specificity of good oral hygiene and absence of gingival inflam mation as predictors of periodontal stability. However, although intensive oral hygiene pro- grams are effective in reducing the incidence of den- tal caries and the level of gingival inflammation in children and adults (10, 31, 32), these programs may not be as effective in preventing aggressive forms of periodontal diseases (11). In addition, there is evi- dence to suggest that it may be difficult to achieve aGlobal risk factors and risk indicators for periodontal diseases satisfactory level of oral hygiene to eliminate chronic periodontitis and periodontal tissue loss in the gen- eral population (171). Smoking ‘The effects of smoking have been studied extensively during the past several years and the body of evi- dence suggests @ very strong association between various types and intensity of smoking habits on gin- gival tissue status, periodontal tissue loss, and sever- ity of periodontitis (232). Cross-sectional studies have consistently shown a higher prevalence, extent, and severity of various periodontal disease outcomes in smokers than in nonsmokers (19, 33, 48, 76, 113, 116, 159). Generally, assessment of risk shows that smoking is associated with between 2 and 7 fold in- crease in risk for having periodontitis and/or peri- ‘odontal tissue loss compared to nonsmokers (47, 83, 93, 94, 231). A study assessed the occurrence of se~ vere loss of periodontal attachment and deep prob- ing depth in cigarette-smokers and nonsmokers who were regular dental attenders and found a significant increase in risk (OR=14) in young adult smokers aged 20-33 years (143). Increased risk from smoking has also been found in older age cohorts (119). ‘There also appears to be a dose-effect relationship between cigarette smoking and the severity of peri- odontal disease outcome. Several cross-sectional have been undertaken to study this relation- ship. Heavy smoking was consistently associated with more severe periodontal disease than light smoking (48, 231), and the number of smoking years was significantly associated with tooth loss and peri- odontal disease, irrespective of other social and be- havioral factors (119). Martinez-Canut et al. (159) as- sssed the attachment loss in 889 periodontal pa- tients and found that smoking one, 2-10, and 11-20 cigarettes per day was associated with an inerease in the prevalence of attachment loss of 0.5%, 5% and 10%, respectively. Grossi et al. (93, 94) assessed the risk for clinical attachment loss and radiographic al: veolar bone loss from cigarette smoking after ad. justing for known confounders, and found that the odds ratios for light and heavy smokers, respectively, were 2.0 and 4.8 for clinical attachment loss, and 3.3 and 7.3 for alveolar bone loss. The temporal relationship between cigarette smoking and periodontal disease has also been studied. Insofar, the results show that smoking is as- sociated with a greater increase in probing depth and attachment loss during a 10-years follow up (61), and that quitting smoking may improve periodontal health (19, 48). Albandar et al. (19) and Bergstrom et al. (48) showed that periodontal status of former smokers was somewhere between that of current smokers and nonsmokers. ‘Tomar & Asma (231) used data on 12,329U.S. per~ sons, 18years and older, examined in the NHANES III national survey to study the effects of cigarette smoking on the prevalence of periodontitis. After ad- justing for age, gender, race-ethnicity, education, and income, they found that smoking wes associated with a significantly higher risk for having peri- odontitis in current smokers (OR=4) and in former smokers (OR=1.7) compared to nonsmokers. Among current smokers, persons who smoked =31 and =9 cigarettes per day had an estimated odds ratio of 5.9 and 2.8, respectively, suggesting a dose response relationship between number of cigarettes smoked per day and the odds of periodontitis. Fur- thermore, they estimated that 41.9% of the U.S. adult population prevalence rate of periodontitis is at- tributable to current cigarette smoking and 10.9% to former smoking. Other types of smoking habits including cigar and pipe smoking have been shown to have similar det mental effects on periodontal health as those attri- buted to cigarette smoking (19, 135). On the other hand, smokeless tobacco has been shown to have a limited and more localized effect on periodontal tissue, usually in the form of gingival recession and white mucosal lesions (121) Numerous studies have been conducted to investi- gate the potential mechanisms whereby tobacco smoking habits may predispose to periodontal dis- ease, and a number of mechanisms of action have in elderly twin pairs have ime smoking his- tory have a higher level of alveolar bone loss than their twin partners with a low life-time exposure (46). This illustrates that smoking has an environ- mental effect on periodontal tissue. Many studies have focused on investigating the ef- fects of smoking on dental plaque, as well as on other local and systemic effects particularly on host tissue cells. Studies have shown no conclusive differ- ences in the periodontal microflora between smokers and nonsmokers (72, 188, 223). However, several effects have been disclosed relating to the vasculature and the host immune systems. A study has found differences in the oxygen saturation of hemoglobin in the gingiva of smokers and non- smokers, suggesting that smokers have functional impairments in the gingival microcirculation (103). Significant effects of smoking on the immune system 183Albandar have also been described, including modification of the humoral and cellular immune systems, and cyto. kine and adhesion molecule network (51, 52, 125). Furthermore, it has been shown that nicotine in tobacco inhibits the attachment and growth of hu- man periodontal ligament fibroblasts in vitro (118). Nicotine causes a significant decrease in the protein content and damage to the cell membrane of fibro- blasts, and a decrease in the growth of these cells (24). Upon exposure to nicotine, fibroblast cells typ- ically acquire atypical shapes, and show formation of vacuoles, and these toxic effects become irrevers- ible at higher concentrations of nicotine. It has been found that the difference in peri- odontal tissue attachment loss between smokers and nonsmokers is particularly large at maxillary lingual sites, which may suggest a local effect of cigarette smoking (91). On the other hand, a survey in Finland has found that daily smoking was associated with increased use of sugar in tea or coffee, and with more frequent alcohol consumption (227). Hence, smoking is associated with a change of behavior, and. this suggests that multiple mechanisms of action of the observed effect of smoking may be involved. Clinical studies show that smokers respond less favorably to periodontal treatment compared to nonsmokers. Studies using nonsurgical techniques found less reduction in probing depth and slower healing potential following scaling and root planing (120, 181). Similarly, unfavorable results have been = Diabetics ‘BPersans | NonDiabetics ar er al 2 ° ‘tachment Probing _Gingival__Gingval Loss Depth Recession Bleeding Fig. 4. Percentage of persons 30 years and older with vari- ous periodontal parameters, by diabetes status. Adjusted for age, gender, and race-ethnicity. NHANES Ill, United States 1988-1994 (204). 184 reported following surgical and regenerative peri- odontal treatments (232). In the absence of a suitable experimental design to test causality, results from cross-sectional and longitudinal studies of the effects of smoking have recently been examined in the framework of poten- tial causal association with periodontal diseases. Based on epidemiological criteria it was concluded that cigarette smoking is causally associated with periodontitis (84). Diabetes mellitus Selwitz. ef al. (204) assessed periodontal disease out- ‘comes in 9,680 dentate adults aged 30-90 years com- prising persons previously diagnosed with noninsu- lin-dependent diabetes mellitus (type ID and per sons who had not been diagnosed with diabetes, all examined in the U.S. NHANES III survey in 1988- 1994 (17). The results, adjusted for age, gender, and race-ethnicity, showed that in diabetics and nondi betics, respectively, 31% and 20% subjects had attachment loss of =5mm, 21.6% and 8.8% subjects, had probing depth of =5mm, 31.8% and 22.8% sub- jects had gingival recession of =3mm, and 63.7% and 50.4% subjects had gingival bleeding (P<0.01) (Fig.4). Similarly, diabetics had significantly higher extent (percentage of affected teeth) of periodontal disease than nondiabetics. The corresponding as: sessments for extent of disease in the two groups were 11.4% and 5.8% teeth with attachment loss, 4.9% and 1.6% teeth with pockets, 11% and 6.4% teeth with gingival recession, and 23% and 13.3% teeth with gingival bleeding (Fig.5). A study used data from 3 previous surveys in Na- tive American dental patients and found a signi cantly higher prevalence of probing depth of >5. mm (CPITN score 4) among diabetic (34%) tha nondiabetic patients (19%) (213). Similarly, Dolan et al, (76) found that diabetic persons are more likely to present with attachment loss of =4mm than non- diabetics. Based on a survey of 1,426 persons, 25~74 years of age, it was estimated that the odds ratio of having attachment loss in diabetic persons was 2.3 (93). A longitudinal study assessed the risk for alveolar bone Joss in a group of Native Americans with poorly con: trolled noninsulin-dependent diabetes and in per sons with better controlled diabetes or without di betes and found that the cumulative odds ratio of developing bone loss over time was 2.2 in the better controlled diabetics compared to nondiabetics, andGlobal risk factors and risk indicators for periodontal diseases 5.3 in the poorly controlled diabetics compared to the better controlled diabetics (226) ‘There is also evidence that young persons with in- sulin-dependent diabetes, particularly those with poor glycemic control, have poorer periodontal health than nondiabetics (117). A 3-years longitudi- nal study assessed the periodontal status and the re- sponse to periodontal therapy in two groups of sub- jects 24-36 years old comprising a group of insulin- dependent diabetic patients and a control group, and found that diabetic subjects with poor meta- bolic control or with multiple complications related to their diabetic status showed a faster recurrence of deep probing depth and a higher tissue loss after treatment than the control group (228) Based on results of clinical human studies (173) and experiments in animals (138), it has been hypo- thesized that hyperglycemia progressively glycates, body proteins, forming advanced glycation end products (AGE), and these can stimulate phagocytes and the release of inflammatory cytokines that pro- mote periodontal tissue loss, Lalla et al. (138) treated diabetic mice with soluble receptor for advanced glycation end products (SAGE) which bind ligand and blocks interaction with, and activation of, cell- surface RAGE. Although the mice were infected with the periodontal pathogen Porphyromonas gingivalis, the treatment resulted in a decrease in the level of proinflammatory cytokines and matrix metallopro- teinases in the gingival tissue and a reduction in the alveolar bone loss in a dose-dependent manner. This suggested that the advanced glycation end products (AGE) which result from hyperglycemia could con- tribute to the pathogenesis of periodontitis in dia- betes (137), and that the blockage of these products could reduce periodontal tissue loss. Ithas also been shown that diabetic patients have exaggerated inflammatory responses compared to nondiabetics, and this may be one mechanism by which increased tissue loss may occur (197). In ad- dition, there is data showing that periodontal liga- ‘ment cells from patients with long-standing insulin- dependent diabetes mellitus have a reduced ability to form mineralized tissue and an altered response to growth factors (109). This suggests a less favorable response to periodontal treatment and maintenance. ‘These studies provide evidence that poor glycemic control leads to a significant increase in risk for al- veolar bone loss and periodontal disease pro- gression, In addition, persons with controlled dia- betes may have a higher risk for developing destruc- tive periodontal diseases than persons without diabetes, The hormonal and other physiological changes that take place in the development of betes mellitus are also important causal factors in the pathogenesis of periodontal diseases. These in- clude systemic changes in important components of the immune system and alterations in the peri- odontal tissue physiology consisting of blood vessel changes, deficient local immune response to the mi crobial assault, and changes in collagen metabolism. ‘There have been reports of complications follow- ing guided tissue regeneration, and other unfavor- able periodontal outcomes in diabetic dental pa- tients, and this has led investigators to suggest that patients with diabetes and patients with a family his tory of diabetes are ‘risk’ dental patients (160). One study, however, found that metabolically well-con- trolled diabetics and healthy control patients may respond similarly to nonsurgical periodontal therapy (62). A randomized clinical trial in 113 Native Amer cans assessed the effect of periodontal therapy on diabetic status in noninsulin-dependent diabetes and demonstrated that, after 3months, a treatment regimen with scaling and systemic doxycycline re- sulted in a significant reduction in probing depth and subgingival level of P gingivalis compared to the control group, and a 10% decrease in the level of gly- cated hemoglobin compared to the pretreatment level (95). Nevertheless, a recent critical review of current literature suggested that there is not enough. evidence to suggest that periodontal therapy may have a clinical impact on metabolic control of dia- betes (97). %Teeth ™ Diabetics = Non-Diabetics srt - | Br a J Attachment Loss Probing Gingival Gingival Depth Recession Bleeding Fig.5. Percentage of teeth with various periodontal par- meters, by diabetes status. Adjusted for age, gender, and rrace-ethnicity. United States 1988-1994 (204). 185Albandar Age Large epidemiological studies, including the NIDR National Survey of Employed Adults and Seniors, and the NHANES III survey (17, 21), have clearly demonstrated (Table!) an increase in the prevalence (percentage of persons), extent (percentage of teeth per person), and severity of periodontal attachment loss with increasing age. Normally, measurement of the periodontal tissue loss is based on assessing the distance from a reference point (usually the cementoenamel junction) to the base of the peri- odontal defect. and since the level of this reference point in relation to the tooth is relatively stable re- gardless of age, age is indeed a good indicator of the past history of periodontal tissue loss. Cross-sectional epidemiological studies also sug- gest that the prevalence of periodontitis increases with age (21). Furthermore, this relationship appears to be contingent on the severity of periodontitis. Hence, the data from the NHANES III showed that mild periodontitis is more prevalent in the older age groups, whereas moderate and advanced peri- odontitis increased in prevalence to approximately 65 years of age, remained steady until approximately 80 years of age, and then decreased thereafter (Fig. 6. A frequent finding in epidemiological surveys is the absence of marked increases in the probing depth with age. Albandar (21) showed that the preva- lence and extent of =5mm probing depth increase only slightly with age, and the increase is much less than that shown for attachment loss of the same threshold. Consistent with these findings, data from the NHANES III survey in U.S. adults show that the Table L. The percentage of persons (prevalence) and percentage of teeth per person (extent) with =5mm_ attachment loss and =5mm probing depth, by age group. United States 1988-1994. (adapted from Allsandar et al. (17)) Age Attachment loss Probing depth (years) — Prova- Extent’ Preva- Extent lence lence 30-39-80. 15 22 [ipl 40-49 16746 a5 16 50-59 269 83 04-21 60-69 353 IL m7,| lan 7 «417143 Ud iis, 0-90 5149. 68 16 186 percentage of persons with probing depth of =4mm_ was stable between around 50-80 years of age, and decreased in the age group 80-90years. This de- crease in the prevalence of probing depth in older ‘age groups is somewhat similar to the age-pattern for moderate and advanced periodontitis, which has been shown to decrease in prevalence between 75 and 90years of age, but is in significant contrast to the prevalence of attachment loss which continued to increase in older age (Fig.6). Figure7 shows relevant data from the Dental Health Outcomes Survey conducted in 1981 in U.S. adults (21). Analysis of this data by severity of prob- ing depth showed that, whereas the prevalence of shallow and moderate (4-6mm) probing depth in- creased with age, the prevalence of the more ad- vanced disease (=7mm probing depth) increased in the age groups 19-64 years, and decreased thereafter (Fig.7). These data suggest that some of the decrease in the prevalence and extent of periodontitis in the older age groups may be due to loss of the most se~ verely affected teeth. There is indication that the effect of age may be reduced, sometimes rather significantly, after ad- justing for the effects of other confounders. Abdellat- if et al. (2) analyzed the NHANES I data (U.S. 1971- 1974) and found that after adjusting for oral hygiene, age provided a negligible explanatory effect of the level of periodontitis in the population. It should be noted, however, that the validity of the Periodontal Index used the study has long been challenged, and its weaknesses as an epidemiologic method in peri- odontology have been acknowledged (40), Hence, the conclusions of Abdellatif ef al, (2) should be interpreted with caution, and the findings need to be validated in another data set. Im a literature review, van der Velden (233) con- cluded that animal and human studies show that physiological changes occur in the periodontium, and that there is a more rapid development of peri- ‘odontal inflammation with increasing age. Lindhe et al, (145) studied the healing of the periodontal tissues following periodontal therapy in 62 patients and reported that, although age did not seem to have a significant effect on the results of periodontal treatment, there was a tendency for younger patients to have shallower probing depth and gain more peri odontal attachment than older patients. In a longitudinal study, Albandar et al. (4) exam- ined the radiographic alveolar bone change of a group of subjects and showed that the rate of bone loss during 2years increased in the age groups 30- '56 years, and then leveled off and slightly decreasedponer ‘powore = * actin / . = NO 40 ra r 40 eh, 20 20 24 mm probing depth » oo © 0 wo Age in the 56-68 years age group. Furthermore, a 6-year follow up study reported a steady increase in the rate of alveolar bone loss between 24 years and the mid fifties of age, and a decrease in the rate of bone loss in the older age groups (5). These results suggest that age is a good indicator of the degree of periodontal tissue loss that occurs due to periodontal diseases. However, more studies are needed to clarify the role of aging as a risk factor for the development and progression of periodontal tissue loss and in tissue regeneration following therapy. 40 4-6 mm Probing Depth ia a 20 % persons as 10 27 mm Probing Depth tom ase ost Age 16:7. Percentage of pertons by sevesty af probing depth and age- Dental Health Outcomes Survey in adults, United States 1981 (20. Global risk factors and risk indicators for periodontal diseases Fig.6. Percentage of persons with periodontal parameters, by age. United States 1988-1994 (17). moderate and advanced periodontitis | * PH Gender Epidemiological surveys have consistently shown that periodontal diseases and periodontal tissue loss, are more prevalent in males than in females. In the NHANES I survey conducted in 1971-1974 in the USS. population, a better periodontal status was re- ported for females than males in all age groups (Fig. 8) (21). Also a higher prevalence of probing depth of 24mm in males than in females have been shown actoss the different age groups in the NIDR survey of adults and seniors (Fig.9). The male to female prevalence rate ratios in adults aged 18-65 years and, males -females Periodontal Index 611 1247 18-44 45-64 65-74 Age Fig.8, Periodontal status (mean Periodontal Index), by gender and age. United States 1971-1974 (21). 187Albandar in seniors aged 65-80 years were 1.3 and 1.1 for probing depth of 23mm, and 1.7 and 1.4 for prob- ing depth of =5mm, respectively (Fig.10) (21) Hence, 28% more adult males than females had= 3mm probing depth, and this male to female ratio increased to 71% for =5mm_ probing depth. In seniors, the prevalence rate ratio of the two sexes increased from 9% to 40% for the two probing depth “males females % persons f 2% 30 4 0 6 70 80 Age Fig.9. Percentage of persons with =4mm probing depth, by age and gender. National survey of employed adults and seniors, United States 1985-1986 21). Employed Persons: Seniors (18-65 years) (65:80 years) 10 * = males a = females % persons 23mm 25mm e3mm 25mm Attachment Loss Fig. 10. Percentage of employed persons and seniors, by severity of attachment loss and gender. United States 1985-1986. (21). 188 thresholds, respectively. This suggests that males had more severe periodontal disease than females. Similar to other large surveys, findings of the NHANES III survey showed a higher prevalence and extent of attachment loss, deeper probing depths, and a higher prevalence of periodontitis in males than in females in most age groups (Figs. 11 and 12). However, in persons 85-90 years old, males seemed to have better periodontal status than females. This, may be due to the higher prevalence of tooth loss in males, which has been shown to be particularly pronounced in older age groups (157). Attachment loss thresholds of =3mm, =4 mm and =5mm were noted in 23%, 44% and 55% more males than females, respectively (Table2). When the percentages of teeth with attachment loss were com- pared in the two gender groups, the corresponding rate ratios were 48%, 65% and 93%, respectively. A similar pattern of a higher occurrence of disease in males than females was also present for probing depth and gingival recession measurements (Table 2). This suggests that males are more frequently affected and have a more severe loss of periodontal, tissue than females. The Debris Index scores in the NHANES I survey were 0.75 for males and 0.57 for females, and the Calculus Index scores were 0.41 and 0.30, respec- tively. The survey also revealed significantly higher scores for males in all age groups (21). Similarly the NHANES III survey found that males on average had 21% more teeth with dental calculus than females (Table2) (21). These findings suggest a poorer oral hygiene level in males than females. and in addition to the difference in oral hygiene, it is likely that hor- monal and other physiological and behavioral differ- ences between the two gender groups may also con- tribute to the higher risk for periodontal diseases in males than in females. Race-ethnicity Different racial and ethnic groups within a given population often show marked differences in the periodontal diseases outcome. An important finding of the NHANES I survey was its finding of a much higher occurrence of periodontitis in blacks than in whites (Fig. 13), with a Periodontal Index score of 1.28 and 0.76 in the two groups, respectively (21). Similar findings were also described in other U.S. na. tional surveys (22), Among the three largest race-ethnicity groups in the U.S,, adult blacks show the highest prevalence of periodontitis and the most loss of periodontalGlobal risk factors and risk indicators for periodontal diseases followed by Mexican-Americans, whereas whites show the least disease and tissue loss (Figs. 14 and 15). Table2 shows the prevalence rate ratios of various periodontal parameters within these three groups using data from the NHANES II survey. As shown in this table, blacks have a much higher probability of having attachment loss and increased probing depth, and Mexican-Americans havea moderately increased probability, compared to whites. For attachment loss of =3mm, the ratio was 1.26 for blacks, and 1.10 for Mexican-Americans, whereas for attachment loss of =5mm, the ratio was 1.73 and 1.28, respectively. Hence, in the U.S. adult population, the probabilities, of having attachment loss of =3mm and of =5mm, respectively, were 26% and 73% higher for blacks, and 10% and 28% higher for Mexican-Americans com- pared to whites. A similar pattem was observed for other periodontal measures (Table2). For instance, ~-males ~>females % Persons 33 mm Atlachment Loss 23mm Periodontitis 100 100 Probing Depth 100 80 80 80 = : Ne 40 40 20 20 ° ° ° uo mw 0 8 0 mw 0 © © 7 wm Age Age Age Fig. 11. Percentage of persons with various periodontal parameters, by age and gender. United States 1988-1994 (17). “teeth 23 mmaattachment Loss % teeth 60 60 40 40 23mm Probing Depth males females Fig. 12, Percentage of teeth (per per- son) with =3mm attachment loss and =3mm probing depth, by age and gender. United States 1988-1994 an. 189Periodontal Index ent 1247 18-44 45-64 65-74 Age Fig.13. Periodontal status (mean Periodontal Index), by race and age. United States 1971-1974 (17). 3.31 times (or 331%) more teeth in blacks, and 85% ‘more teeth in Mexican-Americans, had probing depth, of =5mm than in whites, ‘These results demonstrate that, among the three groups, adult blacks have the highest risk for devel- oping periodontitis and Mexican-Americans have a moderate increase in risk. These and other similar results of Dolan et al, (76) show that blacks suffer the most severe periodontal tissue loss. Albandar er al. (15) assessed the prevalence of ag. gressive (juvenile) and chronic (incidental) peri odontitis among schoolchildren in a national sample of about 14,000 adolescents representative of stu- dents in grades 9-12 (13-17 years old) selected from 174 school districts throughout the U.S. The study found that early onset forms of periodontitis were present in approximately 10% of adolescent blacks, 5% of Hispanics, and 1.3% of whites. This gives a prevalence ratio of 7.7 for African American adoles- cents, and 3.9 for Hispanic adolescents compared to whites. A study by Mandal et al. (153) used a stratified, random sample of 14-15 years old schoolchildren in Manchester, UK, and found that Asian children had higher periodontal treatment needs than whites. Among other race-ethnicity groups with higher risk for periodontal disease, Grossi er al. (94) reported that Native Americans, Asians, or Pacific Islander subjects were positively associated with a more se~ vere bone loss (OR =2.4). Albandar (21), using data on otal hygiene status and dental calculus (81) assessed in the NHANES I ‘Table2. Prevalence rate ratios of periodontal variables, by gender (males vs. females) and race-ethnicity (blacks vs, whites, and Mexican-American vs. whites) in persons 30 years and older examined in the third National Health and Nutrition Examination Survey (NHANES IID), U.S. 1988-1994. (Albandar er al. (17)) Variable Gender ace-Eihnicity Males/females Blacks/whites Mexican-Americans/whites Prevalence (% persons) Attachment loss =3mm 1.23 126 110. ‘Attachment loss =4mm La 146 122 Attachment loss = 5mm 155 1.73 128 Probing depth = 3mm Lu 124 122 Probing depth =4mm 146: 197 161 Probing depth =5mm 173 2m 179 Gingival bleeding Lit 115 131 Gingival recession =1mm 1.12 1.03 094 Gingival recession =3mm 1.54 129 1.09 Dental calculus 1.02 1.05 1.06 Extent (% teeth per person) tachment loss =3mm 148 Ls 7 Attachment loss =4mm 1.65 175 24 ‘tachment loss =5mm 193 2.06 133 Probing depth =3mm 139 179 148 Probing depth =4mm 1.63 247 1.65 Probing depth =5mm 2.00 331 185, Gingival bleeding 124 131 1.53 Gingival recession =1mm 1.30 13 095 Gingival recession =8mm 67 Lag 113 rat 149 135 Dental calculus 190survey, reported that the mean Debris Index scores, for blacks and whites were 0.94 and 0.62, and the mean Calculus Index scores were 0.62 and 0.32, re- spectively (Fig.3). In addition, data from the NHAN- ES III survey show that blacks and Mexican-Ameri cans have 49% and 35% more teeth with dental cal- ulus than whites (Table2). These data suggest that Global risk factors and risk indicators for periodontal diseases of the three race-ethnicity groups reported, blacks had poorer oral hygiene level, and Mexican-Amer cans have a somewhat better oral hygiene level than blacks. Another study has found that blacks were less, likely than whites to be regular users of dental care, use dental floss, and be nonsmokers (76). Schenkein et al. (202) assessed the neutrophil ~=-blacks -—-Mexican-Americans ~~whites wing 23mm tachment Loss 23 mm p Probing Depth Periodontitis 100 100 100 eo 0 80 60 60 60 40 0 40 20 20 20 0 0 o =» 0» © ww wo oe no a «© 8 © 7 we Age Fig. 14. Percentage of persons, by periodontal parameters, age and race-et Age Age ity. United States 1988-1994 (17). —=blacks > Mexican-Americans 23 mm Attachment Loss, % persons 23mm Probing Depth Fig. 15. Percentage of teeth (per per- son), by periodontal parameters, age and race-ethnicity. United States 1988-1994 (17). 191Albandar chemotaxis response to N-formyl-methyl-leucyl- phenyl-alanine (fMLP) antigens in periodontally healthy persons and in persons with periodontitis, and compared these responses in whites and blacks. Their findings showed that in healthy persons the response was similar in the same race group (Fig. 16), but significantly higher in whites than in blacks (Fig. 17). The findings of the latter study suggest that the increased risk for periodontal disease in blacks may be partly due to biological predisposition. Fur- thermore, there is data suggesting significant differ- ences between races in the prevalence of certai periodontitis-associated genotypes (28) Genetic factors arly studies did not detect a significant association between genetic factors and the occurrence of peri odontal diseases relative to other environmental fac- ors (63). More recent studies, however, suggest that genetic factors contribute to a significant proportion of the between-person variation in the prevalence and severity of periodontitis. Studies in twins suggest that 38% to 82% of the population variance in clin- Healthy — m Healthy % Persons 2» ‘Blak ck Bock White inte white s 105 3 sa002 P08 Fig. 16. Chemotaxis response of periodontally healthy persons by race (202). = Healthy =P % Persons » 5 Bla Bick te hee Peat P=0.002 Fig.17. Chemotaxis response of periodontally healthy and juvenile periodontitis persons by race (202). q92 ical measures of periodontal diseases may be attr buted to genetic factors (166). However, the exact role of these factors in predisposition to peri codontitis has not been elucidated. Ithas been recognized that certain disorders which are accompanied by periodontal manifestations have a significant genetic component. For instance, the in- trafamiliar occurrence of Papillon-Lefevre syndrome was described decades ago (64), and data about the precise role of genetic factors in the pathogenesis of, this disease and its periodontal component are now ‘emerging (245). Severe periodontal manifestations in, other heritable syndromes have also been established (239, 241) Increased susceptibility to the early onset prepu- bertal forms of periodontal diseases typically has an interfamilial pattern (36, 200, 221) and the disease has been attributed to various defects in the host re- sponse to microbial infections (167). Generalized prepupertal periodontitis has been shown to be as- sociated with leukocyte adhesion deficiency (239) and other leukocyte abnormalities (25) which cause abnormal local recruitment of neutrophils and monocytes and inadequate host immune response. Both autosomal recessive (150) and autosomal dominant (205) modes of inheritance of prepubertal, periodontitis have been suggested. Family studies show that aggressive (juvenile) periodontitis occurs in families, and this suggests that genetic factors are parily responsible for the in- creased susceptibility to this aggressive form of peri odontal diseases (45, 54, 59, 122, 164). Studies inves- tigating the modes of inheritance of aggressive peri- odontitis have shown inconsistent findings, and results suggesting X-linked dominant (164, 221), autosomal recessive (53, 149, 199), and autosomal, dominant (110, 155, 205) modes of inheritance have been reported. ‘There is evidence of interindividual differences in the rate of production of the inflammatory cytokines interleukin-1 (IL-1), tumor necrosis factor-a. (TNF- ©), and prostaglandin E, following endotoxine stimulation of monocytes (169). In addition, it has been shown that certain gene polymorphisms are as- sociated with stable interindividual differences in IL- 1 and TNE production (133). Carriage of allele 2 of the TL-1a.~*° gene locus was associated with an ap- proximately four-fold increase in IL-1a. protein levels in severe periodontitis patients, with nonsmokers showing the most pronounced increase in protein level (210), Hence, it is thought that this gene poly- morphism may act to modulate IL-la protein pro- duction. IL-1 and TNE-c are potent stimulators ofbone resorption, and as hyperproduction of these cytokines following infection by periodontal patho- gens is believed to be one of the mechanism of peri- odontal tissue destruction, it has been hypothesized that genetic variation in cytokine expression may be an important risk marker for aggressive and adult periodontitis. Several gene polymorphisms have been investi- gated as candidates for use as markers of increased susceptibility for periodontal diseases, and several recent studies have focused on the relationship be- tween the frequency of IL-1 gene polymorphisms and the occurrence of severe attachment loss. A study of a composite genotype comprising IL-la~®*? and IL-18*9% in nonsmokers of north European heritage found that this genotype occurred signifi- cantly more often in subjects with advanced peri- odontitis (67%, OR = 18.9) compared to subjects with mild or no periodontitis (22%) (131). The study sug- gested that carrying allele 2 in either the hetero- zygous or the homozygous state at both loci predis- poses to a greater risk for developing severe peri- odontitis. Another study in nonsmokers investigated a different IL-1 gene cluster consisting of IL-La*#%5 and IL-18*°% and reported that genotype positives had a higher risk (OR=3.8-5.3) for having severe periodontitis compared to genotype negatives (161). Studies have also investigated the potential use of the IL-1 genotype as a risk marker for aggressive periodontitis. In a group of Caucasians aged 16-62 years diagnosed retrospectively as having aggressive periodontitis or with no disease it was found that the IL-1 genotype positives (defined as homozygous for allele 1 of the IL-18*9 SNP) had a significantly higher susceptibility for aggressive periodontitis (OR=2.2) and to localized juvenile periodontitis (OR=2.6) compared to IL-1 genotype-negatives (185). Stratification of the study group by smoking status showed that smokers who also were IL-1 genotype-positive had a higher risk (OR=4.9) for having aggressive periodontitis than smokers who were genotype negatives. On the other hand, non- smokers who were IL-1 genotype positive did not have a higher risk for having aggressive peri- odontitis, ‘The association between these same IL-1 geno- types and the occurrence of aggressive periodontitis was studied in a group of African American and Cau- casian American families with 2 or more affected members using linkage disequilibrium analysis, and it was found that the genotype positives had a higher risk for aggressive periodontitis irrespective of race or smoking status (74). It was also suggested that IL- Global risk factors and risk indicators for periodontal diseases 1 polymorphism was more important as a risk fac- tor for disease than IL-la polymorphism. Both studies suggested that allele 1 at both IL-lo and IL- 1 loci was transmitted more frequently with the ag- gressive periodontitis phenotype, and that carriage of IL-1p allele 2 may be protective (74, 185). However, there are also reports showing that these polymorphisms may play a less significant role as risk factors of disease occurrence. A recent study found no direct association between IL-la~®* and susceptibility to occurrence of chronic periodontitis or disease severity, and no association between IL- 18+ and the occurrence of early onset peri- odontitis (193). The study could not confirm an as- sociation between the composite genotype IL-la and IL-1 and severe periodontitis. A case-control study found that the IL-1a*#® and IL-1*#°° com- posite genotype correlated with the severity of peri- odontitis and the antibody responses to periodontal microbiota, but did not distinguish between peri- odontitis patients and controls (184). A study of the associations between various IL-1 gene polymorph- isms and generalized aggressive periodontitis in Caucasians found no significant differences between patients and controls irrespective of smoking status, and concluded that these genotypes may not be use- ful as markers of susceptibility for this disease (111) In addition, there is evidence that tooth loss and the response to periodontal therapy during 10 years in a well-maintained periodontal population are not as- sociated with IL-1 genotype (60). There are also data showing that IL-1 genotype may contribute a modi- fying effect, though it may not be a true risk factor for periodontal disease progression (70). So far, studies show that IL-1 polymorphisms may be rare in certain race-ethnicity groups. The preva- lence of IL-1 gene polymorphisms was investigated in a group of African-Americans and it was found that the IL-1" allele 1 was carried by all local- ized juvenile periodontitis patients and about 99% of the controls, and therefore the high frequency of this allele may not provide predictive information of tisk for this disease among African-Americans (240). In addition, it has been demonstrated (28) that IL-la, and IL-1 polymorphisms are much less prevalent in Chinese persons than in Europeans. For instance, the composite IL-1 genotype which has been re- ported associated with severe periodontitis (131, 161) was found in only 2.3% of 300 Chinese subjects examined (28). Hence, the potential use of IL-1 poly- morphisms as a risk marker for severe periodontitis, may not be straightforward. A significant association has been observed be- 193