Genetic risks for periodontal diseases: a clinical perspective

Introduction

Reduced to its most basic components, the etiology of any disease or disorder affecting mankind may be attributed to genetic and/or environmental influences. There may be a predominance of one of these factors or the two may interact in varying degrees to produce disease. The role of genetics in periodontal disease has been the subject of several excellent scientific reviews (^{Gorlin et al. 1967} ; ^{Sofaer, 1990} ; ^{Michalowicz, 1993}, ¹⁹⁹⁴ ; ^{Hart, 1994}, ¹⁹⁹⁶ ; ^{Hart and Kornman, 1997} ; ^{Hassell and Harris, 1995}). The purpose of this paper, therefore, is not to provide another extensive review of the genetic aspects of periodontal disease, but rather give a brief overview of evidence for genetic risk in periodontal diseases, and to discuss the clinical implications of recent findings.

For many years, clinicians suspected that genetic factors affected risk for periodontal diseases. This suspicion was reinforced by the association of periodontal diseases with rare genetic disorders, the familial aggregation of some juvenile forms of periodontal disease, and evidence that individuals generally exposed to the same environment were not equally affected by periodontal diseases. More recently, studies using twins and genetic markers have added to the expanding body of evidence suggesting that genetics have a significant influence in adult chronic periodontal diseases. It is unlikely that genetic-based prevention or treatment methods will become available in the foreseeable future. However, as the knowledge of genetic risk for periodontal diseases increases, it will have increasing significance for targeting environmentally-based preventive methods, and perhaps even host-based prevention and treatment to those individuals who, because of genetic make-up, are most at risk for periodontal diseases.

Periodontal diseases and genetic disorders

Various types of periodontal disease have been associated with rare genetic disorders including metabolic, vascular, connective tissue, hematologic, or dermatologic disorders. As noted by ^{Gorlin et al. (1967}), these conditions are often caused by a single gene mutation in which severe periodontal disease is a constant and prominent component in all environments. Examples of such conditions include acatalasia, cyclic neutropenia, hypophoshatasia, Chediak-Higashi Syndrome, Ehler-Danlos Syndrome, and Papillon-Lefèvre Syndrome. Each of these conditions is associated with severe forms of periodontal disease leading to early tooth loss.

Early onset forms of periodontitis

Clinicians are well aware of the profound effects that neutropenia may have on the pathogenesis and risk for periodontal diseases. Indeed, familial neutrophil defects in chemotaxis have been reported in patients with juvenile periodontitis (^{Van Dyke et al., 1985} ; ^{Boughman et al., 1992}). Neutrophil defects have also been identified in families with prepubertal periodontitis (^{Page et al., 1983}), and there is evidence that leukocyte adhesion deficiencies place individuals at increased risk for developing generalized prepubertal periodontitis (^{Waldrop et al., 1987} ; ^{Etzioni et al., 1992}). Recently, however, a possible autosomal dominant pattern of inheritance was reported in a kindred for prepubertal periodontitis who did not exhibit any leukocyte adhesion defects (^{Shapira et al., 1997}). This report highlights the possibility that a number of underlying genetic conditions may be expressed with similar clinical features.

The familial aggregation of juvenile periodontitis provided early evidence for a genetic role in the etiology and/or pathogenesis of periodontal diseases (^{Benjamin and Baer, 1967} ; ^{Butler, 1969} ; ^{Fourel 1972} ; ^{Jorgenson et al., 1975} ; ^{Saxen, 1980}). Several studies indicated that this disease was inherited primarily as a X-linked or autosomal recessive trait (^{Saxen, 1980} ; ^{Saxen and Nevanlinna, 1984} ; ^{Long et al., 1987} ; ^{Beaty et al., 1987}). Others have reported an autosomal dominant mode of inheritance (^{Boughman et al., 1986} ; ^{Marazita et al., 1994}), especially when additional genetic models are considered and when female ascertainment bias is considered (^{Hart et al., 1992}). Regardless of the mode of transmission, it is clear from these studies that there is a definite familial component to both localized and generalized juvenile forms of periodontitis. Indeed, ^Boughman ) reported genetic linkage of an autosomal dominant form of juvenile periodontitis to the long arm of chromosome 4. Although this finding was not confirmed in other populations (^{Hart et al., 1993}), this report of genetic linkage to a specific chromosomal loci provides additional compelling evidence for a strong genetic component in periodontal diseases.

Since varying modes of Mendelian inheritance for juvenile forms of periodontitis have been reported, there may be multiple underlying genetic conditions with different modes of inheritance that are manifest as a common clinical condition or phenotype. Indeed, strategies for prevention and treatment of the various forms of juvenile periodontitis may vary according to the mechanisms involved in the etiology or pathogenesis of the diseases. For example, if one variant of juvenile periodontitis is primarily associated with a leukocyte defect, prevention and treatment may be quite different than for another variant that is associated primarily with local tissue invasion by specific bacteria. Until clinicians are able to more accurately diagnose specific genotypes of affected individuals, preventive and treatment strategies will most likely remain similar for all forms of the disease. This type of therapy is likely to result in varying outcomes depending on the specific role that genetic factors have in the disease process. Since genetic and environmental influences both contribute to risk, failure to recognize and address both of these factors could adversely affect treatment outcome.

Disease susceptibility

Clinicians have, for some time, suspected that certain racial or ethnic groups have greater susceptibility to periodontal diseases. Indeed, there is evidence that American blacks have more severe disease that their white counterparts (^{Beck et al., 1990} ; ^{Oliver et al., 1991}) and that people from Sri Lanka and the South Pacific have more severe disease than other population groups studied (^{Baelum et al., 1996}). This does not necessarily mean that genetic factors are responsible for differences in periodontal disease among different ethnic groups or populations. Indeed, differences in environmental factors may be largely responsible for the reported variability in disease. It is, however, interesting to note that in a population of Sri Lankan tea laborers with a homogenous environment, there was a distinctly heterogenous pattern of disease (^{Löe et al., 1986}). Relatively few (8 %) experienced rapid disease progression, most (81 %) had moderate progression and relatively few (11 %) experienced no progression over a period of 15 years. Again, these data do not prove a genetic influence, but raise the possibility that variations in disease progression both within and between populations may be due to differences in genetic risk.

Twin studies

Twin studies offer a uniquely simple and powerful way to estimate genetic contributions to common diseases. Twin studies have been used to identify genetic influences on many chronic diseases such as coronary heart disease and hypertension, inflammatory bowel disease, peptic ulcer, heart disease, and schizophrenia (^{Berg, 1983, 1984} ; ^{Borhani et al., 1976} ; ^{King et al., 1992}). Similarly, twin studies have contributed to the genetic knowledge of diverse physical traits such as vision, personality, pulmonary function, serum immunoglobulin levels, and circadian characteristics of heart rate (^{Hubert et al., 1982} ; ^{Knoblock et al., 1985} ; ^{Hanson et al., 1984} ; ^{Kouvalainen et Moilanen, 1987} ; ^{Tellegen et al., 1988}). Moreover, twin studies have revealed a significant genetic influence in various craniofacial characteristics (^{Nakata, 1985}) and dental caries (^{Boraas et al., 1988}).

Certain fundamental assumptions underlie the classic twin study method. One of these assumptions is that monozygous or identical twins share 100 % of their genes while dyzygous or fraternal twins share on average, just like ordinary siblings, 50 % of their genes. Other assumptions are that identical and fraternal twins, reared together in the same family, share a common family environment, and that the two twin types are from the same population gene pool. Under these assumptions, identical twins raised in the same family will be more alike (concordant) than fraternal twins for discrete (presence or absence) traits that have a significant genetic component. For continuous traits (measured on a continuous scale) such as probing depth or clinical attachment loss, any quantitative differences between reared-together identical and fraternal twins must be due to genetic variability.

Early twin studies gave some indication of a significant genetic influence on periodontal diseases, since identical twins showed a high concordance for the presence of periodontitis (^{Noack, 1940}). However, other factors in this twin sample, including shared environmental factors and lack of a control group (fraternal twins), made it difficult to separate genetic from environmental influences. A study by ^Ciancio ) found no genetic influence on various measures of periodontal disease, but this study involved a limited sample of young twins aged 12 to 17 years. It is unlikely that these young twins would exhibit significant periodontal disease. More recently, we reported the results of an adult twin study involving 110 pairs of adult twins (^{Michalowicz et al., 1991a}) and additional results of an expanded sample of 164 adult twin pairs, including 21 pairs of reared-apart identical twins, 17 pairs of reared-apart fraternal twins, 83 pairs reared-together identical twins, and 43 pairs of like-sexed, reared-together fraternal twins (^{Michalowicz, 1994}). Examples of twins seen in this study are given in ^{figures 1a}, ^1b, ^1c and ^1d and ^2a, ^2b, ^2c and ^2d . Results of these studies clearly indicated that genetic factors have a strong influence on risk for adult periodontitis (^{table I}). Comparisons between reared-apart and reared-together identical twins indicated no significant difference in presence or severity of periodontal disease. This finding suggests that the early family environment, shared by reared-together twins but not reared-apart twins, had no significant influence on clinical attachment loss in adults (^{Michalowicz, 1994}). Furthermore, the assessment of proportional radiographic bone height in 120 pairs of adult twins also revealed that there was a significant genetic influence for this parameter (^{Michalowicz et al., 1991b}). Taken together, these data coupled with an independent study of another twin sample which assessed self-reported periodontal disease (^{Corey et al., 1993}), clearly indicate that there is a substantial genetic risk in adult periodontitis.

It is important for the clinician to understand the limitations of twin studies. Although twin studies offer a powerful tool to determine if there is a genetic influence in a particular trait or disease, they are less efficient at estimating the specific magnitude of the genetic influence. For example, our twin research using reared-together twins estimated that about 48 % of the population variance for clinical attachment loss could be attributed to genetic factors (^{Michalowicz et al., 1991a}). The 90 % confidence interval for this estimate was quite large and varied between 21 % and 71 % (^{table I}). Therefore, unless very large samples of twins (several hundred pairs) are examined, the estimates of genetic influence remain rather imprecise. In this respect, identical twins that are reared-apart offer a much more efficient sample since the estimate of a genetic effect may be made directly from the correlation coefficient between these rare twin types without the need for comparisons to fraternal twins as required in the reared-together design.

It is also important that clinicians clearly understand that twin studies only estimate population variances due to genetic influences. This means that in any sampled population as a whole, a given percentage of the periodontal disease variability is due to genetic influences. It does not mean that for any given patient a certain percentage of their disease is necessarily due to a genetic effect. For individual patients, the genetic effect may be much greater or much less than the estimated population variance. Thus, if a given patient has very little periodontal disease in the presence of an abundance of local etiologic factors such as pathogenic bacterial plaque and dental calculus, he/she is more resistant to periodontal disease. The resistance may be due in large part to some genetically programmed protection from environmental influences that ordinarily would result in disease. On the other hand, patients are more susceptible who have advanced disease in the presence of relatively few environmental factors that ordinarily would cause disease. This disease susceptibility may be mediated by genetically determined host factors.

Another aspect of twin studies that clinicians must bear in mind is that they do not give any indication of the mechanism by which genetic factors have an effect in the etiology or pathogenesis of the disease process. For example, use of the classical twin study alone cannot determine whether the genetic influence on periodontal disease is manifest through the humoral or cellular immune system, or if the effect is simply expressed by anatomic features such as tooth and dental arch form that predispose the dentition to periodontal disease. While twin studies are an important first step in defining the genetic aspects of periodontal disease, they must be followed by other types of research if a specific genetic mechanism is to be determined. Such studies generally involve family studies in which linkage of disease to specific known genetic markers on chromosomes are studied.

Genetic markers

A genetic marker is a specific gene or sequence of DNA that has been mapped to a specific loci on a chromosome. For example, the DNA located at specific areas (GC loci) on the long arm of chromosome 4 encodes for a vitamin D binding protein and another gene close to this area encodes for dentinogenesis imperfecta. It has been reported that an autosomal dominant form of juvenile periodontitis is linked to the GC loci and the gene for dentinogenesis imperfecta (^{Boughman et al., 1986}). As noted by ^Hart ), there are several genes in this area of chromosome 4 that may be important in the etiology of juvenile periodontitis. These include osteopontin, which may function as a connective tissue attachment factor, annexin III which may be important in inflammation, and interleukin 8 which functions as a neutrophil chemotactic factor. These genes make this area of chromosome 4 an attractive candidate area for study in formal linkage studies of juvenile periodontitis. However, the linkage of this disease to genetic markers on chromosome 4, reported by ^Boughman ), was not confirmed in another population of patients with early onset periodontitis (^{Hart et al., 1993}). It is likely that the sample studied by ^Boughman ) was from a unique population of individuals that had a form of early-onset periodontitis not found in other populations. Regardless of the findings, these studies provide excellent examples of the type of family studies needed to determine linkage of a specific gene or group of genes to a disease. Once linkage to a specific region of a chromosome is established, additional work can be done to more precisely localize the gene or group of genes that affect risk for disease.

As reviewed by others (^{Sofaer, 1990} ; ^{Michalowicz, 1994} ; ^{Hart, 1996} ; ^{Hart and Kornman, 1997}) there are many chromosomal areas in the human genome that might be candidates for linkage or association with various forms of periodontal disease. Among others, these include genetic loci on chromosomes 1, 2, 6, 9, 12, and 20 that are associated with the host immune response to microbial infection (^{Hart and Kornman, 1997}). Indeed, many studies have investigated the prevalence of class I and II HLA antigen specificities and blood group markers in various types of periodontal disease (see review by ^{Sofaer, 1990} ; ^{Michalowicz, 1994}). Antigen specificities encoded by the HLA region of chromosome 6 could confer increased susceptibility to periodontal disease. To date, however, the results of genetic linkage and association studies with specific HLA genes and various forms of periodontal disease have been inconsistent. However, there is recent evidence that certain HLA specificities are associated with generalized, but not the localized form of early onset periodontal disease (^{Shapira et al., 1994}). The overall inconsistency of genetic linkage and association studies may be the result of genetic heterogeneity for the periodontal diseases. In other words, various forms of periodontal disease may be associated with a variety of genetic influences. Furthermore, genetic influences may be more prominent in certain disease phenotypes than others. The inability to distinguish these phenotypes on a clinical level severely limits the ability of genetic studies to establish linkages or associations with known genetic markers. Laboratory techniques to detect subclinical phenotypes that differentiate among the various forms of periodontal disease are clearly needed (^{Potter, 1989}).

Recently ^Kornman ) reported that the occurrence of a specific interleukin-1 genotype was associated with severe periodontitis in a sample of patients from three private dental practices. They reported that the odds ratio of severe vs. mild disease for having the specific genotype was 6.8 for all non-smokers and 18.9 for non-smokers aged 40-60 years. When smokers were included, no association with these genetic markers was found. These are interesting data because, if confirmed in different population samples, it could mean that this is one specific mechanism by which genetic influences may have an effect on the pathogenesis of periodontal disease. As noted by ^Kornman ), interleukin-1 is a proinflammatory protein that is involved in the degradation of the extracellular matrix and bone of the periodontal tissues (^{Birkedal-Hansen, 1993} ; ^{Tatakis, 1993} ; ^{Tewari et al., 1994}). Moreover, since this association was not found in smokers, it reinforces the concept that some environmental factors may have a predominant role in the etiology of some types of periodontal disease and may mask or overwhelm the influence of genetic factors.

Clinical implications of genetics in prevention and therapy

It is unlikely that genetic-based prevention and treatment methods for periodontal diseases will become common in the foreseeable future. The knowledge gained from genetic studies will, however, allow clinicians to target environmentally-based preventive and treatment strategies to susceptible individuals. For example, if it is known that a specific family has a genetic-based susceptibility to early-onset periodontal disease, specific means to control environmental factors such as infection by specific bacterial species may be effective in preventing the disease. Similarly, if individuals can be identified genotypically as being at risk for adult periodontitis, other preventive means of reducing environmental factors may be effective. It is important to understand that the study of genetics in periodontal disease is in its infancy, and that it is difficult to predict the clinical applicability of such studies. At the present time, molecular methods such as proposed by ^Kornman ) to screen patients for a genetic marker may offer the potential to identify patients who will develop disease. However, it remains to be established if prevention is effective for « genetically susceptible » patients. The success of preventive programs ultimately will be determined by the magnitude of the environmental influence in the disease and the effectiveness of the particular preventive strategy. For example, it is well established that tobacco use is a major risk factor in adult periodontitis. The rise of disease attributed to smoking may be so strong that it overwhelms any genetic susceptibility or resistance to disease (^{Kornman et al., 1997}). For these patients, preventive strategies must address the overwhelming environmental factor-tobacco use. However, preventive programs aimed at tobacco cessation may have limited success. It is also possible that an operational genetic mechanism in periodontal disease may be discovered that can be down-regulated or modulated by host-based treatment methodologies. An example might be the modulation of genetically determined, host-based, destructive inflammatory processes by anti-inflammatory medications. These might be extremely effective for specific individuals diagnosed with genetically determined, intrinsic host factors that result in accelerated periodontal tissue destruction during inflammation. The identification of specific genetic risk factors that can be targeted with therapy may enhance the prevention and treatment of some disease forms that are currently difficult to control using non-specific, environmentally-based prevention and treatment programs.

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