Genetic influences in the pathogenesis of destructive periodontal diseases and diagnostic implications

Introduction

Periodontal disease (gingivitis and periodontitis) is initiated by microbial plaque which is allowed to accumulate in the gingival crevice region. Gingivitis will progress in many individuals to periodontitis but this progression is governed by the subject's host response. The host response depends to some extent on previous experience (acquired immunity) but is predominantly determined by the subject's genetic make-up. Individuals respond to their environment differently and this ultimately controlled by their genes which may produce variations in tissue structure, antibody responses or inflammatory mediators. Genetic factors which have been considered to influence the host response and may be relevant to periodontal disease fall into two main categories : those obvious genetic factors which result in overt systemic diseases such as Papillon Lefèvre syndrome (PLS) and leucocyte adhesion deficiency (LAD) and in which subsequently periodontal manifestations appear ; or those more covert genetic factors which otherwise do not perceptibly affect the general health of the subject but predispose to periodontitis nonetheless. Although, evidence for the latter scenario is embryonic at present and is difficult to prove with any certainty, these genetic aspects have tremendous potential and need to be considered. The diagnostic possibilities of genetics in screening for periodontal disease are developing and merit discussion.

Evidence for a genetic predisposition to periodontal disease

There is now strong supporting evidence that genes play a role in the predisposition to periodontal disease (^{Michalowicz et al., 1991a} and ^b ; ^{Michalowicz, 1994} ; ^{Hart, 1996} ; ^{Hassell et al., 1997)}. This section will outline the evidence emanating from studies based on families with more than one individual affected by periodontitis which support this contention and these will cover twin studies, family segregation analyses and both adult periodontitis and early onset forms of periodontitis.

Periodontitis severely affects a high risk group representing around 15 % of the population in whom the disease progresses from chronic gingivitis to chronic periodontitis quickly ^{(Jenkins and Kinane, 1989)}. This progression is particularly rapid in patients with early-onset periodontitis (EOP) ^{(Ranney, 1992)}. EOP appears to be a multifactorial disease in which the genetic component is pertinent. The presentation of disease in an individual, or the phenotype of any characteristic is a combination of the effects of environment and genetics (^{fig. 1}). In periodontal disease this simple equation holds true also but importantly the effect of time has to be considered. In adult periodontitis the phenotype or disease characteristics do not present significantly until the third decade of life and in early-onset forms of periodontal disease presentation can be in the second, third and fourth decade. This variability in presentation of significant signs of disease makes diagnosis difficult, not only in declaring if a patient suffers from the disease but also to categorically state that they do not suffer from the disease or to differentiate between adult and early-onset forms of periodontitis. The problems associated with periodontal disease are not uncommon in genetics as similar problems arise when studying other delayed onset hereditary traits. The effect of environment, for example plaque accumulation or other risk factors such as smoking, have a major influence on disease experience as has time (^{fig. 1}) and these tend to confuse the diagnosis of early-onset periodontitis which is so dependant on age of presentation of signs for its diagnosis. Huntington's chorea is an example of a hereditary disease where the diagnosis is only possible relatively late in life as for periodontal disease. The problems of genetic model testing in EOP have been highlighted by ^Boughman . These authors state that EOP has a variable age of onset and is often not recognized until after puberty, that the upper age limit of expression of the disease is curtailed (artificially by our current diagnostic definition that loss of attachment in patients older than 35 years is attributable to adult periodontitis) and the inability to obtain accurate periodontal disease histories for edentulous family members. All of these factors create substantial problems for genetic studies of periodontal disease.

Studying disease presentation in twins is a method of differentiating the variations which occur due to environmental and genetic factors. Twin analyses have been successfully applied in Alzheimer's disease ^{(Räihä et al., 1996)} and diabetes ^{(Poulsen et al., 1997)}. Monozygous (MZ) twins arise from one fertilised egg whereas dizygous (DZ) twins are from two different eggs. MZ twins are genetically identical and DZ twins are genetically as similar as other brothers and sisters would be within the same parents. Discordance or differences in disease experience between MZ twins must be due to environmental factors and between DZ twins they could arise from both environmental and genetic differences. The difference in discordance between MZ and DZ twins can be used to estimate the effects of the extra shared genes in MZ twins, if the environment for twin pairs is the same.

Twin studies for adult periodontitis have so far provided evidence of a genetic predisposition to periodontal disease. A study by ^Corey using questionnaires of periodontal health from 4,908 twin pairs found that approximately 9 % of subjects (average age = 31 years), consisting of 116 identical and 233 non-identical twin pairs, reported a history of periodontitis. The concordance rate, or level of similarity in disease experience, ranged from 0.23 to 0.38 for MZ twins, and from 0.08 to 0.16 for DZ twins. Unfortunately factors such as race, age, sex and smoking status should have been factored into this analysis which otherwise without these adjustments has tended to bias towards correlation between twins. ^Michalowicz studied the clinical periodontal status of twins within the Minnesota Twin Registry. Their studied included 17 pairs of dizygous twins reared apart (DZA), 63 pairs of dizygous twins reared-together (DZT), 83 pairs of monozygous twins reared-together (MZT) and 21 pairs of monozygous twins reared-apart (MZA). The correlation for attachment loss was similar between MZT and MZA twin groups, which indicates genetics has much more influence than environment with respect to attachment loss. The mean probing depth and attachment level scores were found to vary less for MZT than for DZT twin pairs further supporting the role of genetics in this disease. ^Michalowicz went on to investigate alveolar bone height in the twins from this Minnesota study and showed significant variations related to the differences in genotype. The twin groups had similar smoking histories and oral hygiene practices. It was concluded that genetics plays a role in susceptibility to periodontal disease. Unfortunately, these twin studies can not indicate the true nature of the genetic transmission of this susceptibility to periodontitis which may be a single gene or multigene phenomenon where there are complex interactions between alleles at more than one locus.

Strong support exists for a familial pattern in early-onset periodontitis. 40-50 % of siblings in families where one brother or sister has EOP also has the disease ^{(Boughman et al., 1992)}. This aggregation within families strongly suggests a genetic predisposition. It has to be borne in mind however that familial patterns may in fact reflect exposure to common environmental factors within these families and this environmental effect needs to be considered. Thus it is important to consider the shared environmental and behavioural risk factors in any family. These would include education, socio-economic grouping, oral hygiene, possible transmission of bacteria, other diseases such as diabetes and other environmental features such as passive smoking, water supply, sanitation etc. Some of these factors themselves may be under genetic control ; for example, the intelligence quotient of family members (which is genetically influenced) may influence the standard of oral hygiene. The complex interactions between genes and the environment must also be considered when evaluating familial risk for the periodontal diseases. Currently, smoking appears to be one of the most important environmental risk factors for periodontitis ^{(Page and Beck, 1997)}. A study by ^Stabholz on teenagers attending the same Jewish orthodox religious school in Israel, reported a high prevalence of LEOP (localized EOP). Ten of fifteen affected families had more than one affected sibling although only two sets of families were related. The authors concluded that environmental effect was strong in this LEOP population which contrasts with much of the current literature. Linkage and further family studies of this population should help to elucidate the contribution of genes and environment to the disease state seen. The majority of the parents of these subjects originate from the east coast of America and share the same orthodox religious beliefs, it is possible they may be unaware of being distantly related. Although bacterial transmission between subjects has been suggested the observation of bacterial transmission within families is insufficient on its own, to account for the familial clustering seen in EOP ^{(Boughman et al., 1992)}.

The periodontal diseases are currently accepted to be heterogeneous and not easily slotted into firm diagnostic categories. Even within families, multiple forms of disease can co-exist for example generalised prepubertal periodontitis (GPP), LEOP and adult periodontitis (AP) have been reported within the same family ^{(Spektor et al., 1985)}. ^Shapira has documented the sequential appearance of GPP and EOP in the same subject. It appears likely that the various forms of EOP (PP, LEOP and GEOP) have a common genetic background and in fact may be different phenotypic manifestations of the same genetic background occurring in different environmental circumstances ^{(Marazita et al., 1994)}. For most segregation analyses performed so far, investigators have grouped the EOP forms together but the heterogeneity problems and the variations in age of onset discussed previously may clearly further complicate such genetic studies.

^Melnick presented data from 19 sets of brothers and sisters of probands (the presenting sibling) affected by EOP and these sets of siblings suggested that EOP was an X-linked dominant trait with reduced penetrance. They based this on the fact that the female to male ratio was 2/1 for affected siblings, that no father to son transmission was evident and that the segregation or family inheritance pattern suggested a dominant transmission. Two further studies supported this hypothesis ^{(Page et al., 1985} ; ^{Spektor et al., 1985)} although ^Spektor commented that the prevalence in the immediate family was unusually high for an X-linked dominant trait. ^Hart and others found later that there was no female preponderance in segregation analyses of EOP families. It was further suggested that the lack of father to son transmission reported was because fathers were often not examined and included in family studies. ^Boughman suggested autosomal not X-linked inheritance was the mode of transmission in EOP although Saxen suggested that inheritance was by an autosomal recessive trait with high penetrance ^{(Saxen, 1980} ; ^{Saxen and Nevanlinna, 1984)}. ^Long compared and evaluated autosomal recessive and X-linked dominant modes of inheritance for LEOP and GEOP and concluded that the autosomal recessive model was far more likely than the X-linked dominant one. ^Long , however, did not test for autosomal dominance, which is the currently held theory for EOP genetic transmission.

The evidence for autosomal dominant inheritance was first reported by ^Marazita who also noted co-occurrence of LEOP and GEOP within families and progression from LEOP to GEOP in many patients. Their conclusion was that autosomal dominant inheritance with approximately 70 % penetrance occurred for both Blacks and non-Blacks. The currently held theory on the genetics of EOP is that PP, LEOP and GEOP are probably due to the same genes which are transmitted in an autosomal dominant manner with reduced penetrance. The expression « reduced penetrance » means that some subjects with the genotype may not express the phenotype, that is clinical manifestations of early-onset periodontitis, while others may express it fully. In the phenotypic expression of this trait the environmental factors (such as smoking and plaque control) may play a large role in allowing the phenotype to present clinically.

Genetic linkage is an important phenomenon which has to be considered in discussing the role of genetics in periodontal disease. Genetic linkage occurs when two genes are close together in distance on a chromosome. During the production of gametes (sperm or ovum cells) the chromosomes exchange sections throughout their length with their corresponding paired chromosome. This results in a mixing of genetic material creating variations between brother and sisters within a family. If genes are very close together then these genes are said to be in linkage disequilibrium and will move to the same chromosome during the rearranging phase in the production of gametes. Thus these genes will be seen clustered within families more commonly than further apart genes which will equilibrate or mix randomly. Linkage studies are undertaken to determine if such diseases as periodontitis may be linked to genes which are relatively easy to detect (marker genes) and are well known. Clearly if linkage can be established between a disease and a gene then although this disease may not be responsible for the disease it might be used as a marker of the disease. The same considerations apply to genetic polymorphisms, which can be considered as slight variations in genes which may or may not result in phenotypic differences but may be in linkage disequilibrium with genes coding for disease susceptibility and thus may be very important in genetic diagnostics as will be outlined later in this review.

Family linkage studies have been performed to date on two families with localised early onset periodontitis (LEOP). ^Boughman identified an autosomal dominant form of LEOP in an extended family from southern Maryland (Brandywine population). The subsequent linkage study on this family uncovered that type III dentinogenesis imperfecta (DGI-III) and a localised form of EOP were segregating as dominant traits. They found that the gene for LEOP was linked to a vitamin D related gene on chromosome 4. ^Hart re-evaluated these findings and showed no significant evidence of linkage to this region, for any of the models tested. They suggested that genetic locus heterogeneity might exist in EOP, or that EOP disease heterogeneity may explain these differences, that is the Brandywine population may have a different form of periodontal disease or different genes coding for this disease than Hart's study population.

^Wang have also performed a large linkage study on EOP finding linkages related to regions on chromosome 6 and 9 but not for chromosome 4. The same group performed a linkage study examining the association between IL-1a and IL-1b gene polymorphisms. These polymorphisms are allelic variations which may occur in the genome and may not in fact have any detectable or phenotypic effect on the gene, alternatively as has been described for some IL-1 related polymorphisms ^{(Pociot et al., 1993)} variations in secretion of cytokine protein may be associated with specific polymorphisms. These researchers looked at the GEOP subjects and found that there were 17 transmissions of allele 1 of the IL-1b⁺ polymorphism ^{(Kornman et al., 1997)} and only 2 transmissions of allele 2 of this polymorphism. These results suggest that the IL-1b polymorphism (allele 1) may be in linkage disequilibrium with a gene coding for EOP but when the siblings of the probands and the probands where paired and analysed the results did not suggest any linkage disequilibrium existed for this polymorphism and EOP genes. A similar analysis on polymorphisms of the IL-10 and TNFα genes indicates no linkage with GEOP ^{(Kinane et al., 1999)}.

Genetic based systemic diseases and periodontitis

Neutrophil functional disorders

Molecular biology has highlighted the important role of several receptors on the polymorphonuclear leucocyte (PMN) surface in adhesion, and emphasised that defects in numbers of these receptors may lead to increased susceptibility to infectious disease ^{(Anderson and Springer, 1987)}. Adhesion is crucial to the proper function of the PMN, affecting phagocytosis and chemotaxis which if deficient might predispose to severe periodontal destruction. ^Page proposed that the generalized form of prepubertal periodontitis (this disease has generalized - GPP - and localized - LPP - forms) is an oral manifestation of the LAD. This is not a widely held view and other researchers have indicated that GPP and LPP occur in otherwise healthy children ^{(Butler, 1969} ; ^{Shapira et al., 1997)}. Leucocyte adhesion deficiency occurs in two forms, both of which are autosomal recessive traits. Circulating leukocytes have reduced or defective surface receptors and do not adhere to vascular endothelial cells, thus they do not accumulate in sites of inflammation where they are needed. Reports of LAD indicate that although the blood vessels are full of neutrophils the disease sites lack sufficient leucocytes to combat the microbial challenge and thus infections ensue rapidly in these patients. Affected homozygotes suffer from acute recurrent infections which are commonly fatal in infancy. Those surviving will develop severe periodontitis which will begin as the deciduous dentition erupts ^{(Waldrop et al., 1987)}.

Other disorders of neutrophil function are associated with severe forms of periodontal destruction. The Chediak-Higashi syndrome (CHS) is a rare disease transmitted as an autosomal recessive trait. Those affected are very susceptible to bacterial infections and this appears to be related to alterations in the functional capacity of the PMN. Man ^{(Hamilton and Giansanti, 1974)} and other animals ^{(Lavine et al., 1976)} with CHS exhibit generalized, severe gingivitis and extensive loss of alveolar bone and premature loss of teeth ^{(Temple et al., 1972)}. The PMN chemotactic and bactericidal functions are thought to be abnormal in these patients.

Clearly these PMN functional diseases are excellent examples of how monogenic defects can cause periodontitis through a clearly attributable mechanism. The host response is made up of a vast number of processes all of which are under genetic control and all of which are feasible candidates for variability which may result in the variability to periodontal disease seen among the population.

Deficiency in neutrophil numbers (neutropenias)

A further neutrophil deficiency is that of infantile genetic agranulocytosis, a rare autosomal recessive disease where PMN numbers are very low and which has been associated with EOP ^{(Saglam et al., 1995)}. Cohen's syndrome is another autosomal recessive syndrome and is characterised by mental retardation, obesity, dysmorphia and neutropenia. Individuals with Cohen's syndrome show more frequent and extensive alveolar bone loss than age, sex and mental ability matched control ^{(Alaluusua and Asikainen, 1991)}. Not all neutropenias result in periodontal disease. Familial benign chronic neutropenia has variable expressivity and although several individuals within a family may be neutropenic, not all are affected either by recurrent infections or by periodontal disease ^{(Deasy et al., 1980)}. These findings might be explained by the variable genetic expression of the disorder or by the variable effects of the environment (for example plaque levels) on these patients.

Papillon-Lefèvre syndrome

The Papillon-Lefèvre syndrome is a disease with autosomal recessive inheritance ^{(McKusick, 1994)}, characterized by the presence of hyperkeratotic skin lesions. Individuals with this disease exhibit diffuse palmar-plantar keratosis associated with a severe generalised periodontitis, which occurs commonly before puberty with early loss of deciduous and permanent teeth ^{(Tinanoff et al., 1986} ; ^{Hanek et al., 1975)}. A frequency of 1 in 4 million in the general population exists ^{(Baer and Benjamin, 1974)}, with 25 % having an increased susceptibility to infection, and a history of consanguinity is noted in 33 % ^{(Hanek et al., 1975)}. Teeth are generally lost in the order of eruption ^{(Hanek et al., 1975)} but as yet there is no general agreement on the success of dental therapy. The pathogenesis of the periodontal tissue destruction remains unclear although several genetically determined defects in host defences have been reported. Deficient neutrophil phagocytosis has been reported by ^{Djawari (1978)}. Although others have suggested that an impaired cementum or defective ligament may be involved in the increased susceptibility of these patients to periodontal destruction. ^Vrahopoulous also noted a decreased lymphocyte response which has been also reported by other workers ^{(Hanek et al., 1975)}. ^Levo however, found decreased lymphocyte reactivity in both the Papillon-Lefèvre syndrome patients and about half of their immediate family. This finding emphasises the need to exercise caution in attributing susceptibility to any disease to a defect without thorough checking whether non-disease affected members of a family have the defect also. Thus it appears that periodontal destruction in Papillon-Lefèvre syndrome is not due to a genetically determined reduced cellular immune response.

In Papillon-Lefèvre syndrome, the clinical presentation shows varying degrees of periodontitis severity as well as great variation in the level of abnormal keratosis ^{(Soskolne et al., 1996)}. The possible aetiology of Papillon-Lefèvre syndrome may involve defects in epithelium ^{(Schroeder et al., 1983)} as well as the defects in lymphocyte function ^{(Soskolne et al., 1996)} and phagocyte function suggested previously ^{(Djawari, 1978)}. Haim-Munk syndrome is similar to Papillon-Lefèvre syndrome but has in addition arachnodactyly and deformity of the terminal phalanges ^{(Puliyel and Sridharan Iyer, 1986)}. Both the Papillon-Lefèvre and Haim-Munk syndromes are inherited as autosomal recessive traits and a high degree of consanguinity has been reported in families with these conditions ^{(Soskolne et al., 1996} ; ^{Pareek and Al Aska, 1986)}. It has been hypothesised that Papillon-Lefèvre syndrome and the early-onset periodontal diseases may be due to a common gene which codes for hyperkeratinisation of the skin and also effects the periodontally crucial junctional epithelial tissue. Thus having the gene for Papillon-Lefèvre syndrome would lead to early and rapid periodontal destruction. However studies examining genome wide linkage scans of consanguineous Papillon-Lefèvre syndrome families have placed the gene for Papillon-Lefèvre syndrome on chromosome 11 ^{(Laass et al., 1997)}. In addition these reports have identified an additional and separate loci for the palmoplantar keratodermas. Thus separate genes may exist for hyperkeratosis and for the periodontitis features seen and these genes may be in linkage disequilibrium, that is they may be so close to each other on the chromosome that they tend to always travel together in normal chromosome rearrangements.

Many conditions arise from different genes yet have the same clinical manifestations and this could be the case for the early-onset periodontal diseases ^{(Melnick et al., 1976)}. In consideration of the genetic aetiology of the early-onset periodontal diseases it is important to distinguish early-onset periodontitis associated with a medical condition such as Papillon-Lefèvre syndrome from early-onset periodontitis in otherwise healthy individuals.

Genetic defects of structural components

Ehlers-Danlos syndrome refers to a collection of connective tissue disorders characterized by defective collagen synthesis. Types IV and VIII of this defect is related to an increased susceptibility to periodontitis ^{(Linch and Acton, 1979} ; ^{Hart et al., 1997)} and is inherited in an autosomal dominant manner. Clinical characteristics of type VIII Ehlers-Danlos syndrome include fragility of the oral mucosa and blood vessels and a severe form of generalized EOP ^{(Apaydin, 1995)}. Other genetic conditions related to defects in structural components of the tissues include the very rare Weary-Kindler syndrome and hypophosphatasia. Early-onset periodontitis has been reported in Weary-Kindler syndrome where abnormalities of the basement membrane occur ^{(Wiebe et al., 1996)}. Clinical manifestations of this condition also include epidermolysis bullosa and poikiloderma congenitale. Patients with hypophosphatasia have a decreased serum alkaline phosphatase and the presence of phosphoethanolamine in the urine ^{(Frazer, 1957)}. There is severe loss of alveolar bone and premature loss of the deciduous teeth ^{(Beumer et al., 1973} ; ^{Casson, 1969)}, particularly anteriorly ^{(Baab et al., 1986)}. There is histological evidence of enlarged pulp chambers and a disturbance in cementogenesis, the cementum being either absent or hypoplastic. The concomitant lack or reduction in connective tissue attachment between the tooth and bone is thought to account for the early spontaneous exfoliation of the deciduous teeth. ^Baab described a family where all three children manifested premature exfoliation of the deciduous teeth similar to that seen in prepubertal periodontitis ^{(Page et al., 1983)}. These children were assigned a diagnosis of hypophosphatasia on the basis of alkaline phosphatase and phosphoethanolamine levels. ^Baab noted that their data suggest an autosomal dominant mode of transmission and suggested that hypophosphatasia might be considered in the aetiology of some forms of prepubertal periodontitis and as a possible explanation for certain site-specific periodontal destruction.

Down's syndrome

Periodontal disease in Down's syndrome is characterised by a generalised rapidly progressive periodontitis, which commences in the deciduous dentition ^{(Brown and Cunningham, 1961)}. The prevalence and severity of periodontal disease in persons with Down's syndrome is extremely high when compared to either their siblings ^{(Orner, 1976)} or mentally retarded individuals ^{(Saxen and Aula, 1982)}. Several cross-sectional studies have reported increased prevalence and severity of periodontal disease in children of older age groups ^{(Cohen and Morris, 1961} ; ^{Johnson and Young, 1963} ; ^{Snajder et al., 1968} ; ^{Cutress, 1971)}. The finding that patients with Down's syndrome have more severe disease than controls, matched in respect of tooth deposits and degree of mental retardation, suggests that the increased susceptibility is associated with the basic congenital disorder itself ^{(Saxen and Aula, 1982)}. Many systemic factors may account for the high periodontal disease susceptibility seen in Down's syndrome and these include abnormal capillary fragility ^{(Dallapicola et al., 1971)}, differences in collagen biosynthesis ^{(Reuland-Bosma et al., 1988)} and anatomically shorter roots which would contribute to early tooth mobility or furcation involvement ^{(Brown, 1971)}. Other factors have been suggested such as impaired PMN and monocyte chemotaxis in Down's syndrome and a reduced phagocytic function (^{Barkin et al., 1980a} et ^b ; ^{Tew et al., 1996)}.

Genetic variations in host defences which may influence periodontitis

Our current understanding is that periodontal disease (gingivitis and periodontitis) is initiated by the microbes within the plaque which accumulates in the gingival crevice region. Gingivitis will progress in many individuals to periodontitis but this progression is governed by the subject's host response. The host response is determined to some extent by previous experience (acquired immunity) but is predominantly influenced by the person's genetic make-up. Individuals respond to different antigens in ways predicted by their genes. A good example of this is in the case of the atopy diseases (viz. eczema, hay fever, asthma). Sufferers of hay fever have specific immunoglobulin E (IgE) antibody responses to antigens such as those in pollen, which initiate a mass release of inflammatory mediators from mast cells in the respiratory system. This excessive inflammation is seen as hay fever. Hay fever, asthma and eczema are genetically related conditions that are grouped within families and show how responses of the immune system can be affected by genetics.

Differences in host response between subjects are not solely confined to differences in immune response, as for our example above, but may also be manifested through differences in the inflammatory response (e.g. complement C1 deficiency giving angio-oedema for example) or in basic innate immune aspects (an example is the dysfunction of sweat glands which predisposes to infection in cystic fibrosis patients). Thus a range of genetic deficiencies or genetic variations in the host response can increase the likelihood of periodontitis if microbial plaque is allowed to accumulate in the gingival crevice region.

The genetic basis of many aspects of the periodontal host response has been discussed in reference to genetic disorders predisposing to periodontal disease. The aim of this section is to summarise the potential influence of innate, inflammatory and immunological genetic variations and to consider where the most promising candidates lie from the viewpoint of a genetic diagnostic approach to periodontitis.

Several features of the host's innate immune system which may contribute to genetic susceptibility to EOP have been outlined already and include epithelial, connective tissue and fibroblast defects. Functional PMN defects or deficient numbers of PMN have profound effects on the host's susceptibility to periodontitis. These defects have been considered previously, however, other aspects of the host inflammatory response namely cytokines have attracted much attention as potentially crucial variants influencing the host response in periodontitis.

Immune variants and periodontal disease

Variation in immunoglobulin G2 (IgG2) levels influence the immune response to periodontal pathogens ^{(Tew et al., 1996)}. A segregation analysis of IgG2 levels in EOP families has suggested an autosomal co-dominant mode of inheritance ^{(Marazita et al., 1996)}. Class II MHC (major histocompatibility complex) molecules are part of the process of recognition of bacterial antigens and may influence susceptibility to EOP ^{(Shapira et al., 1994)}. The MHC or HLA genes determine our response to particular antigens and may thus influence our response to periodontal pathogens and thus our host response to periodontitis. Molecular biological techniques are now available to investigate in detail genetic polymorphisms, such as those demonstrated by the HLA gene cluster. A Japanese study of EOP patients has found a significant association between an atypical BamHI restriction site in the HLA.DQB gene ^{(Takashiba et al., 1994)}. A study performed on Caucasian EOP patients found no association between this restriction site and EOP (Hodge and Kinane, 2000). A further study carried out by the same Japanese group has not been able to fully corroborate this previously reported association ^{(Ohyama et al., 1996)}. Another group has investigated HLA.DR polymorphisms in patients with GEOP and found a significant association between alleles DRB1*0401, 0404, 0405, 0408 and the disease. These alleles have been also associated with rheumatoid arthritis.

Cytokines

^Kornman have suggested that there is an gene and smokers with severe adult periodontitis. There were only 18 patients in the severe non-smoking group and although the odds ratio between severe versus mild AP was large (18.90), the confidence intervals were very wide (1.04-343.05). This report and the claimed association requires corroboration in larger studies of AP patients. It is also interesting to note that the findings of this study differs from Diehl et al.'s study of IL-1 polymorphisms in EOP ^{(Diehl et al., 1998} ; ^{Diehl et al., 1999)}. In the EOP study linkage disequilibrium was found between GEOP and allele 1 of the IL-1b^{+3 953} gene. A study on the prognostic value of the IL-1 genotype on the progression of AP following non-surgical treatment was performed by ^Ehmke . Of the 33 patients studied, 16 were the susceptible genotype-positive according to the ^Kornman criteria. Following 2 years of maintenance care, no differences, in the survival rate of teeth nor in sites exhibiting significant probing attachment loss were detected between those with and without the genotype.

Tumor necrosis factor alpha (TNFα)

^Galbraith determined TNF genotypes in AP patients and healthy controls and found no differences in the 3 bi-allelic polymorphisms of TNFα (- 238, - 308, + 252). They also analysed the distributions of these polymorphisms between patients with different disease severity and found no significant differences.

TNFα and interleukin 10 genes

A further study on the distribution of genes related to TNFα production and interleukin 10 (IL-10) was performed by ^Kinane and found no association between the genes for these cytokines and early-onset periodontitis compared to healthy controls. These cytokines are crucial to both the immune and inflammatory responses. Not only does TNF up-regulate host defences, it has other effects on tissue physiology, including bone resorption ^{(Mundy, 1993)}. Over-expression of TNFα in the periodontium may be harmful to the host. Normally TNFα and other pro-inflammatory agents are regulated by IL-10, suggesting some deficiency in this mechanism may be linked with disease. Allelic variation in cytokine genes and factors regulating their expression give phenotypic differences in cytokine responses between individuals, which can be important in disease susceptibility and progression ^{(Bidwell et al., 1999)}. Analysis of genotypic markers, which correlate with different expression phenotypes allows some understanding of variations between individuals in immune response ^{(Santamaria et al., 1989} ; ^{Derkx et al., 1995)}. Perhaps more importantly, links between some alleles of « marker motifs » and predisposition towards particular diseases have been established ^{(Foissac et al., 1997)}.

Genotypic variations in cytokine response have been shown in vitro for TNF and IL-10, and specific alleles are implicated in diseases such as systemic lupus erythmatosus (SLE) and rheumatoid arthritis (RA). Two microsatellites at the IL-10 locus, IL-10.R and IL-10.G, and one microsatellite at the TNF locus, TNFα, were recently typed for 77 GEOP patients ^{(Kinane et al., 1999)}. Due to the highly polymorphic nature of the microsatellite loci, a statistical comparison with ethnically-matched healthy controls (TNFα : n = 91, IL-10.R : n = 94, IL-10.G : n = 102) was conducted using a Monte Carlo simulation for each marker. No significant differences were observed for any of the three markers, although there were possible indications of trends similar to those observed in SLE for the IL-10.G marker. Interestingly, a bias toward TNFα2 in other chronic disease populations, for example RA, has also been reported ^{(Gallagher et al., 1997} ; ^{Field et al., 1998)}.

There is little to suggest variation at IL-10.R in GEOP, whereas in RA a significant trend toward IL-10.R2 has been shown ^{(Eskdale et al., 1998)}. It seems the genotype represented by this allele plays little if any role in GEOP. IL-10.G showed the greatest variation between GEOP and control populations, which seems mainly due to a 12 % decrease in IL-10.G9 occurrence versus other alleles in the GEOP population. Whilst this is insignificant, it shows a trend which is similar to SLE (not RA) ^{(Eskdale et al., 1997)}. GEOP could have similarities in these causative genetic factors to other chronic inflammatory disorders, but not consistently enough to begin to classify GEOP with any other disease genotype. It is possible that GEOP has no single clear mode of inheritance because GEOP may represent a heterogeneous group of diseases ^{(Baelum et al., 1996)}. Different immunological defects may render individuals susceptible to GEOP but manifest the same clinical phenotype. Complex and multifarious interactions between host-response, the environment and bacteria make elucidation of genetic factors difficult. This may be particularly pertinent to the periodontal arena given the sensitive nature of the gingival environment to imbalance in bacterial and immuno-inflammatory stimuli. It should be borne in mind that micro-satellites are only markers ; they do not themselves contribute to disease. Screening micro-satellite markers provides a useful tool to focus on areas of the genome which may then be subject to more detailed investigations.

Fc-gamma receptor

Fc-gamma receptor (FcγR) is the receptor present on phagocytes which binds immunoglobulin G (IgG) and is thus crucial in the opsonophagocytosis of bacteria. Two studies of adult periodontitis patients have investigated associations between FcγR polymorphisms and susceptibility to AP ^{(Kobayashi et al., 1997} ; ^{Van Schie et al., 1998)}. No associations were found for FcγR-IIa and FcγR-IIIb genotypes between maintenance patients and healthy controls ^{(Kobayashi et al., 1997)}. The authors also considered the influence of various covariates together with the FcγR-IIIb allele 2, which included serum IgG subclass, baseline and follow-up clinical indices and smoking. None of these covariates were found to be significant. It was concluded that presence of the FcγR-IIIb allele 2 may be a risk factor for recurrent periodontitis.

^{Van Schie} studied a US Caucasian population with moderate to severe periodontitis and age-matched healthy controls for the presence of specific FcγR-IIa and FcγR-IIIb genotypes. A composite genotype of 2 FcγR alleles was found more frequently in patients and a further composite genotype was noted to be significantly lacking in patients. When the genotype pairs were examined individually they showed no association with disease. These results are odd in that one pair of FcγR alleles is part of both composite genotypes and one of the genotypes, FcγR-IIa-H/H131, is considered to have immune functional protective advantages ^{(Sanders et al., 1995)}. It is feasible that the combined genotypes are in linkage disequilibrium (found close together on the chromosome) with more crucial alleles and the FcγR-IIb combined genotypes are thus part of a gene pattern or haplotype which may predispose subjects to periodontitis.

^Colombo have investigated serum levels of IgG2, Gm(23) allotype and FcγR-IIa and FcγR-IIIb allotypes in 32 refractory, 54 successfully treated and 27 periodontally healthy subjects. No significant differences in serum IgG2 levels, Gm(23) allotypes or FcγR genotypes were found between the three groups and these variables could not be related to the clinical status of the subjects.

Genetic screening for periodonitis risk

It is important to highlight the use of clear diagnostic criteria in the investigation of hereditary diseases. Genetic analyses must be underpinned by reliable clinical diagnoses, within heterogeneous populations, otherwise assessments of genetic transmission will be erroneous. A number of aspects of the inflammatory and immune response, which may play a role in the development of periodontal disease, have a clearly defined genetic basis. Associations between several of these aspects of immune defence and genotype have been discussed previously.

Future research will undoubtedly focus on other aspects of the immune and inflammatory response, in the hope of further elucidating the pathogenesis and genetic aetiology of EOP. However, a degree of caution should be observed with regard to the interpretation of initial investigations into new areas of genetic immune regulation. It is essential that early findings are corroborated in large homogeneous populations, before pronouncements are made concerning genetic markers of periodontal susceptibility. At the moment we still await reliable, robust and useful genetic markers of AP.

Performing clinical periodontal assessments of siblings of EOP probands is one of the simplest and crucial actions that genetic considerations in periodontology have indicated to us. By doing this we may pick up susceptible patients early and instigate therapy which may prevent the more significant disease aspects occurring. We still await further data and better candidate genetic diagnostic tests especially on polymorphisms, which may be linked with adult periodontitis and early onset periodontitis.

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