Genetic Relationship to Periodontal Disease : A Review

Periodontal disease is the most widespread and prevalent disease in the world which involves complex interactions between plaque microorganism and host immune system resulting in the loss of periodontal structures surrounding the tooth. Till recently the disease was thought to be caused by environmental factors, but now research is pointing to genetic causes of many of these diseases. Researchers are trying to identify the genetic mutations or polymorphism in respect to the various aspects of immunity. This article is a review of the monogenic disorders are caused by mutation of single gene and referred to as single gene disorders and polygenic alterations at multiple areas of the genes, each with a small contribution and is called polymorphism, that are influenced by environmental and behavioral factors.


INTRODUCTION
Periodontal disease is the most widespread and prevalent disease in the world which involves complex interactions between plaque microorganism and host immune system resulting in the loss of periodontal structures surrounding the tooth.Most of these diseases are chronic, but a small percentage of the people develop rapidly progressing irreversible destruction of the periodontal tissues.A wide variety of risk factors have been implicated for the manifestation and progression of the disease including microbial plaque, tooth associated factors, systemic and genetic factors, social, behavioral and environmental factors.The disease has remained an enigma and the prediction and predilection of the disease has always been a problem.
Until recently, periodontitis was thought to be determined by environmental factors alone.It is a common observation that although people are exposed to the same conditions only some people develop aggressive forms of the disease while some others suffers from mild or no disease.This suggeststhat the individual's susceptibility to the disease and perhaps a genetic basis for the susceptibility.
Genetic factors influence the inflammatory and immune response of periodontitis.As immune system plays an important role in the pathogenesis of the disease, researchers have been trying to identify the genetic mutations or polymorphism in respect to the various aspects of immunity.The effects of these genetic variations may be minor or insignificant or very significant and severe. 1

Monogenic disorders
Genetic diseases have been broadly classified into two groups: simple Mendelian diseases and complex disease 1 .The simple mendelian disease or monogenic disorders are caused by mutation of single gene and referred to as single gene disorders.These may be of autosomal recessive or dominant type of inheritance.Severe periodontitis is part of the clinical manifestation of several monogenetic gene mutations with the syndromes having biochemical defects 1 .The significance of these conditions is that the genetic mutation occurs at a single locus and is sufficient to produce the clinical phenotype to cause the disease.The impact of the gene is same in all families.The genetic alteration is associated with a disease phenotype and there is no compensatory mechanism to overcome the effects of the genetic defect.Such a genetic alteration is termed 'mutation' as in the case of Mendelian diseases. 2

Complex genetic diseases (Polygenic disorders)
This is more prevalent than monogenic disorders occurring in more than 1% of the population.They are a result of genetic alterations at multiple areas of the genes and are influenced by environmental and behavioral factors.These qualitative trait disorders are regulated by several genes, associated with variations in multiple genes, each with a small contribution and is called polymorphisms.When a specific allele occurs, in at least 1% of the population, it is said to be genetic polymorphism.The simplest type of polymorphism results from a single base mutation which substitutes one nucleotide for another, and has recently been termed as a single nucleotide polymorphism (SNP).Other types of polymorphism are restriction fragment length polymorphism (RFLP) and simple tandem repeats (STRs), consisting of relevant allele or nucleotide repetition. 3 contrast to Mendelian inheritance these genetic polymorphisms are not directly linked to the disease but specific alleles are reported more frequently in the diseased individuals than nonaffected individuals. 1The results are evident only when two different genetic alterations coexist.The resulting complex periodontal diseases are mostly mild phenotype and chronic, slowly progressive in nature. 3Variations in a number of genes encoding different proteins result in a genetic predisposition to a clinical phenotype.Thereare no Mendelian inheritance patterns and gene mutations are not present.Environment and life-style are major contributors to the pathogenesis of complex diseases.
The progression of periodontal disease is governed by host response which is influenced by the genetic makeup.Genetic deficiencies or variations can increase the likelihood of periodontal disease.A gene may be considered as a causative or modifying factor in periodontitis if the physiological process determined by the genes has been associated with the presence or severity of disease. 4Clinical and scientific data from a variety of sources suggest that the genetic variants are major determinants of syndromic and non-syndromic periodontitis.
Various syndromes, which have periodontal disease manifestations as part of syndromic manifestations are Papillon Lefevre syndrome, Chediak-Higashi syndrome, Ehler-Danlos syndrome, cyclic neutropenia, and leukocyte adhesion deficiency, Hereditary gingival fibromatosis is found to be associated with a mutation in the SOS (Son of Sevenless) gene. 1,5he significance of these conditions is that they clearly demonstrate that a genetic mutation at a single locus can impart susceptibility to periodontitis.
Currently, little is known about which genes may be involved in periodontitis as disease modifying genes.Several immune response traits have been associated with clinical forms of periodontitis and some of these factors the underlying genetic determinants are known.Although it is unlikely that polymorphisms in all these genetic determinants impart differential susceptibility to periodontal disease, it is reasonable to expect that multiple genes will be found to be important and that knowledge of these may permit determination of individual susceptibility.The key will be able to identify the genetic factors that are important enough to impart significant clinical risk.
The technological advances in the human genome projects have changed the understanding of diseases, prediction of risk factors and its treatment based on genomic approach to target molecular pathways of disrupting the disease process.The genomic studies leads to the understanding of the mechanisms modulating the inflammatory process and the knowledge of the complement of genes should be possible to identify the metabolic pathways involved in periodontal destruction and regeneration.

Inheritance
There a paradigm shift in understanding periodontal disease and there is more emphasis on host genetic and other non-microbial environmental factors.The characteristic feature of periodontitis is that, whatever be the cause, the symptoms are deepening of periodontal pocket, loss of attachment, and alveolar bone loss.It is the likelihood of the overlapping clinical phenotypes existing between different forms of periodontitis.The development of periodontitis depends on the environmental risk factors and the genetic factors inherited or present at that point of time.The increased number of the genetic factors inherited, the greater the genetic predisposition and higher chances of developing early onset periodontal disease.

CONCLUSION
Despite the advances made in the genetic search, we still have not determined the genetic basis of aggressive and chronic periodontitis.No major mutations which could cause periodontitis in otherwise healthy individuals have been identified.The studies have failed to quantify the magnitude of the contribution of a particular disease associated allele to disease risk.Even among studies with subjects of same ethnic background no consistent results have been obtained.

The table summarizes candidate gene polymorphisms investigated in relation to periodontitis.
Interleukin 1 IL-1á -889 and IL-â+3954 2q13.These functionally similar molecules (IL-1á and IL-1â) are encoded on separate genes in the same chromosome 2.
Frequency of allele 2 of the IL-1B +3953 SNP was significantly increased in patients with advanced periodontitis.Studies in both chronic and aggressive periodontitis showed mixed results 6,7,20,21,24 .
Interleukin 4 (IL4) No difference was found in the frequency of IL-4 gene polymorphisms between control and periodontitis group in African-American-Brazilian population 7,24 .
Interleukin 6 (IL6) IL-6 in intron 2 and in the promoter region (PP-and IP-) gene polymorphisms in chronic periodontitis suggested that -572 G/C polymorphisms of IL-6 gene might be one of the protective factors associated with lower susceptibility to chronic periodontitis 7,23.25 Interleukin 10 (IL10) IL-10 promoter polymorphisms at position -824 and other at -597 in chromosome 1, on aggressive and chronic periodontitis found no association between the genes for the cytokine and aggressive periodontitis while IL-10 1087 was susceptible to periodontitis 7,26,27 ..

Fc gamma
The Fc-gamma receptor is the receptor present on phagocytes, receptor FcãR) which binds to IgG..There are three main classes of FcR: FcãRI (CD 64 ), FcãR II (CD 32), FcãR III (CD 16) in chromosome 1.FcãR IIIa and FcãR IIIb, is associated with chronic periodontitis.FcãR IIIb has a NA1-NA2 polymorphism.NA1 is a more efficient opsono-phagocytic agent than NA2 6,28 .Toll-like receptors Signal molecules essential for the cellular response to bacterial cell wall (TLR-2,-4) gene polymorphism components.TLR 2exhibits polymorphism ( Arg to Thr at 677, Arg to Gly at 753) losing their ability to respond to cell wall components.Polymorphism of TLR4 (Asp 299 Arg 677 Trp; Arg753 Gln) have been associated with impaired LPS signal transduction.Their relationship has still not been established 6,7,29 .CD14 gene polymorphismThe R-allele in the promoter region of CD14 at position -260(-159) enhances the transcriptional activity of the gene.Studies with Caucasian subjects investigated the CD14-260 polymorphism in chronic periodontitiswith no significant associations.A higher frequency of the N -allele and the N/N genotype of CD14-1359 polymorphism was found in patients in severe periodontitis6,7 .Card 15 gene polymorphisms The 3020insC and 2104 C >T polymorphisms of the CARD15 (NOD2) gene leads to impaired activation of nuclear factor-kappa B, resulting in altered transcription of pro inflammatory cytokine genes and reduced expression of these cytokines.However no role for CARD 15 found in Caucasians 6 .