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GENETIC POLYMORPHISMPresented ByDr. M. Shiva ShankerIst Year Post Graduate Student ,Dept of Periodontics, Mamata Dental College.

contentsIntroductionGenetics TerminologiesTypes of genetic disordersSingle gene defectsMultifactorial diseasesMethods of genetic analysis genetic study designsHuman gene polymorphismsVarious type of polymorphisms and their relationship to the periodontal diseaseProving a disease/polymorphism relationshipFuture application of genetic informationConclusion

introductionThe science of genetics is concerned with the inheritance of traits, whether normal or abnormal, and with the interaction of genes and the environment.Individuals may respond differently to common environmental challenges, and this differential response is influenced by the individuals genetic profile.The genetic origin of a disease is either partly or wholly due to abnormalities within the genetic code.

cellCells are the basic building blocks of all living things. The human body is composed of trillions of cells. They provide structure for the bodyCells consists of various parts

NucleusThe nucleus serves as the cells command center, sending directions to the cell to grow,mature, divide, or die. The nucleus is surrounded by a membrane called the nuclear envelope,which protects the DNA and separates the nucleus from the rest of the cell.


In the nucleus of each cell, the DNA molecule is packaged into thread-like structures called chromosomes.Each chromosome has a constriction point called the centromere.centromere divides the chromosome into two sections, or arms.The location of the centromere on each chromosome gives the chromosome its characteristic shape, and can be used to help describe the location of specific genes.

dnaDNA consists of chemically linked sequences of nucleotides; these are the "building blocks" of the DNA and always contain a nitrogenous base.Four nitrogenous bases exist: adenine (a), guanine (g), cytosine (q and thymine (t).The bases are linked to a sugar (2-deoxyribose), where a phosphate group is also added.

DNA contain the genetic code .The genetic code is read in groups of three nucleotide ,and called as codon. Coding regionPromoter region

Variant forms of a gene that can occupy a specific chromosal site (locus) are called alleles. when different alleles of a given gene co-exist in the human population, we speak about genetic polymorphisms.An alteration that changes in single point base pair is called a point mutationThe most common class of point mutations is the transition, comprising the substitution of one nucleotide with anotherTermed as single nucleotide polymorphism

TERMINOLOGIES:Allele: alternate forms of a given gene differing in DNA sequence assumed to arise by mutation and affecting the function of a single product.Chromosome: a nuclear structure carrying genetic information arranged in a linear sequence.Genetic code: the consecutive nucleotide triplets that specify the sequence of aminoacids for protein synthesis.Genome: a term used to refer to all the genes carried by an individual or cell

Genotype: the genetic makeup of an organism or cell distinct from its expressed features.Locus: the physical location a gene occupies within a chromosome or portion of genomic DNA.Linkage: the tendency for certain genes to be inherited together due to their presence on the same chromosome.Linkage disequilibrium: occurrence of some genes together more often than would be expected by random distributionPolymorphism: when a mutation increases to a level involving more than 1% of the population, it is referred to as a polymorphism, which merely means that there are multiple forms of the specific nucleotide sequence that may be found at the genetic locus.Single nucleotide polymorphism (snp): common, but minute, variations that occur in human DNA at a frequency of one in every 1,000 bases. These variations can be used to track inheritance in families. SNP is pronounced, "snip".

TYPES OF GENETIC DEFECTSMendelian disorders (single-gene defects)Non-mendelian disorders (multifactorial disorders)

SIMPLE Vs MULTIFACTORIAL GENETIC TRAITSSIMPLE MENDELIAN TRAITSMutations of critical genes alter gene function causing disease phenotype.Mutations of a specific gene are typically rare (C polymorphism was significantly higher in both the moderate and the severe periodontitis patient group than in the control group.

References Periodontitis Subjects Ethnicity Smoking Association D aluto et al 2004Chronic 94 subjects with severe generalized periodontitisMixed Smokers and non smokersNon significantLaine et al 2005Chronic 100 patients with severe periodontitis and 99 healthy controlsCaucasian Smokers and non smokersNon significantBerdeli et al 2007Chronic 83 patients with CP and 106 periodontally healthy subjectsCaucasian Smokers and non smokersNon significantImamura et al 2008Chronic 43 patients with periodontitis and 49 healthy controlsJapanese Non significant

CD 14 GENE POLYMORPHISMThe CD14 receptor is a glycoprotein that is expressed primarily on the surface of monocytes ,macrophages,neutrophils and gingival fibroblasts and is involved in the process of cellular response to bacterial LPS. The cd14 protein is expressed in two phenotypic forms .M cd 14 and sCD 14. Scd14 is present in the serum. LPS induced upregulation of sCD14 seems to elicit an increased production of il-2 by apc (antigen presenting cells). Systemic level of soluble cd14 increases in periodontal disturbances.

CD14 gene exists as a single copy gene. This polymorphism comprises a C to T substitution to position -159 to the 5flanking region of the CD 14 gene.It has been demonstrated that C to T transformation at position -159 is related to the production of s cd14. Frequency of c allele carriage tends to be larger in subjects with severe periodontitis.The systemic level of the soluble form of cd14(scd14) is significantly increased in patients with periodontal disease(hayashi et al 1999)CD14 expression within the periodontal tissue was found to be negatively correlated with the amount of attachment loss(jin 2001).Reduced expression of cd14 on monocytes was suggested to an increasing susceptibility for EOP (buduneli et al 2001).

References Periodontitis Subjects Ethnicity Smoking Association Yamazaki et al 2003Chronic 163 subjects with periodontitis and in 104 healthy controlsJapanese Non smokersNon significantLaine et al 2005Chronic 100 patients with severe periodontitis and 99 controlsCaucasian Smokers and non smokersSignificant James et al 2007Chronic and aggressive 73 subjects with AP, 95 subjects with CP, 95 healthy controlsCaucasian Smokers and non smokersNon significantDonati et al 2008Chronic 53 subjects with generalized and severe periodontitisCaucasian Smokers and non smokersNon significant

CARD15/NOD2 GENE POLYMORPHISMNucleotide-binding oligomerization domain receptors, including NOD1, NOD2, and ICE protease activating factor(ipaf), are cytoplasmic receptors for recognition of microbial products.These receptors detect organisms that enter the cytoplasm of the cell, or products that may be released or transported into the cytoplasm by processes such as phagocytosis and degradation of microbes. Nod1 and Nod2 interact with receptor interacting protein 2(RIP2), also called RICK, a protein consisting of a kinase domain and a CARD.

RIP2 directly interacts with inhibitor of NFkB kinase (IKK ), leading to ubiquitinylation of IKK and activation of the kinase activities of ikk and ikk, this results in the activation of the proinflammatory responses mediated by nfkb (ferrero et al 2007)A clear mrna expression of NOD1 and NOD2 was revealed in gingival fibroblasts(uehera et al 2007) and in oral epithelial cells(sugawara et al 2006).

References Periodontitis Subjects Ethnicity Smoking Association Laine et al 2004Chronic 104 dutch Caucasians with severe adult periodontitis and in 97 healthy controlsCaucasian Smokers and non smokersNon significantNoack et al 2006Aggressive 86 generaized aggressive periodontitis patients I comparison with 67 healthy controlsCaucasian Smokers and non smokersNon significant

MISCELLANEOUS GENE POLYMORPHISMSINTERLEUKIN-2 (IL-2) GENE POLYMORPHISM IL-2 is a proinflammatory cytokine derived from Th1 cells.Il-2 is involved in b-cell activation and stimulates macrophages, nk cells, t cell proliferation, and osteoclast activity.A polymorphism in the position -330 (T-G) of the il-2 gene promoter was identified by john et al. (1998). This polymorphism could be useful as a marker to diagnose susceptibility to inflammatory diseases.

INTERLEUKIN-6 (IL-6) GENe POLYMORPHISMInterleukin-6 (IL-6) plays a role in B cell differentiation and t-cell proliferation. It also stimulates hematopoiesis and accelerates bone resorption. High levels of il-6 in biological fluids and blood have been determined in chronic inflammatory diseases. Higher levels of il-6 were found in sites with gingivitis when compared to healthy sites.Polymorphism occurs due to transition of G to C at position 174 in the promoter region of IL6 geneThe C allele was shown to alter the IL-6 gene transcription response to stimuli such as LPS and IL-1. Trevilatto 2003 first reported that the genotype g/g of the il-6_174 polymorphism was significantly associated with susceptibility to chronic periodontal disease

MMP POLYMORPHISMSThe degradation of periodontal tissues is mainly mediated by matrix metalloproteinases (MMPs). Many types of MMPs have been identified in inflamed periodontal tissues and these enzymes are thought to play an important role in tissue destruction in periodontal diseases (birkedal-hansen 1993).

MMP-1 PROMOTER POLYMORPHISMFibroblast type collagenase (MMP-1) is the major type of proteolytic enzyme that can cleave native interstitial collagens type I and III, which are the most abundant protein components of periodontal extracellular matrix. Matrix metalloproteinase-1 seems to play an important role during the destruction of the extracellular matrix in periodontal disease. The MMP-1 gene is located in 11q22 and is translated in a wide variety of cells, e.G. Fibroblasts, macrophages, endothelial, and epithelial cells.

The level of MMP-1 expression can be influenced by the polymorphism in the promoter region of the MMP-1 gene resulting from a guanine insertion at 1607 bp (i.E., The GG versus G variants), which results in the creation of a binding site for the ets family of transcription factors as well as in the increased transcription of the MMP-1 gene and increased enzyme activity polymorphism in the promoter region of human MMP-1 gene has been describedThe two alleles (1G and 2G) are formed by an insertion/deletion of a guanine at position 1607Izakovicova 2004 reported that the polymorphisms in the MMP-1 promoter may have only a small effect on the etiopathogenesis of chronic periodontitis.Astolfi 2006 investigated the relationship between polymorphisms in mmp-1 (-1607 1g/2g, -519 a/g) with chronic periodontitis in a brazilian population. And showed that no significant association is found for the MMP-1 polymorphisms with susceptibility of periodontitis.

MMP-3 PROMOTER GENE POLYMORPHISMAstolfi 2006 studied MMP-3 (-1612 5A/6A) gene promoter polymorphisms using PCR-RFLP methods and showed that the 5A/5A genotype was significantly more frequent in the periodontitis group and reported that MMP-3 gene polymorphism may contribute to periodontal tissue destruction during periodontitis in brazilian subjects.

MMP-9 PROMOTER GENE POLYMORPHISMKeles JC 2006 investigated the association between MMP-9 promoter polymorphism and severe generalized chronic periodontitis in a turkish population. The alleles of the C/T polymorphism at position -1562 in the promoter region of the MMP-9 gene showed a significant difference in MMP-9 genotypes between chronic periodontitis patients and healthy controls suggesting that MMP-9 promoter gene polymorphism seems to be associated with severe generalized chronic periodontitis.

RAGE GENE POLYMORPHISM AND PERIODONTITISRAGE (receptor for advanced glycation end products) is a multiligent member of the ig super family of cell surface molecules, initially identified as a cellular interaction site for AGEs. RAGE gene is localized to the sixth chromosome region. Polymorphism of RAGE gene may contribute to individuals susceptibility to develop chronic periodontitis, independently of diabetes .

PROVING A DISEASE/POLYMORPHISM RELATIONSHIPPolymorphism must influence the gene product.Biases in the study population should be recognized and controlled.Affected gene product should be the part of disease etio-pathology.Confounders such as smoking and socioeconomic class must be controlled.

CLINICAL UTILITY OF GENETIC KNOWLEDGEPolymorphisms associated with periodontitis illustrate a number of important points with respect to the clinical interpretation of this type of information.The associations between particular genes and disease may only (thus far) be apparent in certain populations and not in others. Thus, genetic tests based upon these genes may not apply to all patients.The associations between groups of interacting genes and disease may be stronger than those between individual genes and disease. Therefore, as more genetic risk factors are found, genetic tests for disease risk will continually evolve and merit scrutiny and evaluation.The associations between disease and genes may be indirect, that is, genetic factors may be associated with environmental risk factors for periodontitis (e.g. Smoking) and thereby influence disease only in those patients with the relevant biological exposure.

GENETIC SCREENING FOR PERIODONTITIS RISKThe current practical clinical utility of genetic knowledge in periodontics is limited. However, performing clinical periodontal assessments of siblings of AgP probands is one of the most useful actions we can perform to ensure the early diagnosis of this disease.By careful clinical diagnostic procedures, we may detect susceptible patients early and instigate therapy, which may prevent the more significant disease aspects from occurring. In the pursuit of better genetic diagnostic tests for chronic and aggressive periodontitis, we must plan our research using plausible biological arguments and carefully avoid bias and misinterpretation of genetic associations with disease.

FUTURE APPLICATION OF GENETIC INFORMATIONPrognostic tests:Genetic tests, should predict the likelihood of disease initiation before it occurs and ultimately will be linked to knowledge of the environmental factors that can initiate the inappropriate activation of genes that are problematic.Knowledge of the genetic profiles of individuals who are susceptible to periodontitis will identify those individuals whose environmental exposures must be modified in order to prevent disease.

DIAGNOSTIC TESTSA great deal of research has been performed in an attempt to detect active disease or subclinical initiation of disease but no universally accepted test has emerged for clinical application.Prognosis and diagnosis can become tightly linked because both a genetic profile would be available and a gene-expression profile could be monitored over time. Once the genetic risk and specific genetic risk factors for a given patient are known, tests of gene activation might be individually targeted and test intervals could be tailored to the susceptible patient.The specific environmental exposures leading to gene activation may be more clearly known.

CONCLUSIONPeriodontitis is clearly multifactorial and researchers need to design studies that examine the role of important environmental and genetic factors simultaneously. Given the large number of genes in the human genome and bacteria in the oral cavity, it is likely that genes and the environment interact in important yet unrecognized ways to alter disease risk. Identifying specific genetic risk factors may be academically appealing but is of little use unless it leads to improvements in the prevention/treatment of disease.

REFERENCESClinical text book of periodontology, newmann, takei, carranza. 10th edition, pg no:193-206.Clinical periodontology and implant dentstry, 5th edition, jan lindhe. Pg no:329-340.Fundamentals of periodontics, thomas g wilson, 2nd edition, pg no:171-182.Periodontal medicine and systems biology, brian hinderson.Periodontics, b meley, 5th edition, pg no 49-50.Modifying disease genes in relation to periodontics.Genetic polymorphisms in periodontal disease: an overview, r vijayalakshmi et al, indian journal of dental research, 21(4), 2010.Gene polymorphisms and periodontitis, jingai zhang et al, periodontology 2000, vol 56, 2011, 102-124.The role of genetic polymorphisms in periodontitis, hiromasha yoshie et al, periodontology 2000, vol 43, 2007, 102-132.

Determinants of host susceptibility in aggressive periodontitis, huanxin meng, periodontology 2000, vol 43, 2007, 133-159.Genetic polymorphism studies in periodontitis and fc receptors, jperiodontal research 2012, 47, 273-285.Influence of mmp8 promoter polymorphism in early osseointegrated implant failure, f.R costa et al, clinical oral investigation 2013, 17:311-316.Association of il8 gene polymorphism with clinical parameeters and chronic periodontitis, hengameh khosropanah et al, journal of dentistry 2013, vol10,no4.Association between il6 polymorphisms and periodontitis in indian non smokers.Mendelian form of periodontitis, thomas c. Hart et al, periodontology 2000, vol 45, 2007, 95-112.The association of fc receptor iiib genetic polymorphism and susceptibility to periodontitis in taiwanese individuals, ho y-p et al, journal of clinical periodontology 2010, 37: 145-151.Association of toll like receptor 9 haplotypes with chronic periodontitis in czech population. Holla li et al, JCP 2010, 37: 152-159.A comparative study of th role of cytokine polymorphisms il10 and tnf in susceptibility to implant failure and chronic periodontitis. Ceyda gurol et al. The international journal of oral and maxillofacial implants 2011, 26:955-960.Genetic polymorphism of fc receptors iia, iiia and iiib in south indian patients with generalized aggressive periodontitis, journal of oral science, vol 53, no4, 467-474.