Genetic factors and periodontal disease
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The document discusses the genetic and environmental factors influencing periodontal disease, highlighting that approximately 48-59% of its clinical severity is attributed to genetic factors. It outlines the complexities of disease modifiers such as smoking and diabetes, and the role of various genes and polymorphisms in disease susceptibility. Additionally, the document introduces contemporary genetic research methods and emphasizes the need for understanding gene-environment interactions in developing effective periodontal therapies.
Genetic factors and periodontal disease
- 1. Richa Sharma MDS 2nd yr Dept of Periodontology and Oral Implantology
- 2. INTRODUCTION Bacteria cause periodontal disease, but other factors determine how severe that disease will become and how specific a patient responds to the therapy. Recently, the clinical severity of periodontal disease was evaluated in 117 sets of adult identical (monozygous) and fraternal (dizygous twins. It was determined that around 48-59% of the clinical severity of the disease was explained by genetic factors.
- 3. LEADING PERIODONTAL DISEASE CONCEPTS1965 – 1995 Three popular assumptions guided periodontal treatment: Populations with poor plaque control and limited professional care have widespread severe periodontitis. Individuals with poor plaque control for many years have severe generalized periodontitis. The severity of disease depends on the combination of the bacterial challenge (ie plaque control) and length of time of exposure to bacterial challenge.
- 4. CURRENT CONCEPTS Periodontitis requires specific bacteria for initiation and progression of attachment loss and bone loss. There is a ‘normal’ host response to this bacterial challenge. Although the normal tissue response is primarily ‘protective’, it also causes tissue destruction. Healing and repair are constantly going on in the periodontal tissues. In majority individuals with moderate bacterial challenge, protection and repair dominate destruction.
- 5. Some patients have ‘altered’ host responses and develop more severe destruction. Altered host responses may develop from a) heavy bacterial challenge and b) presence of disease modifiers that reduce the protective component of the host response or amplify the destructive component. Examples of disease modifiers include: smoking, diabetes and IL-1 genetic variations.
- 6. DISEASE MODIFIERS The factors that determine severity and response to treatment are often called disease modifiers. These, when present in patient, change the trajectory of clinical disease expression over time.
- 8. INTRODUCTION TO GENES The human genome is made of DNA. Just before each cell undergoes division, it condenses to form chromosomes. The DNA is a twisted ladder, a double helix in which the rungs of ladder are pair of compounds called nucleotide bases. Each nucleotide base is attached to two supporting backbones. A=T and G=C
- 10. There are estimated to be 25,000–50,000 different kinds of genes in the human genome. Genes can exist in different forms or states. Geneticists refer to the different forms of a gene as allelic variants or alleles. Allelic variants of a gene differ in their nucleotide sequences. When a specific allele occurs in at least 1% of the population, it is said to be a genetic polymorphism
- 11. Polymorphism arises as a result of mutation. The different types of polymorphisms are typically referred to by the type of mutation that created them. Single nucleotide polymorphism (SNP): The simplest type of polymorphism results from a single base mutation which substitutes one nucleotide for another. The frequency of SNPs across the human genome is estimated at every 0.3–1 kb
- 12. Restriction Fragment length polymorphism (RFLP) Digestion of a piece of DNA containing the relevant site with an appropriate restriction enzyme could then distinguish alleles or variants based on the resulting fragment sizes via electrophoresis. Insertion-deletion polymorphism Results from insertion or deletion of a section of DNA. Most common type is the existence of variable numbers of repeated base or nucleotide patterns in a genetic region
- 13. Kinane and Hart (2003) presented the classic relationship among phenotype, environment, and genotype as follows: Phenotype = Environmental risk factors (smoking status, plaque control, socio-economic status, diabetes, etc.) + genotype (includes gene–gene interactions) + genotype * environment (that is the interaction between environment and genotype).
- 14. It has been widely accepted that the differences among individuals at risk for developing most diseases have a substantial inherited pattern. ENVIRONMENTAL FACTORS (diet, smoking, preventive care, exposure to pathogens) GENETIC FACTORS INTERACT WITH EACH OTHER TO DETERMINE PERSON”S HEALTH OUTCOMES. Determines if and when the disease affects the person, how fast and how severely symptoms of the disease progress and how the person responds to different treatments in terms of both side effects and success of alternative therapies.
- 15. DISEASES where GENETIC component of the risk PREDOMINATES and ENVIRONMENTAL differences play a MINOR ROLE: CYSTIC FIBROSIS MUSCULAR DYSTROPHY DISEASES where ENVIRONMENTAL component of the risk PREDOMINATES and GENETIC COMPONENT play a MINOR ROLE: INFECTIOUS DISEASES eg. HIV CANCERS like mesothelioma (associated with asbestos exposure)
- 16. Most cases of periodontitis appear to fit this complex genes and environmental model. The inherited variation in DNA has a role roughly equal to that of the environment in determining who remains periodontally healthy versus who is affected by this disease. In genetic studies, over 23,000 genes need to be considered as potential hypothesis or candidates for being disease risk factors.
- 17. GENETIC AND GENOMIC METHODS OF THE 21st CENTURY Human Genome Project officially began in 1990. Genomic advances have contributed very little to advance our understanding of the molecular-pathologic causes of periodontitis or ways for improving treatment through ‘individualized approach’, based on patient’s inherited genetic variation. Recently, progress has been realized based on newly available genomic tools and approaches of Genome Wide Association Studies (GWAS, pronounced “geewas”) “next generation” DNA sequencing.
- 18. PATTERNS IN POPULATION AND PEDIGREE Genetic epidemiology: that field of research that unearth the complex interactions between genes and environment that underlie individual differences in disease susceptibility. Populations adapted genetically to their local environment. NATURAL SELECTION (Differential survival or reproduction) Eg. Sickle cell hemoglobin variant that protects against the infectious disease malaria. It is common in areas where malaria- borne parasite is an endemic because it provides strong protection against this disease.
- 19. Another example of natural selection: Ability to digest the milk sugar lactose as an adult that evolved in Europeans in conjunction with the domestication of dairy cattle over 8000 years ago. Genetic Drift Also causes populations with little or no migration between them to differentiate genetically over the time, so one cannot assume that every population difference observed has a functional biological basis.
- 20. Comparison of periodontitis in different populations across the globe is extremely challenging because of the lack of calibrated examiners and standardized disease definitions. Comparison of disease occurrence or severity in identical (monozygotic) versus nonidentical (dizygotic) twins is a very powerful method for distinguishing between effects caused by variation in genes versus factors in environment.
- 21. If VARIATION among individuals in disease susceptibility or severity is caused ENTIRELY BY FACTORS IN ENVIRONMENT : pairs of identical twins are no more similar to each other than pairs of nonidentical twins. If VARIATION among individuals in disease susceptibility or severity is caused ENTIRELY BY GENETIC FACTORS : genetically identical twin pairs will be more similar to each other than nonidentical twin pairs. This is because identical twins share 100% of the same genes, whereas non identical twin pairs share only 50% of their parent’s genes on average.
- 23. FAMILY STUDIES The aggregation of diseases within families strongly suggests a genetic predisposition. Thus, it is important to consider the shared environmental and behavioral risk factors in any family. These would include education, socio-economic grouping, oral hygiene, possible transmission of bacteria, diseases such as diabetes, and environmental features such as passive smoking, sanitation, etc.
- 24. Some of these factors, such as lifestyle and behavior and education, may be under genetic control and may influence the standard of oral hygiene. The complex interactions between genes and the environment must also be considered in the evaluation of familial risk for the periodontal diseases (Kinane and Hart 2003).
- 25. TWIN STUDIES Studying phenotypic characteristics of twins is a method of differentiating variations due to environmental and genetic factors. Monozygous twins arise from a single fertilized ovum and are therefore genetically identical and always the same sex. Dizygous twins arise from the fertilization of two separate ova and share, on average, one half of their descendent genes in the same way as siblings do.
- 26. Any discordance in disease between monozygous twins must be due to environmental factors. Any discordance between dizygous twins could arise from environmental and/or genetic variance. Therefore, the difference in discordance between monozygous and dizygous twins is a measure of the effects of the excess shared genes in monozygous twins, when the environmental influence is constant (Hodge and Michalowicz 2001).
- 27. POPULATION STUDIES A genetic polymorphism is the long-term occurrence in a population of two or more genotypes that could not be maintained by recurrent mutation. A significant difference in the frequency of a specific polymorphism, between a diseased group and a control group, is an evidence that the candidate gene plays some role in determining susceptibility to the disease. An association indicates that either the candidate gene directly affects disease susceptibility or that it is in linkage disequilibrium with (very close to) the disease locus.
- 28. This method can help to elucidate the pathogenesis of a disease process, identify causal heterogeneity, and ultimately identify individuals most at risk for the disease. In population studies, it is important to clearly define the disease status. Likewise, because of the possibility of racial heterogeneity, it is important to insure that the patient and control groups are racially matched (Hodge andMichalowicz 2001).
- 29. HERITABILITY It estimates the portion of all variations in the trait that is attributable to inherited genetic variations. Traits whose variation is determined entirely by differences in environmental exposure have heritability of 0.0. Traits with variation attributable solely to genetic differences have heritability of 1.0 Heritabilities are sometimes reported as a percentage ranging from 0 to 100%. Most human diseases and non disease traits fall in the middle of this range between 0.25 and 0.75.
- 30. Eg. Type II diabetes have a heritabililty of 0.26 and abnormal glucose intolerance has 0.61 in one study. For periodontal disease, only chronic periodontitis occur frequently enough to have been studied using the twin design. Two twin studies of modest size (110 and 117 pairs ) have been reported, and these estimate heritability of measures of chronic periodontitis ranging between 40% and 80%, thus clearly implicating genetic variation in disease risk.
- 31. HERITABILITY OF GINGIVITIS It is feasible that genes implicated in the regulation of inflammatory process of periodontal tissues associated with plaque accumulation may play a role in explaining the individual variability in the severity of both plaque-induced gingivitis and destructive periodontitis (Dashash et al. 2007). Periodontal disease development and progression can be caused by MMPs produced by both infiltrating and resident cells of the periodontium.
- 32. One of the most important MMPs, MMP-9 (also known as gelatinase B or 92-kD type IV collagenase), is active against collagens and proteoglycans. The coding gene is located on chromosome 20q11.2- q13.1, and several polymorphisms have been detected in the MMP-9 gene (Vokurka et al. 2009).
- 33. GENES ASSOCIATED WITH GINGIVITIS RISK: IL-1 cluster, IL-6,10, 12,18 MMP-9 TNF Fibrinogen LT-A.
- 34. HERITABILITY OF AGGRESSIVE PERIODONTITIS Some types of aggressive periodontitis seem to be inherited in a Mendelian manner, and both autosomal modes and X-linked transmission have been proposed. Most of the evidence for a genetic predisposition to aggressive periodontitis comes from segregation analyses of families with affected individuals in two or more generations The results in different sets of families are consistent with both autosomal-dominant and autosomal- recessive inheritance, as well as X-linked dominant inheritance, but no single inheritance mode that would include all families has been established (Meng
- 35. GENES ASSOCIATED WITH AP RISK: IL-1 cluster, IL-4,6,10,12,13,18 TNF-a TGF-b Vit D receptor Estrogrn receptor LF RANK/RANKL/OPG, MMP 1,2,3,9, TIMP HLA CD14 Cathepsin C, IFN-gamma.
- 36. Polymorphisms in genes of Cell-surface receptors for immunoglobulins (Fc) Formyl-methionyl-leucyl-phenylalanine (FMLP) Human leukocytic antigen (HLA) Vitamin D Are promising candidates for susceptibility assessment of aggressive peridontitis. (Yoshie et al. 2007).
- 37. HERITABILITY OF CHRONIC PERIODONTITIS In contrast to aggressive periodontitis, chronic periodontitis does not typically follow a simple pattern of familial transmission or distribution. The twin study is probably the most popular method that supports the genetic aspects of chronic periodontitis. This study substantiates the contribution that genes make vs. the environment in a phenotypic expression.
- 38. Michalowicz et al. (1991) examined the relative contribution of environmental and host genetic factors to clinical measures of periodontal disease through the study of twins reared together and monozygous twins reared apart. Heritability estimates indicated that between 38 and 82% of the population variance for these periodontal measures of disease may be attributed to genetic factors. Adult periodontitis was estimated to have approx 50% heritability, which was unaltered following adjustments for behavioral variables,including
- 39. Corey et al. (1993) revealed that approximately half of the variance in disease in the population is attributed to genetic variance.
- 40. CANDIDATE GENES FOR CHRONIC PERIODONTITIS Interleukin-1, 2, 4, 6, 10 Fcg receptor TNF Vitamin D receptor
- 41. STUDY DESIGNS FOR IDENTIFYING THE DNA VARIANTS LINKAGE ANALYSIS A technique used to map a gene responsible for a trait to a specific location on a chromosome. These studies are based on the fact that genes that are located close to each other on the chromosomes tend to be inherited together as a unit. These genes are said to be linked.
- 42. It requires use of initially very expensive DNA markers , this was originally only considered justified after finding strong evidence of a genetic basis for a trait using segregation analysis or family aggregation analysis. Drawback: Many diseases are caused by multiple genes (each contribute to a small amount to the phenotype/disease/ trait). It has extremely low statistical power for complex diseases and in which there is extensive heterogeneity among different families that have different combinations of susceptibility genes and environmental exposures.
- 43. ASSOCIATION ANALYSIS This analysis aims to identify which genes are associated with the disease. It includes CANDIDATE GENE APPROACH, a gene mapping approach that tests whether one allel of a gene occurs more often in patients with the disease than in subjects without the disease. Candidate genes are chosen on the basis of their known or presumed function (i.e. they have some plausible role in the disease process such as producing a protein that is important in disease pathogenesis).
- 44. These are sometimes referred to as case control studies . Genotype frequencies of an inherited DNA variant for a group of periodontitis cases are statistically compared to periodontally healthy control subjects. If the genotype frequencies differ so greatly that the results are very unlikely to occur by chance, it is concluded that the genotype that is mor ecommon in cases than controls is associated with increased disease risk.
- 45. ADVANTAGES: It is a boon for discovery of inherited genetic variation important for a wide range of complex diseases including diabetes, cardiovascular disease, metabolic disorders, obesity, and mental illness.
- 46. SEGREGATION ANALYSIS Statistical analysis of the patterns of transmission of a disease in families in an attempt to determine the relative likelihood that the disease is caused by a single gene with dominant or recessive inheritance, by multiple genes or entirely by variation in exposure to risk factors. This is relatively straightforward for traits in which mutation in a single gene causes the disease to develop with nearly 100% certainty in carriers, whereas persons who donot inherit the mutation are at little or no risk.
- 47. Eg. Huntington’s disease is a sinle dominant gene disorder because it is transmitted with 50% probability to offspring of affected individuals Parents of cystic fibrosis individuals are affected rarely and 25% siblings are affected .
- 48. HIGHLY COMPLEX DISEASES Combination of multiple genetic and environmental factors make the challenge of deciphering genetic mechanisms by merely observing transmission patterns in families using the segregation analysis. High risk gene does not automatically lead to development of the disease (REDUCED PENETRANCE) Several genes or even dozens od different genes may influence disease susceptibility (OLIGOGENIC INHERITANCE and GENETIC HETEROGENEITY ) Environment al exposures are also important modifiers of disease risk.
- 49. GENETIC MARKER It can be any type of biomolecule or assay that allows us to read inherited differences among individuals in their DNA sequences. Blood groups, protein isozymes, and human leukocyte antigen (HLA) were the first developed markers. Recently developed : “next generation” DNA sequencing methods.
- 50. GENOME WIDE ASSOCIATION STUDIES(GWAS) The entire human genome is searched. Here, about half of the statistically definitive findings point to genes that experts in the field had no suspicion whatsoever were involved in the disease’s etiology. This allows the researchers to open up entirely new pathways for investigation that may lead to insights about the disease’s biologic mechanism and suggest novel molecular strategies for pharmaceutical or other therapeutic interventions.
- 51. PERIODONTITIS IN GENETIC SYNDROMES AND OTHER DISEASES Diseases that follow predictable and generally simple patterns of transmission have been called Mendelian conditions. These diseases follow a classic Mendelian mode of inheritance (autosomal dominant, autosomal recessive, or X-linked). Usually, the prevalence of these Mendelian conditions is rare (typically much less than 0.1%), with the exception of some unique populations that have been isolated from other human populations.
- 52. PAPILLON-LEFEVRE SYNDROME Rare autosomal recessive congenital differentiation disorder of chromosome 11p14-q21. Occurs in children from consanguineous marriages. Gene responsible: Cathepsin C, lysosomal protease (Toomes et al.1999). Cathepsin C is suggested to be implicated in a wide variety of immune and inflammatory processes (Toomes et al. 1999). Prevalence : 1-4 per million, equal in males and females. (Hattab et al. 1995)
- 53. Two essential features of Papillon-Lefèvre syndrome: Hyperkeratosis of the palms and soles (either diffuse or localized) and generalized rapid destruction of the periodontal attachment apparatus resulting in premature loss of both primary and permanent teeth (Deas et al. 2003).
- 54. External signs are hyperkeratosis of the palms and soles (Kressin et al. 1995). Changes in the skin observed by electron microscopy revealed the diminution of the tonofibrils, alterations of the keratohyaline granules, and acanthosis in the stratum spinosum (Kressin et al. 1995).
- 55. INTRAORALLY, periodontal symptoms affect primary and permanent dentitions. Extensive loss of periodontal attachment accompanied by generalized, severe, and rapid destruction of the alveolar bone, that frequently lead to premature tooth loss.
- 56. Histologically, the gingiva demonstrates epithelial hyperplasia, increased collagen synthesis, parakeratosis, acanthosis, and focal aggregates of lymphocytes and plasma cells. In addition, reduced osteoblastic activity and reduced thickness of cementum have been described (Ghaffer et al. 1999; Hattab et al. 1995).
- 58. Virulent gram-negative anaerobic microbiota has been considered to be an important initiator of the destructive periodontitis observed in these patients. Aggregatibacter actinomycetemcomitans has been reported to be the major periodontal pathogen. Capnocytophaga gingivalis, Eikenella corrodens, black-pigmented Bacteroides, and Fusobacterium spp : subgingival periodontal lesions in Papillon-Lefèvre syndrome patient (Ishikawa et al. 1994; Lundgren et al. 1998; Rudiger and Berglundh 1999; Velazco et al. 1999).
- 59. Papillon-Lefèvre syndrome has been associated with decreased neutrophil chemotaxis reduced random neutrophil migration impaired neutrophil phagocytosis reduced myeloperoxidase activity increased superoxide radial neutrophil production, associated with a decreased lymphocyte response to pathogens (Lundgren et al. 1998; Velazco et al. 1999).
- 60. EHLER DANLOS SYNDROME Also known as dystrophia mesodermalis and fibrodysplasia elastica generalisatica. Heterogenous group of inherited disorders of connective tissue, which may affect the skin, ligaments, joints, eyes, and vascular system (Reichert et al. 1999). EDS is divided into 11 types in accordance with clinical, genetic, and biochemical features (Majorana and Facchetti 1992).
- 61. The primary cause may be a Type I or type II collagen deficiency, a lysyl hydroxylase deficiency Deletion of N-telopeptide, or Disorders of copper homeostasis and fibronectin defects (Reichert et al. 1999).
- 62. Immunological analysis revealed that the concentrations of IgA in saliva and IgA, IgG, and IgM in serum were within normal limits, with unpaired phagocytic capacity of the peripheral blood leukocytes (Reichert et al. 1999). The temporomandibular joint often demonstrates profound laxity in conjunction with generalized joint mobility and dislocation (Fridrich et al. 1990).
- 63. Periodontal conditions have been reported with EDS types I, VII, and VIII. Defective dentinogenesis, resulting in aplasia or hypoplasia of root development affecting the mandibular incisors, and predisposition for localized periodontal disease was reported in EDS type I. Radiographic appearance of a bulbous enlargement of the roots together with pulp stones at other teeth were reported.
- 64. EDS type VII is an autosomal dominant/ recessive disease. Poor healing after extractions Prevelance of dental caries A radiographic evidence of pulp stones, and/ or malformed teeth have been described.
- 66. EDS type VIII is an autosomal dominant form characterized by Fragile skin Abnormal scarring Early onset of periodontal disease, with premature loss of the permanent teeth. Fragility of the alveolar mucosa and increased bleeding tendencies have also been suggested
- 67. EDS can also be associated with Ligneous periodontitis (generalized membranous gingival enlargement due to an accumulation of fibrin deposits associated with severe alveolar bone loss) Plasminogen deficiency seems to play a central role in its pathogenesis.
- 68. CYCLIC NEUTROPENIA Rare condition, characterized by cyclical depletion of polymorphonuclear leukocyte numbers, typically in 3-week cycles, although this can be between 2 and 5 weeks. Episode of neutropenia is usually short, but the patient polymorphonuclear leukocyte count never returns to normal levels, and the differential blood-cell count for polymorphonuclear leukocytes is at least 40% less than normal levels.
- 69. Periodontal manifestations include Inflamed gingiva Gingival ulceration Periodontal attachment, and bone loss (Kinane 1999; Rezaei et al. 2004).
- 70. FAMILIAL NEUTROPENIA Inherited as an autosomal dominant trait, and in these patients, neutrophils are not released properly from the marrow. A slight monocytosis occurs, possibly as compensation, together with the moderate neutropenia. The condition is often diagnosed in patients with a history of recurrent infections.
- 71. Susceptibility to these infections tends to vary with neutrophil count. The periodontal manifestations include Fiery red edematous gingivitis, which is often hyperplastic and Accompanied by periodontal bone loss (Kinane 1999).
- 72. CHEDIAK HIGACHI SYNDROME It is a rare autosomal recessive disease associated with impaired function of cytoplasmic microtubules or microtubule assembly in PMNs (Oh et al. 2002). The susceptibility to infections, although humoral and cellular immunity are normal, leads to early death (often before 5 years of age).
- 73. The disease reveals itself periodontally by Severe gingivitis and Rapid loss of attachment, leading to exfoliation of the teeth.
- 74. LEUKOCYTE ADHESION DEFICIENCY Two LADs have been described in humans: LAD I and LAD II. Both diseases block a sequence of leukocyte– endothelial-cell interactions, which is generally referred to as the multistep adhesion cascade. LAD is a rare but well-defined autosomal recessive disease that results in the formation of nonfunctional intracellular adhesion molecule (ICAM receptor).
- 75. The disease results from mutations in the region on the CD18 gene encoded on chromosome 21q22.3, which codes for the b2 integrin subunit of the leukocyte adhesion molecule. The defective or absent expression of these molecules on the surface of leukocytes decreases their ability to adhere to endothelial cells and to migrate to sites of infection.
- 76. Clinical features usually present in infancy or early childhood and consist of Recurrent, indolent bacterial infections of the skin, mouth, and the respiratory tract. Delayed separation of the umbilical cord. Skin infections may progress to large chronic ulcers that may become polymicrobial in character.
- 77. These individuals are susceptible to fungal infections but do not show an increased susceptibility to protozoal or viral infections. In addition, lack of swelling, redness, heat, or pus is noted in the area of the infection
- 78. Severe gingivitis with an early loss of primary teeth, followed by the early loss of secondary teeth, is seen. Individuals with LAD defect in innate host defense display a severe form of periodontitis that does not require specific periodontal pathogens because of entrapment of neutrophils within the blood vessel.
- 79. Congenital Disorder of Glycosylation Type IIc CDG- IIc (Also Known as LAD II) LAD II is much less common than LAD I LAD II is characterized by a defect in the vascular endothelial receptor, which prevents the normal leukocyte from adhering to the endothelium.
- 80. It is considered to be a congenital disorder of glycosylation (CDG) and fructose metabolism and a failure to express the ligand for E- and P- selectin, sialyl Lewis-X (CD15s) expressed on the leukocytes. In addition, immunoglobulin M and G (IgM and IgG) heavy chains are also not fucosylated, although they are present in normal amounts
- 81. Recurrent infections Periodontitis Neutrophilia Reduced neutrophil binding to E- and P-selectin Reduced neutrophil rolling Reduced neutrophil transmigration under shear
- 82. Reduced DTH reactions Severe psychomotor and mental retardation Microcephaly and cortical atrophy Growth retardation Muscular hypotonia Facial and skeletal abnormalities
- 83. CDGs (formerly carbohydrate-deficient glycoprotein syndrome) are a heterogenous group of autosomal recessive disorders characterized by defects in the N- glycosylation pathway and subsequent aberrant formation of glycoproteins. CDG-IIc is caused by mutations in the GDP- fucose (Fuc) transporter (encoded by FUCT1).
- 84. This syndrome is characterized by nonfucosylated oligosaccharides and presents with severe mental retardation and immunodeficiency due to an adhesion defect of the leukocytes (probably due to absence of a-1,3-fucosylated sialyl-Lewis selectin ligands). Diagnosis is based on oligosaccharide and mutational analyses.
- 85. COMMON GUIDELINES FOR ASSOCIATION STUDIES Candidate genes are chosen on the basis of known or presumed function that are thought to have some plausible role in the disease. Three types of CANDIDATE GENES: Functional Positional Expressional
- 86. Functional genes: derived from an existing knowledge of the phenotype and the potential function of gene involved after clinical or physiological studies of affected individuals. Positional Genes: based on the involvement of genes to a marked location after genetic linkage analysis. Expressional Genes: determined through differences in gene expression using microarrays. Some issues and concerns should be addressed (Yoshie et al. 2007) to produce scientifically sound and meaningful disease-association studies
- 87. 1. Ethnic Heterogenity In the presence of large biological and environmental variability, genetic effects can differ across different populations, or even among generations within the population. Variation in genotype frequencies across diverse populations may affect the number of individuals at increased risk for a disease, and population substructure imbalances may create spurious differences in genotype frequencies of the compared groups in gene disease association studies.
- 88. 2. Clinical Classification Investigators should strictly adhere to the classification set during the American Academy of Periodontology workshop in 1999. Moreover, subjects falling into the gray zone between aggressive and chronic periodontitis should be excluded in the study (Yoshie et al. 2005, 2007).
- 89. 3. Functional Polymorphisms Kinane and Hart (2003) outlined the requirements in providing a disease-polymorphism association: • The polymorphism must influence the gene product. • Biases in the study population should be recognized and controlled for. • Confounders such as smoking and socio-economic class must be sorted out. • Affected gene product should be part of the disease etiopathology.
- 90. 4. Study sample size The size of subjects clearly contributes to the differences in statistical power of the results, especially in a complex disease like periodontitis (Yoshie et al. 2007). 5. Choice of Controls Defining the appropriate controls for a case-control study in periodontitis still lacks clarity. Some reports generally described their control as healthy, while others specifically characterized controls as patients with gingivitis or slight periodontitis (Yoshie et al. 2007).
- 91. 6. Data Presentation Expressing the results only in P-values is extremely popular in all types of studies in periodontitis. It was suggested that the data presented should be evaluated using confidence intervals (CIs) and relative risk (RR) values, as these portray the effect size with a description of its precision.
- 92. CLINICAL UTILITY OF GENETIC KNOWLEDGE The discovery of the association between polymorphisms in IL-1 genes and severity of periodontitis has been described as a major breakthrough in clinical practice, and the observed increase in risk due to this single genetic factor has been confirmed in a population of “typical” dental practice patients. The clinical test for such a genetic risk has been proposed as a component of the risk assessment profile for chronic periodontitis that can be used to provide a rationale for explaining individual patient susceptibility, providing early preventive or therapeutic intervention, and allowing superior prognostic capabilities (Schenkein 2002).
- 93. CONCLUSION Genetics are a major determinant of the severity of chronic periodontitis in adults. It must be emphasised that this type of genetic influence is different from the “single gene” defects (Tay Sachs) or chromosome abnormalities (Down’s syndrome) in which a genetic factor causes a disease.
- 94. It is likely that a few genetic variations with a high prevelance in the population will be found to influence chronic periodontitis. Currently, the presence if IL-1 gene variations appear to identify individuals who are at increased risk for more severe disease and for less predictable response to therapy.
- 95. THANK YOU !!!