Genetics and their effects in periodontal disease.pptx

Genetics and their effects in periodontal disease.pptx

1. DEPARTMENT OF PERIODONTOLOGY AND ORAL IMPLANTOLOGY PRESENTER- DR.TANYA ATTRE GENETICS AND PERIODONTAL DISEASE

2. INTRODUCTION EVIDENCE FOR ROLE OF GENETICS IN PERIODONTICS BASIC TERMINOLOGIES POLYMORPHISM VS MUTATION GENETIC STUDY DESIGNS SYNDROME IN ASSOCIATION WITH PERIODONTAL DISEASE GENETICS IN RELATION TO DISEASE GENE ASSOCIATION TO PERIODONTITIS FUTURE ASPECTS CONCLUSION REFERENCES CONTENTS

3. Periodontitis is a chronic inflammatory disease of the supporting tissues of the teeth. In subjects susceptible to destructive periodontal disease, there is an imbalance between the host’s immune system and the oral Bacteria. The host’s immune system changes over time and can be positively or negatively influenced by lifestyle. It was determined that around 38-82% of the clinical severity of the disease was explained by genetic factors .( Michalowicz  et.al 1991) INTRODUCTION Lindhe’s Clinical Periodontology & Implant Dentistry 7 th Ed

4. Genetic elements play a vital role in influencing the inflammatory and immune response of the periodontal disease Genetic diseases are broadly classified into two entities . INTRODUCTION Simple Mendelian Disorders Complex Genetics Disorder Taba Jr M, Souza SL, Mariguela VC. Periodontal disease: a genetic perspective. Brazilian oral research. 2012;26(spe1):32-8.

5. EVIDENCE OF ROLE OF GENETICS IN PERIODONTITIS In a population in Sri Lanka without access to dental care and absence of oral hygiene,Löe et al. (1986) were able to identify three subpopulations: a group with no progression (11%), a group with moderate progression (81%), and a group with rapid progression of periodontal breakdown (8%). Van der Velden et al. 2006 found that 20% of the subjects developed severe breakdown , whereas the remaining population developed minor-to-moderate breakdown, and suggested that not everybody is equally susceptible to periodontitis . This shaped the hypothesis that host susceptibility may have a genetic background Lindhe’s Clinical Periodontology & Implant Dentistry 7 th Ed

6. Page RC, Kornman KS. The pathogenesis of human periodontitis: An introduction. Periodontol 2000 1997; 14:9- 11

7. CHROMOSOME NOMENCLATURE

8. CHROMOSOME NOMENCLATURE

9. OTHER TERMINOLOGIES

10. DNA contains the genetic code The genetic code is read in groups of three nucleotides; each trinucleotide sequence (triplet) is called a codon. Written in the conventional direction from left to right. Lindhe’s Clinical Periodontology & Implant Dentistry 7 th Ed

11. A gene consists of two parts : (1) a coding region, i.e. a reading frame starting at nucleotide position +1, containing a multitude of triplets that codes for a sequence of amino acids to form a protein; and (2) a promoter region, i.e. a sequence of nucleotides upstream (left) of the coding region starting with nucleotide position - 1. Within the coding region intermittent areas of non-coding DNA exist; these regions are called introns. The true coding areas within the coding region are called exons Lindhe’s Clinical Periodontology & Implant Dentistry 7 th Ed

12. POLYMORPHISM VS MUTATION

13. GENETIC STUDY DESIGNS The studies that show evidence of genetic predisposition to periodontitis can be grouped into four areas of research based on the statistical approaches to determine genetic components and genetic model Family studies Segregation analysis. Linkage studies Association studies Population studies Twin studies

14. Familial aggregation could result from shared genes, shared environmental exposures and behavioural risk factors like education, socio economic grouping, oral hygiene, possible transmission of bacteria, diseases like polygenic disorder, passive smoking, exposure to pollutants and sanitation. Therefore , the complex interactions between genes and also the surroundings should even be thought-about in the analysis of familial risk for periodontic diseases FAMILY STUDY Kinane DF, Hart TC. Genes and gene polymorphisms associated with periodontal disease. Crit Rev Oral Biol Med 2003;14(6):430-449

15. This longitudinal interventional case–control study aimed to evaluate the impact of parental periodontal disease on the acquisition of oral pathogens in their offspring. Subgingival plaque and clinical periodontal metrics were collected from 18 parents with a history of generalized aggressive periodontitis and their children (6–12 years of age), and 18 periodontally healthy parents and their parents at baseline and following professional oral prophylaxis. Children of periodontitis parents were preferentially colonized by  Filifactor alocis ,  Porphyromonas gingivalis , Aggregatibacter actinomycetemcomitans ,  Streptococcus parasanguinis ,  Fusobacterium nucleatum  and several species belonging to the genus  Selenomonas  even in the absence of periodontitis,  This study highlights the critical role played by parental disease in microbial colonization patterns in their offspring and the early acquisition of periodontitis-related species and underscores the need for greater surveillance and preventive measures in families of periodontitis patients.

16. Genes are passed from parents to kids in an exceedingly foreseeable manner, and typically segregate in families as foretold by Mendel’s laws. Pattern of transmission of disease through generations is analysed in several families and compared with those expected under different models of inheritance to choose the best fitting model. SEGREGATION ANALYSIS

17. In this way, segregation analysis helps to identify the best model that simulates the ascertained transmission of a trait in a given population by sequential comparison with all the available models. Segregation analysis is applied by geneticists to determine whether a trait transmission belongs to Mendelian mode of genetic transmission SEGREGATION ANALYSIS

18. Advantages Segregation analysis helps to assess whether the disease gene is autosomal or sex linked, recessive or dominant . Limitations 1. Minimal power to resolve heterogeneity (Multiple causes) 2 . Cannot distinguish between genetic and environmental influence 3 . Does not find or aim to find a specific gene responsible for a trait.

19. TWIN STUDIES Twin studies are commonly used to study the influence of genetic and environmental factors on the complex diseases like periodontitis with multifactorial aetiology. Sir Francis Galton in 1875 was the first scientist to use this concept . The subject of interest in twin studies can be monozygotic or dizygotic twins .

20. Michalowicz BS, Aeppli D, Virag JG, et al. (1991) Periodontal findings in adult twins. J Periodontol 62:293–299.

21. Therefore, the difference in concordance between MZ and DZ twins for a specific phenotype could be used to evaluate the relative contribution of genes (heredity) and environmental factors to a disease and analysing disease presentation in twins is an essential first step in this process. Though twin studies overcame the drawbacks of segregation analysis, few such studies have been conducted because of the inadequacy of such twins .

22. POPULATION STUDY Environmental or behavioural risk factors for a disease are usually first detected in significant epidemiological or population-based studies . A genetic polymorphism is the long-time manifestation in a population of two or more genotypes that could not be maintained by frequent mutation . Pihlstrom BL, Michalowicz BS, Johnson NW. Periodontal diseases. Lancet. 2005; 366(9499): 1809-1820

23. The frequencies of polymorphisms of candidate genes can be compared between diseased individuals and controls . It can be proved that the candidate gene determines the vulnerability to disease when there is a clear cut difference in the frequency of a specific polymorphism, between a case group and a control group. In this way, pathogenesis, causal heterogeneity of disease process and individuals most at risk for the disease can be interpreted well. POPULATION STUDY Pihlstrom BL, Michalowicz BS, Johnson NW. Periodontal diseases. Lancet. 2005; 366(9499): 1809-1820

24. Linkage analysis is a technique used to map the gene responsible for a trait to a specific position on a chromosome. The distance between two allele at different loci will determine whether they will recombine. This is termed as recombination or crossover event. There is 50% chance that any two maternal or paternal alleles will recombine and be transmitted together to an offspring. Inheritance of a disease can be established if the distance between marker and disease allele is within 20–30 centimo grams ( cM ). LINKAGE ANALYSIS Boughman JA, Halloran SL, Roulston D, Schwartz S, Suzuki JB et al. An autosomal dominant form of periodontitis: its localization to chromosome 4 and linkage to dentinogenesis imperfecta . J Craniofac Genet Dev Biol 1986; 6: 341-350.

25. Test to compare the likelihood that two loci are linked, vs the likelihood that the two loci are unlinked. LOD SCORE Boughman JA, Halloran SL, Roulston D, Schwartz S, Suzuki JB et al. An autosomal dominant form of periodontitis: its localization to chromosome 4 and linkage to dentinogenesis imperfecta . J Craniofac Genet Dev Biol 1986; 6: 341-350.

26. Linkage studies have been successful only in identifying the genetic basis of simple Mendelian traits, where mutation of a single gene can cause a disease. Genetics and Periodontal Disease . Nevertheless, Linkage studies of complex diseases are not successful since complex diseases are due to the combined effect of multiple genes of minor effect and each gene contribute a small amount to the disease phenotype It has extremely low statistical power for diseases in which there is extensive heterogeneity among different families that have different combinations of vulnerable genes and environmental exposures. LIMITATIONS

27. ASSOCIATION STUDY Associations indicate that the presence of an allele confers risk for disease within a specific environment . Allele association helps to identify whether the frequency of an allele is considerably increased or decreased in a particular disease Schafer AS, Jepsen S, Loos BG. Periodontal genetics: a decade of genetic association studies mandates better study designs. J Clin Periodontol 2011; 38(2): 103-107.

28. Genomic wide Analysis

29. Schafer AS, Jepsen S, Loos BG. Periodontal genetics: a decade of genetic association studies mandates better study designs. J Clin Periodontol 2011; 38(2): 103-107. Advantages- Association studies are beneficial for discovery of inherited genetic variation important for a wide range of complex diseases including diabetes, cardiovascular diseases, metabolic disorders, obesity and mental illness. Disadvantages In the presence of pathogens, individuals with the low response allele develop disease. On the other hand, no relationship may exist between the disease and this allele in populations where the particular bacteria is absent. • Low power to evaluate small genetic effects • Small presentation of actual causal or rare variants

30. SYNDROMIC FORM OF PERIODONTITIS

31. Papillon-Lefèvre syndrome is a rare autosomal recessive congenital disorder. The gene responsible for this syndrome is cathepsin C, lysosomal protease ( Toomes et al. 1999 ). The two essential features of Papillon-Lefèvre syndrome are 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) PAPILLON-LEFÈVRE SYNDROME Ahuja V, Shin RH, Mudgil A, et al. (2005) Papillon-Lefèvre syndrome: A successful outcome. J Periodontol 76:1996–2001.

32. HAIM-MUNK SYNDROME Although the palmoplantar findings and severe periodontitis were suggestive of Papillon-Lefèvre syndrome, the association of other clinical features, particularly nail deformities and arachnodactyly , argued that HaimMunk syndrome was a distinct disorder (Hart et al. 1997) Hart et al. reported that the mutated gene of Haim -Muck syndrome is cathepsin C. Hart TC, Hart PS, Michalec MD, et al. (2000a) Haim-Munk syndrome and Papillon-Lefevre syndrome are allelic mutations in cathepsin C. J Med Genet 37:88–94.

33. EHLERS-DANLOS SYNDROME 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. Radiographic appearance of a bulbous enlargement of the roots together with pulp stones at other teeth were reported. 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 ( Badauy et al. 2007 ;

34. CHEDIAK-HIGHACHI SYNDROME Chediak-Higachi syndrome 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 increases leads to early death (often before 5 years of age) ( Steenberghe 1997). The disease reveals itself periodontally by severe gingivitis and rapid loss of attachment, leading to exfoliation of the teeth ( Bailleul-Forestier et al. 2008; Steenberghe 1997).

35. CYCLIC NEUTROPENIA Cyclic neutropenia is a rare condition, characterized by cyclical depletion of polymorphonuclear leukocyte numbers, typically in 3-week cycles, although this can be 5weeks. Periodontal manifestations include inflamed gingival, gingival ulceration, periodontal attachment, and bone loss ( Kinane 1999; Rezaei et al. 2004 ).

36. Familial neutropenia is inherited as an autosomal dominant trait. 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. 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 FAMILIAL NEUTROPENIA

37. LEUKOCYTE ADHESION DEFICIENCY

38. MODIFYING DISEASE GENES IN RELATION TO PERIODONTITIS Interleukin-1 gene polymorphisms Transforming growth factor- alpha gene polymorphisms Fc Receptor Polymorphisms CD-14 polymorphism. TLR polymorphism Matrix metalloproteinase polymorphisms

39. Cytokines such as interleukin-1 (IL-1) and tumor necrosis factor (TNF) have important roles in bony destruction. IL-1 family consists of at least three well-studied genes: IL-1a and IL-1b, which have agonist activity, and IL-1Ra, a physiologic antagonist to the other IL-1 cytokines INTERLEUKIN-1 GENE POLYMORPHISMS

40. Interleukin-1 Genotype and Experimental Gingivitis No evidence was provided that the IL-1 risk genotype was associated with higher gingival crevicular fluid (GCF) volume and percentage bleeding on probing during the development of experimental gingivitis ( Jepsen et al. 2003). Interleukin-1 Genotype and Chronic Periodontitis Kornman et al. (1997) showed that a composite polymorphism of the IL-1A (at position −889) and IL-1B (at position +3953) genes seems to cause an almost sevenfold increased risk for progressive adult periodontitis in nonsmoking patients of Caucasian origin.

41. Interleukin-1 Genotype and Experimental Gingivitis

42. Interleukin-1 Genotype and Chronic Periodontitis

43. INTERLEUKIN-1 GENOTYPE AND AGGRESSIVE PERIODONTITIS With regard to the relationship between IL-1 genotype and aggressive periodontitis susceptibility, conflicting results have been presented in different ethnic populations. Fiebig et al. (2008) conducted a casecontrol association study on 415 northern European Caucasian patients with aggressive periodontitis and 874 healthy controls to examine 10 single-nucleotide polymorphisms (SNPs) in the genes of the IL1 cluster for association with IL1A, IL1B, CKAP2L (cytoskeleton-associated protein 2-like), and IL1RN (IL-1 receptor antagonist). It was concluded that the results do not support an association between variants in the IL1 gene cluster and aggressive periodontitis.

44. IL-10 gene polymorphisms IL-10 is located on chromosome 1, in a cluster with closely related interleukin genes, including 1L-19, IL20 and IL-24. IL-10 plays a role in the regulation of pro-inflammatory cytokines such as IL-1 and TNF-a. Functional disturbance in IL-10 due to genetic polymorphisms could be detrimental to host tissues and could be linked to periodontal disease susceptibility. IL-10 gene polymorphisms have been investigated in relation to aggressive periodontitis

45. TUMOR NECROSIS FACTOR-ALPHA

46. Shimada Y, Tai H, Endo M, et al. (2004) Association of tumor necrosis factor receptor type 2 +587 gene polymorphism with severe chronic periodontitis. J Clin Periodontol 31:463–469

47. FC RECEPTOR POLYMORPHISMS Dijstelbloem HM, van de Winkel JG, Kallenberg CG (2001) Inflammation in autoimmunity: Receptors for IgG revisited. Trends Immunol 22:510–516.

48. FcgRIIa was shown to have two allelic forms: HR (high responder) and LR (low responder). These names are based on the capacity of T cells from normal individuals to proliferate in response to the monoclonal antibody (IgG1) anti-CD3.

49. The gene for the CD14 receptor is on chromosome 5 (region q23–21), encodes a protein of 375 amino acids. D ata have shown the strong relevance of the CD14 receptor activity in the clinical manifestation and development of periodontitis. The systemic level of the soluble form of CD14 (sCD14) is significantly increased in patients with periodontal disease (Hayashi et al. 1999 ). CD14 GENE POLYMORPHISMS Folwaczny M, Glas J, Torok HP, Fricke K, Folwaczny C. The CD14-159C-to-T promoter polymorphism in periodontal disease. J Clin Periodontol 2004;31:991-5

50. CD14 gene polymorphisms The R-allele in the promoter region of CD14 at position -260(-159) enhances the transcriptional activity of the gene. A higher frequency of the N –allele and the N/N genotype of CD14-1359 polymorphism was found in patients in severe periodontitis. Folwaczny M, Glas J, Torok HP, Fricke K, Folwaczny C. The CD14-159C-to-T promoter polymorphism in periodontal disease. J Clin Periodontol 2004;31:991-5

51. TLRs are important initiators of innate immunity, recognizing diverse microbial products which are collectively known as pathogen-associated molecular patterns (PAMPs ). Toll like receptor, TLR2 and TLR4 Gene Polymorphisms Barton GM, Medzhitov R (2004) Toll signaling : RIPping off the TNF pathway. Nat Immunol 5:472–474

52. Toll like receptor, TLR2 and TLR4 Gene Polymorphisms

53. Schröder et al. (2005) reported that TLR-4 single-nucleotide polymorphisms (Asp299Gly and Thr399Ile) were correlated with CP (OR = 5.56, 95% CI: 2.19–14.04, P < 0.0001), but not with aggressive periodontitis . Fukusaki et al. (2007) revealed that the frequency of the C/C genotype in TLR4 3725G > C polymorphism was significantly higher in both the moderate and the severe periodontitis patient group than in the control group

54. MATRIX METALLOPROTEINASE POLYMORPHISMS MMPs are one of the most important groups of enzymes involved in periodontal connective tissue destruction (Reynolds et al. 1994; Uitto et al. 2003 ). It was demonstrated that the MMPs collagenase, gelatinase A, stromelysin-1, and their specific inhibitor TIMP-1 can all be detected in gingival tissues by immunological assays, both from patients with periodontitis and from patients undergoing crown-lengthening procedures

55. GENE THERAPY Chatterjee , Singh, Nidhi ; Saluja , Mini. Gene therapy in periodontics. Journal of Indian Society of Periodontology 17(2):p 156-161, Mar–Apr 2013

56. NUTRIGENOMICS

57. Nutrigenomics is a new, rising feld of science that creates a spider web connecting both nutrition and genome activity . N utrients ingested form the stimuli or the “dietary signals” that are captured by the sensory systems in the cells and directly impacting patterns of gene, protein and metabolite expressions. Examples are -Cytochrome P450 enzymes and genes Glutathione S- transferases (GSTs ) Methylenetetrahydrofolate reductase (MTHFR) NUTRIGENOMICS Neemat M. Kassem , Yassmin A. Abdelmegid , Mahmoud K. El- Sayed , Rana S. Sayed , Mahmoud H. Abdel- Aalla , Hebatallah A. Kassem,Nutrigenomics and microbiome shaping the future of personalized medicine: a review article,Journal of Genetic Engineering and Biotechnology,Volume 21,Issue1,2023,134

58. EPIGENETICS

59. CONCLUSION With recent evidence implicating the role of periodontal disease on systemic health, an understanding of the potential role of genetic polymorphisms on periodontal disease may help in modifying our treatment plan to improve periodontal health, as well as, general health.

60. REFRENCES Umesh , S. G. , Ramachandran , L. , Karthikeyan , J. , Mani, A. . Genetics and Periodontal Disease: An Explicit Insight. In: Surlin , P. , editor. Periodontology - Fundamentals and Clinical Features [Internet]. London: IntechOpen ; 2021 Wankhede AN, Wankhede SA, Wasu SP. Role of genetic in periodontal disease. J Int Clin Dent Res Organ 2017;9:53-8. Genes and gene polymorphisms associated with periodontal disease; Crit Rev Oral Biol Med:14(6):430-449 (2003) Kinane DF, Hart TC. Genes and gene polymorphisms associated with periodontal disease. Crit Rev Oral Biol Med 2003;14(6):430-449 Michalowicz BS, Diehl SR, Gunsolley JC, Sparks BS, Brooks CN, Koertge TE et al. Evidence of a substantial genetic basis for risk of adult periodontitis. J Periodontol 2000; 71(11). ): Folwaczny M, Glas J, Torok HP, Fricke K, Folwaczny C. The CD14-159C-to-T promoter polymorphism in periodontal disease. J Clin Periodontol 2004;31:991-5 1699-1707

61. REFRENCES Chatterjee , Singh, Nidhi ; Saluja , Mini. Gene therapy in periodontics. Journal of Indian Society of Periodontology 17(2):p 156-161, Mar–Apr 2013 Barton GM, Medzhitov R (2004) Toll signaling : RIPping off the TNF pathway. Nat Immunol 5:472–474. Taba Jr M, Souza SL, Mariguela VC. Periodontal disease: a genetic perspective. Brazilian oral research. 2012;26(spe1):32-8. Pihlstrom BL, Michalowicz BS, Johnson NW. Periodontal diseases. Lancet. 2005; 366(9499): 1809-1820 Hart TC, Hart PS, Michalec MD, et al. (2000a) Haim-Munk syndrome and Papillon-Lefevre syndrome are allelic mutations in cathepsin C. J Med Genet 37:88–94. Dijstelbloem HM, van de Winkel JG, Kallenberg CG (2001) Inflammation in autoimmunity: Receptors for IgG revisited. Trends Immunol 22:510–516 . Neemat M. Kassem , Yassmin A. Abdelmegid , Mahmoud K. El- Sayed , Rana S. Sayed , Mahmoud H. Abdel- Aalla , Hebatallah A. Kassem,Nutrigenomics and microbiome shaping the future of personalized medicine: a review article,Journal of Genetic Engineering and Biotechnology,Volume 21,Issue1,2023,134

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