Genetics and epigenetics inPeriodontal Disease .pptx

Genetics and epigenetics inPeriodontal Disease

1. GENETIC FACTORS ASSOCIATED WITH PERIODONTAL DISEASE

2. GENETICS AND GENE GENETICS is the science of heredity and variation. The basic units of inheritance are known as GENES.

3. HISTORY OF GENETICS Gregor J. Mendel(1900) Term genetics coined by William Bateson(1905) Thomas H. Morgan(1910) Watson & Crick(1953)

4. Allele : Variation in the nucleotide sequence at specific locations on chromosome Locus : specific location on the chromosome Exon : the expressed portion of DNA or RNA that will ultimately be converted to a protein

5. Intron : the non-coding portion of DNA or RNA that is removed during RNA processing Phenotype: the observable characteristics in an individual as influenced by the interaction of genes and environment

6. Every gene has three regions EXON INTRON PROMOTER CODING REGION TERMINATION SEQ Promoter – turns the gene on and off. Coding region – encodes the information Termination sequence – signals the end of gene Structure of gene

7. MOLECULAR BASIS FOR INHERITANCE DNA: forms the molecular basis for genes Chromosome: the nuclear structure carrying genetic information arranged in a linear sequence. Gene refers to a combination of DNA segments that together constitute an expressible unit

8. STRUCTURE OF DNA

9. STRUCTURE OF CHROMOSOME

10. From genotype to phenotype DNA pre mRNA mRNA protein Transcription Splicing Translation Gene expression :

11. Information is transmitted from DNA to mRNA Five steps: 1.Pre-initiation 2.Initiation 3.Promoter clearance 4.Elongation 5.Termination TRANSCRIPTION

12. STEPS IN TRANSCRIPTION

13. TRANSLATION gets associated with ribosomes mRNA serves as a template tRNA present in the cytoplasm receives activated amino acid at one end the ribosomes with tRNA + amino acid, moves along mRNA molecule until it identifies a stop codon .

14. Base to base reading of the entire 3 billion nucleotide long human genome . Goals are : creation of genetic maps development of physical maps determination of DNA sequence in humans Humans share 99.9% genes 0.1% variation This variation is involved in disease susceptibility, drug and treatment response in periodontitis THE HUMAN GENOME PROJECT

15. Information from Human genome project…. 30,000 genes and 1.5 million proteins…. 300 TERABYTES per gene 30,000 x 300 TERABYTES information !!!!! Stored, organized and retrievable…. 50 completely sequenced genomes

16. MUTATIONS

17. CHROMOSOMAL MUTATION

18. GENETICS AND PERIODONTICS

19. Trott & Cross(1966): Some individuals more at risk for periodontitis Loe et al(1986) van der Velden et al(2006) Variation

20. INDIVIDUAL SUSCEPTIBILITY TO PERIODONTITIS

21. GENETIC disease model

22. GENETIC study designs

23. CHRONIC PERIODONTITIS GENE POLYMORPHISMS IL-1 IL-1 α +889T, IL-1 β +3954T TNF- α TNF- α -308 allele 1 TNF β , ET -1 and ACE gene TNF- β , ET-1 gene, ACE gene (deletion /insertion polymorphism) Fc γ RIIIb allotype Fc receptor polymorphisms

24. IL-1: proinflammatory cytokines IL-1 α , IL-1 β The gene encoding IL- α and IL- β are located in close proximity in the IL-1 gene cluster on chromosome 2. The combined carriage of R-alleles IL-1 α +889 T and IL 1 β +3953 T is designated as the IL-1 composite genotype Single nucleotide base pair mutation: IL-1 β +3954 has been associated with a four fold increase in IL-1 β production

25. TNF α : proinflammatory cytokine The TNF α gene is located on chromosome 6 within the major histocompatibility gene cluster Polymorphism :G to A transition

26. Fc γ RIIIb polymorphisms: The Fc receptors on IgG is designated as Fc γ The receptor on the immune cells that bind to the Fc γ portion is referred to as the Fc γ R. Polymorphisms: variation in antibody binding and phagocytosis .

27. Reichert et al,2008 :Interferon- γ .IL-12 gene polymorphisms Schulz et al,2008: TNF- α Agarwal,2006: IL- α and IL-1 β gene polymorphisms in chronic periodontitis

28. STUDY DESIGNS ASSOCIATED WITH CHRONIC PERIODONTITIS Twin studies: Noack (1940): Minnesota group study of MZ twins Association studies : Kornman et al(1997)- genotype + ve non-smokers were 6.8 times more likely to have severe periodontal disease. Gore et al(1998) Galbraith et al (1998) Engebretson et al(1999)

29. POLYMORPHISMS GENE DISEASE ASSOCIATION IL α (+889), IL-1 β (+3954) IL-1 Gene EOP IL-4 Promoter & Intron polymorphisms IL-4 Gene EOP Fc γ RIII b allotype Fc receptor gene polymorphism EOP/GEOP Gc locus chromosome 4q unknown EOP/LJP VDR gene Vitamin D receptor polymorphism EOP/LJP AGGRESSIVE PERIODONTITIS

30. IL-4 GENE POLYMORPHISMS : Stimulating production of B-lymphocytes and production of IgG and IgE antibodies. Inhibits IL-1 production. VITAMIN D RECEPTOR GENE POLYMORPHISMS: Affects both bone metabolism and immune functions

31. Nibali et al,2009: IL-6 polymorphisms associated with aggressive periodontitis Reichert et al,2008: IL-1O promoter halotype ATA is a putative risk factor for aggressive periodontitis Nibali et al,2008: Vitamin D receptor Polymorphisms Marida de Freitas,2007: IL-1 and TNF- α gene Polymorphisms Gonzales,2007: IL-4 and IL-13 gene polymorphisms

32. Hodge et al,2001: IL-1A & IL-1B genetic polymorphisms , no association Parkhill et al,2000: IL-1B genotype in combination with smoking in periodontitis Kobayashi et al,2000: Fc γ RIIIb linked with aggressive periodontitis

33. Segregation Analysis : Segregation analysis: Used to determine the most likely mode for transmission of trait Errors: difficulty in diagnosis in older people variable clinical appearance etiologic and genetic heterogenity Linkage studies : To map the disease alleles to specific regions on the chromosome Boughman et al Saxen & Koskimies STUDY DESIGNS FOR AGGRESSIVE PERIODONTITIS

34. PERIODONTAL SUSCEPTIBILITY TEST PST Genetic Susceptibility Test is the first and only genetic test that analyzes two interleukin 1 (IL1) genes. Individuals with a positive PST genotype are approximately 3 times more likely to lose teeth than individuals who are genotype negative.

35. Clinically, PST is used in: • New periodontal patients to assist in developing treatment plans. • Patients requiring extensive periodontal and/or implant therapy to determine prognosis, improve patient acceptance and optimize treatment outcomes. • Smokers • Maintenance patients . • Patients with early signs of disease .

36. DISORDER PROTEIN OR TISSUE DEFECT LEUCOCYTE ADHESION DEFICIENCY TYPE I CD18 LAD TYPE II CD15 ACATALASIA CATALASE ENZYME CHRONIC AND CYCLIC NEUTROPENIA UNKNOWN CHEDIAK-HIGASHI SYNDROME MUTATIONS IN LYSOSOMAL TRAFFICKING ENZYMES EHLER-DANLOS SYNDROME TYPE III COLLAGEN(EDS TYPE IV) PAPILLON-LEFEVRE SYNDROME CATHEPSIN C HYPOPHOSPHATASIA TISSUE NON-SPECIFIC ALKALINE PHOSPHATASE TRISOMY 21 MULTIPLE PRE-PUBERTAL PERIODONTITIS CATHEPSIN C KINDLER SYNDROME DEFECT IN ACTIN-EXTRACELLULAR MATRIX LINKAGE SYNDROMIC ASSOCIATIONS WITH PERIODONTITIS

37. SYNDROMIC ASSOCIATIONS WITH PERIODONTITIS Papillon - Lefevre syndrome : Papillon and Lefevre (1924) Autosomal recessive genetic disease Severe periodontitis & hyperkeratosis (Carvel,1969) Mutation of the cathepsin C gene located on chromosome 11 (Hart,1999) - affecting host response - epithelial integrity Van Dyke et al-1984 Yang et al,2007 , Noack,2008

38. Chediak Higashi syndrome : Affects 1q43 chromosome Clinical features: Partial albinism , photophobia, nystagmus , neutropenia Mutation of the lysosomal trafficking regulator gene is responsible for this condition. Clark and Kimball (1971)- anomalies of blood cells and neutrophilic destruction. Tempel et al (1973)- neutropenia , gingivitis , periodontal disease

39. Cyclic neutropenia : Disease of unknown etiology Cohen and Morris(1964) Chadwick et al (1989)- oral mucosal ulcerations, gingivitis, periodontitis Mutation in neutrophil elastase gene

40. Leucocyte Adhesion Deficiency TYPE I: Inability to produce or failure to express cell surface integrin CD18. Autosomal disorder affecting 21q22.3 chromosome. Generalized Prepubertal Periodontitis affects both deciduous and permanent teeth. TYPE II: Selectin ligand deficiency Recurrent bacterial infections Neutrophil rolling does not increase in response to inflammation Severe early onset periodontitis ( Price,1994)

41. Hypophosphatasia : Mutation in tissue non-specific alkaline phosphatase gene ( Root,1996) Skeletal abnormalities Cemental hypoplasia Premature loss of primary and occasionally perm anent teeth

42. Gingival enlargement: Hereditary Gingival Fibromatosis Slowly progressive benign enlargement of gingival tissues Non- syndromic inherited as autosomal dominant traits Mutation at gene locus present at chromosome 2p 21-22

43. HUMAN GENE THERAPY

44. GENETIC ENGINEERING Also known as Recombinant DNA technology , Gene transfer , Gene splicing, Gene cloning It involves removing, modifying and adding genes to function better. It also prepares genes to be inserted into new species. It develops transgenes .

45. PHARMACOGENOMICS

46. PHARMACOGENOMICS Influence of genetic variation on drug response in patients by correlating gene expression with drug’s efficacy or toxicity. Genetic information can be used to improve the drug discovery and development process

47. Recent trends IN GENETIC RESEACH Microarray: detecting genes involved in complex diseases & to detect the genetic polymorphisms regulating gene expression Transcriptome : A transcriptome represents that small percentage of the genetic code that is transcribed into RNA molecules—estimated to be less than 5% of the genome in humans ( Frith et al. , 2005 ). Serial Analysis of Gene Expression(SAGE ): analysis of gene expression patterns

48. SAGE

49. FUTURE TRENDS IN GENETICS Genetic bioengineering will impact all phases of dental practice. Control pathogenicity of dental infectious agents. Restoration and Reconstruction of dental tissues. Building disease-resistant dental structures

50. As environmental causes of disease become better controlled, so genetic factors assume relatively greater importance. Opportunities to investigate the genetic contribution to disease have increased dramatically through the remarkable technological developments of recent years. As such a “master gene” responsible for periodontitis has not yet been recognized and further research is needed in this regard. CONCLUSION

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