Genetic factors

genetic gactors play a very important role in periodontitis.

1. GENETIC FACTORS ASSOCIATED WITH PERIODONTITIS DR RAMYA GANESH SENIOR LECTURER MALABAR DENTAL COLLEGE AND RESEARCH CENTRE

2. CONTENTS INTRODUCTION TYPE OF GENETIC STUDIES STUDIES RELATED TO CHRONIC PERIODONTITIS STUDIES RELATED TO AGGRESSIVE PERIODONTITIS IL1 GENE POLYMORPHISMS TNF GENE POLYMORPHISMS FC ϒ R GENE POLYMORPHISMS IL10 GENE POLY MORPHISMS ANRIL CAMTA1 GLT6D1 COX2 NPY VIT D RECEPTOR IMPLANT FAILURE GENES REFERENCES

3. INTRODUCTION

4. Genetics is defined as the science of heredity primarily concerned with understanding biological properties that are transmitted from parent to offspring.

5. Mendelian principle 1865

6. Terminologies

7. Gene Is the basic unit of heredity that occupies a specific position (locus) on a chromosome and has specific effect on the phenotype of the organism.

8. Chromosome A  chromosome  is an organized structure containing DNA

9. Allele Variations in the nucleotide sequence at a locus.

10. Autosome A chromosome that is not a sex chromosome Dominance : Relationship between alleles of one gene, in which the effect of one allele masks the contribution of a second allele on the same locus

11. Gene expression The process by which information in a gene is utilized via transcription and translation leading to production of protein.

12. Traits   In  genetics , a  trait  refers to any  genetically  determined characteristic.

13. Mutation Changes in DNA sequence of genome can result from errors that occur during DNA replication or meiosis and can be caused by radiation, viruses, mutagenic chemicals. Microsatellite markers Are di-, tri-, or tetra nucleotide tandem repeats in DNA sequences .

14. Concordance The probability that a pair of individuals ( eg twins) both have a certain characteristic ( eg periodontal disease). Penetrance The proportion of individuals who have a particular allele / genotype who express an associated trait (phenotype) Probands A person serving as starting point for genetic study in a family. Open reading frame  ORF is the part of a reading frame that has the potential to be translated Cluster of differentiation The cluster of differentiation is a protocol used for the identification and investigation of  cell surface molecules  providing targets for immunophenotyping of cells in the form of receptor or ligand.

15. Polymorphisms Polymorphisms exist when two or more different phenotypes exist within different individuals of same population.

16. SNP VNTR STR

17. Patterns of transmission

18. TYPES OF GENETIC DEFECTS

19. SIMPLE & MULTIFACTORIAL GENETIC TRAITS SIMPLE MENDELIAN TRAITS -Mutations of critical genes alter gene function causing diseased phenotype. -Mutations (<1%)- MENDELIAN GENES Inherited in a predictable pattern-simple mendelian fashion. MULTIFACTORIAL GENETIC TRAITS   Interactive effect of multiple gene products modulated by environmental agents. Functional polymorphism. Polymorphisms can be enhanced by environmental agents.

20. SYNDROMES ASSOCIATED WITH PERIODONTITIS Condition Biochemical/tissue defect Inheritance Periodontal Disease Papillon Lefevre Syndrome Cathepsin C Autosomal recessive AP Halm Munk Syndrome Cathepsin C Autosomal recessive AP Ehlers Danlos Syndrome Collagen Autosomal Dominant AP Cyclic Neutropenia Neutrophil Elastase Autosomal Dominant AP, CP Chronic Familial Neutropenia Defect unknown Autosomal dominant AP, CP Chediak Higashi Syndrome Lysosomal trafficking regulator gene Autosomal recessive AP Congenital disorder of glycosylation Type 11C Glucose diphosphate frucose transporter 1 Autosomal recessive AP Leukocyte adhesion deficiency Type 1 Leukocyte chain adhesion molecule CD18 Autosomal recessive AP, CP

21. Papillon lefevre syndrome

22. Epigenetics Used to describe the changes in phenotype or gene expression that result from mechanisms other than changes in underlying DNA sequences.

23. Linkage A term used to describe the tendency for certain genes to be transmitted from parent to offspring because they are located so close to each other. Linkage disequilibrium The occurrence of specific alleles at different locations in the DNA that are relatively close to each other more often than would be expected by chance alone.

24. Genetic association studies

25. Candidate gene approach A gene mapping approach tests whether one allele of a gene occurs more often in pts than in subjects without disease. Author Study Results Boughman et al 1986 Localized Aggressive periodontitis AgP seggregates with dentinogenesis imperfecta. Localized to long arm of chromosome 4 near the gene for dentinogenesis imperfecta . Tabeta K et al 2009 SNP’s and Microsatellites in chromosome 19 A single microsatellite marker allele 17 of 1902 G 31 on chromosome 19- associated with severe chronic periodontitis

26. Case control studies Studies in which genetic makeup is compared in cases and controls . The populations need to be carefully matched.

27. Genome wide analysis studies(GWAS) GWAS investigates genetic variation across entire genome simultaneously with aim of identifying genetic associations related to a trait or disease of interest.

28. Microarray - Micro array technologies are capable of assaying >0.5M SNPs Type 2 diabetes >30 genes were discovered

29. Familial aggregation study Many diseases run in families and the degree of clustering within the family can be estimated by comparing the number of disease cases in relatives of patients to the risk of disease in the general population. AUTHOR,YEAR SUBJECTS FINDINGS Chung 1977 In a Hawaii racially mixed populations . A total of 939 subjected from 241 nuclear families was included in the analysis. Sex, age, years of education and smoking were significantly associated . No significant contribution of genotype to susceptibility for periodontitis .It was concluded that common family environment was a determining factor of variability in pdl health. Beaty et al.1993 Studied familial aggregation of plaque index, gingival index and attachment loss. The sample included 178 volunteers from 75 families (mostly African-Americans) and was mainly females < 40 years. Genotype influences plaque index , but not GI and attachment loss. Mother offspring correlation was stronger than father for both GI and attachment loss.

30. Twin studies Comparison of traits, including diseases in monozygotic, dizygotic or usually both types of twins aimed at determining whether variation in the trait among members of a population is caused by genetic variation in inherited DNA sequences, environmental exposures or combination of both. Author Study Results Corey LA et al 1993 4908 twin pairs: questionnaire based study- history of periodontal disease. 116 MZ twin pairs and 233 DZ pairs Concordance rate of MZ twins: 0.23 to 0.38 and for DZ twins: 0.08 to 0.16 Michalowicz et al 1999 1967-1999 169 twin pairs : presence of P.ging , A.a , P.intermedia , E.corrodens , F.nucleatum Concordance rate in P.ging-11%, A.a - 22%, P.intermedia - 19%, E.corrodens - 0.34%, F.nucleatum-40%. Michalowicz BS et al 2000 64 MZ, 53 DZ twin pairs: influence of smoking and utilization of dental services Chronic periodontitis- 50% heritability independent of smoking and dental services.

31. Seggregation analysis Statistical analyses of the patterns of transmission of a disease in relative likelihood that the disease is caused by a single gene with dominant or recessive inheritance, by multiple genes. Author Study Results Marazita ML et al 1994 EOP- 104 probands - 100 families , blacks and non blacks families Autosomal dominant mode of inheritance among blacks and non blacks with 70% penetrance Marazita ML et al 1996 Segregation analysis of IgG2 levels in EOP a mong african americans and caucasians Autosomal co-dominant mode of inheritance Hodge PJ et al 2000 Caucasian family from Europe with EOP Autosomal dominant or X-linked mode of inheritance De Carvalho FM et al 2009 Aggressive periodontitis- Brazilian population Semi general mode of transmission : few loci with small effects contribute to periodontitis.

32. Linkage analysis A technique used to map a gene responsible for a trait to a specific location on a chromosome. AUTHOR SUBJECTS FINDINGS Boughman et al., 1988 A large, five-generation family from southern Maryland (more than 70 individuals) An AD mode of JP : its localization to chromosome 4 and linkage to dentinogenesis imperfecta Hart et al., 1993 Fifteen African–American and four Caucasian families (228 individuals) 4q candidate region associated with EOP Li et al., 2004 Four African–American families (28 subjects) LAgP is linked to human chromosome 1q25

33. Polymorphisms

34. IL 1 gene polymorphisms IL 1A …….IL-1 α IL1B…...…IL-1 β IL1RN…….IL-RA Genes Chromosome 2 This study reports on IL1 composite genotype but no data were presented on carriage rates of individual IL1 R alleles. The following IL1 genetic polymorphisms were studied in relation to periodontitis : IL1A(- 889) IL1 B(+3954) IL1RN VNTR (+2018). Kornmann et al

35. Parkhill et al 2000 Over representation of N allele among early onset periodontitis is responsible for over expression of N allele among early onset periodontitis among African American and Caucasian population whereas in Japanese populations carriage of N alleles was found to be low. Found an association between R allele and periodontitis . Three studies have reported carriage rates for IL1B (511) R allele and this genetic polymorphism is not associated with periodontitis . This carriage rate was high among Japanese people (67-78%) than Caucasians (59%). Gore et al 1998, Tai et al 2002, Soga et al 2003 Patients with IL 1 composite genotype more often harbor periodontal pathogens and have increased counts of pathogens. Socransky et al 2000

36. Caucasian and non Caucasian studies Association between IL1 composite genotype and severity of periodontal destruction has also been reported by two cross sectional studies in non Caucasians. McDevitt et al 2000, papanaou et al 2001 other studies have failed to corroborate IL1 as risk factor in periodontitis in Caucasians . Meisel et al 2002,2003 2004 ,Laine et al 2000 Walker et al 2000 Armitage et al 2000 In south American populations the carriage rate of IL1 composite genotype was lower than that reported for Europeans and north American subjects.

37. Mcguire and Nunn 1999 It was reported among periodontitis patients in maintenance of 5-14 years that IL1 composite genotype increased the risk of tooth loss by 2.7 fold. Mcguire and Nunn 1999 IL1 composite genotype in combination with heavy smoking increased the risk of tooth loss by 7.7 fold . Australian study Culinan et al 2001 A study was done in 295 subjects with gingivitis and moderate periodontitis which were followed for 5 years and IL1 composite genotype was determined and results showed that among non smoking subjects >50 years with IL1 positive had greater probing depths and also was influenced by environmental factors such as age , smoking and the presence of p.gingivalis which suggests IL1 as contributory but non essential risk factor for periodontitis .

38. IL 10 polymorphisms

39. Kinane et al 1999 IL10 gene microsatellite markers have been investigated in relation to aggressive periodontitis . Berglund et al 2003 N-allele were more abundant in periodontitis particularly among non smokers in Caucasian populations which lead to production of higher levels of autoantibodies leading to increased periodontal destruction.

40. TNF α gene polymorphisms

41. Soga et al 2003 Among Japanese subjects , with periodontitis have been observed for SNPs TNF α in 1031 and -863. Galbraith et al 1998 Association of TNF α polymorphism was found at position -308 among caucasians

42. Fc ϒ R polymorphisms They play role in pathogenesis of periodontitis acting as a bridge between the cellular and humoral branches of immune system . Microorganisms and bacterial antigens are opsonized by a variety of APC’s Leukocyte Fc ϒ R genes are found on chromosomes 1 and encode 3 main receptor classes Fc ϒ R1(CD 64) , Fc ϒ R2(CD 32), Fc ϒ R3(CD16).

43. Colombo et al 1998 Meisel et al 2001 Studies established that the carriage rates of R allele is relatively high 63-77% in Caucasians and African americans . Loos et al 2003 In Caucasians there was more of N allele expression rather than R allele and that periodontitis patients were homozygous for N allele which lead more periodontal breakdown as compared to those to subjects carrying two R alleles Kobayashi et al 2000 In Japanese patients the Fc ϒ R111b Rallele was associated with generalized EOP and was found more in adult patients with disease reccurence .

44. McPherson et al 2007 ANRIL is also considered as most important genetic risk factor in myocardial infarction as identified in GWAS on CAD. ANRIL encodes a large antisense non-protein coding RNA molecuele , 126.6 kb full length transcript of 19 differently spliced exons yielding different RNA molecueles of various lengths. ANRIL gene polymorphisms

45. VAMP3 gene polymorphisms

46. Divaris et al 2012 In a GWAS on periodontal pathogen colonization, a large stretch of VAMP3 region is reported to be strongly associated with increased quantities of pathogenic bacteria . Bochenek et al 2013 Study showed that VAMP3 identified several SNP located at this pathogen specific region to be significantly associated with aggressive periodontitis. Dupuis et al 2010 Franke et al 2010 Borderline associations with aggressive periodontitis were found in C11ORF10 and adjacent genes FADS1 and FADS2 . These alleles were identical to previously identified associations with type 2 diabetes , inflammatory bowel disease and crohn’s disease .

47. GLT6D1 gene polymorphisms

48. Ho et al 2008 Xie et al 2009 In Taiwanese and Chinese periodontitis case-control populations, the central portion of COX 2 genetic region was independently shown to be associated with severe periodontitis which was also found true in European population with aggressive periodontitis . COX-2 gene polyorphisms

49. Bedoui et al 2003 . Binding of NPY to Y1 receptors on a variety of immune cells is thought to be responsible for promoting the anti-inflammatory Th2 response . Lundy et al 2009 NPY is potentially important in the coordination of inflammation and bone metabolism Freitagwolf et al 2014 A second GWAS t hat systematically analysed gene sex interactions in german cases of aagressive periodontitis and controls observed that a sexually dimorphic role of genetic variants upstream of NPY was associated with aggressive periodontitis . NEUROPEPTIDE Y

50. Vitamin D receptor polymorphisms Consequences of periodontitis are tooth mobility and eventually tooth exfoliation. Genetic polymorphisms are being identified in genes coding for mediators for bone homeostasis in VDR gene.

51. Henning et al 1999 -Studies have identified a VDR polymorphisms in relation to periodontitis at positons Taq-1, Bsm-1, Fok-1. -The carriage rate of R allele ranges between 12 and 66 % among Brazilians than in Japanese populations. Tachi et al 2003 Association with N allele has been found in Japanese populations.

52. Disease modifying genes in implant failures

53. Early failures in implant dentistry Shimpuku et al 2003 Shimpuku et al 2003 Homozygosity if IL1B -511 R-allele has been reported to be associated with marginal bone loss around dental implants in Japanese populations. Santos et al 2004 Carriage of MMP1 -1607 R-allele is associated with early implant loss . BMP plays an important role in bone remodelling and the R allele is of Alu1 polymorphism of the BMP 4 gene associated with marginal bone loss around implants in Japanese patients .

54. Late failures in implant dentistry Rogers et al 2002 laine et al 2006 Studies reported on IL1A -889, IL1B -511, IL1B +3954 and IL1RN VNTR polymorphisms separately in association with late implant failures. Feloutzis et al 2003 -In a study of 90 Caucasian patients were investigated for peri-implant bone loss at time of re-examination [mean 5.6 years ] - 28 patients carrying IL1 composite genotype were stratified in to non-smokers , former smokers and heavy smokers - Heavy smokers were found to have more annual bone loss. Gruica et al 2004 IL1 composite genotype and smoking were significantly associated with peri-implant bone loss after 8 years in function among Caucasians.

55. Evidence for the role of genetics in periodontitis A study was done on 77 siblings of 39 probands with LJP and GJP and it was found that 50 % of siblings suffered from JP. 11 families a co-occurrence of LJP and GJP was present. [ Boughman et al 1992]. A family with 527 subjects : 60 with LJP , 72 with GJP , 254 unaffected subjects and 141 with unknown periodontal condition in Caucasians and African American families . The authors concluded that the most likely mode of inheritance was autosomal dominant in both American and Caucasian with penetrance of 70% in African americans and 73 % in Caucasians .[ Marizata et al 1994] Aggressive periodontitis

56. Chronic periodontitis A study was done in 75 families consisting of 178 subjects to determine familial aggregation . The results showed both gingival index and attachment loss showed a stronger correlation between mothers and offspring compared with fathers and offspring. [ Beaty et al 1993 ] A study analysed periodontal condition in an untreated population in Guatemala consisting of 109 siblings from 40 nuclear families with an age range of 35-60 years. They failed to show familial clustering for periodontal disease.[ Dowsett et al 2002] A study was done in 78 subjects and was found that significant sibling relationship effect on plaque, calculus and loss of attachment but not for pocket depth.[van der Velden et al 1993]

57. Conclusion In an individual the development of periodontitis depends on collective presence of a number of environmental risk factors in conjunction with a number of genetic risk factors at a given point during life. However, till date major disease gene mutations have not been identified. A multitude of polymorphisms in genes, most of which code aspects of host immune responses have been explored. In general, the genetic studies in relation to periodontitis are hampered by population heterogenicity and differences in patient selection and diagnostic criteria. Future studies applying candidate gene approach could be guided by results from genome wide searches or by results from gene expression signatures or family linkage analysis to prove a strong association.

58. REFERENCES Textbook of periodontology 11 th edition by newman takei Carranza chapter : genetic factors associated with periodontitis ; pg 361 Textbook of periodontology 5 th edition by jan lindhe Chapter : susceptibility pg Textbook of periodontology 6 th edition by jan lindhe Chapter host susceptibility pg Hart, T.C. and Kornman , K.S., 1997. Genetic factors in the pathogenesis of periodontitis.  Periodontology 2000 ,  14 (1), pp.202-215 . Michalowicz , B.S., 1994. Genetic and Heritable Risk Factors in Periodontal Disease*.  Journal of Periodontology ,  65 (5s), pp.479-488.