This document summarizes genetic factors associated with periodontitis. It discusses various genetic studies related to chronic and aggressive periodontitis, including studies on gene polymorphisms like IL1, TNF, FCγR, IL10, and others. It also covers genetic terminology, types of genetic studies like twin studies, family studies, case-control studies and genome-wide association studies. Specific gene mutations linked to syndromes associated with periodontitis are mentioned.

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
• FCϒR GENE POLYMORPHISMS
• IL10 GENE POLY MORPHISMS
• ANRIL
• CAMTA1
• GLT6D1
• COX2
• NPY
• VIT D RECEPTOR
• IMPLANT FAILURE GENES
• REFERENCES

3. INTRODUCTION
Association of periodontitis with a genetic component was first found in 1965 and studies
were carried out extensively from 1990’s
Diseases are associated with variations in multiple genes each having a small overall
contribution for developing disease process.
Presence of genetic risk factors directly increases the probability of periodontal disease
development.

5. Genetics is defined as the science of heredity primarily concerned with understanding
biological properties that are transmitted from parent to offspring.
GENETICS
Transmission
genetics
Molecular genetics
Population genetics
Quantitative
genetics

6. Mendelian principle 1865

7. Terminologies

8. 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.

9. Chromosome
A chromosome is an organized structure containing DNA

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

11. 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

12. Exon
Protein coding regions of DNA
Intron
A DNA region within a gene that is not translated to
protein

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

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

15. 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.

16. Dizygotic twins
Twins that have
resulted from
fertilization of two
separate eggs. They
are no more similar
to each other than
are non twin siblings.
Monozygotic
twins
twins with identical
genetic make up as a
result of fertilization
of a single egg that
splits in to two
embryos.

17. 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.

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

19. SNP VNTR STR

20. Patterns of transmission
Whether disease alleles
are contained in sex
chromosomes or
autosomes
Whether they are
dominant or recessive
Whether they are fully or
partially penetrant

21. TYPES OF GENETIC DEFECTS
Mendelian
disorders (single-
gene defects)
Non-mendelian
disorders (multifactorial
disorders)

22. 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.

24. SYNDROMES ASSOCIATED WITH PERIODONTITISCondition 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

25. CTSC gene which was observed in 8 families and was found that these mutations
resulted in complete loss of enzyme.[Hart et al 1999].
CTSC mutations have also been identified in families with prepubertal periodontitis .
It has also been found that polymorphic functional variants of CTSC may be involved
in more common type of aggressive periodontitis.
Papillon lefevre syndrome

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

27. 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.

28. Genetic association studies

29. Association
analysis
Familial
aggregation
and relative
risk
Twin studies
Seggregation
analysis
Linkage
analysis

30. Associationstudies
Case control
Candidate approach
Genome wide

31. 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

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

33. 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.
-To identify genetic
contributions to
common diseases.
- Large clinical sample
sizes are required to
reduce likelihood
differences between
cases and controls .

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

35. 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
Genotype influences plaque index,
but not GI and attachment loss.
Mother offspring correlation was
stronger than father for both GI and
attachment loss.

36. 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
Chronic periodontitis- 50%
heritability independent of smoking

37. 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 among 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.

38. 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

39. Polymorphisms

40. IL 1 gene polymorphisms
IL 1A …….IL-1α
IL1B…...…IL-1β
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

41. 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

42. 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.

43. 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.

44. IL 10 polymorphisms
IL 10 is closely located on chromosome 1, in a cluster
with closely related IL genes such as IL19, IL20, IL24.
IL10 plays a role in regulation of proinflammatory
cytokines such as IL-1 and TNF α
Autoantibodies which are produced by stimulation of
IL10 and genetic polymorphisms is being found to be
detrimental to host tissues and is being found to be
linked with periodontitis

45. 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.

46. TNF α gene polymorphisms
TNFα gene is located on chromosome 6 within
MHC gene cluster.
Case control studies in Caucasians and non
Caucasians have proved TNFα as a putative risk
factor for periodontitis.
SNP’s in gene coding TNF α are studied mainly in
promoter regions (-1031, -863 ,-367, -308, -208,
489)

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

48. FcϒR 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 FcϒR genes are found on chromosomes 1 and encode 3 main receptor classes
FcϒR1(CD 64) , FcϒR2(CD 32), FcϒR3(CD16).

49. 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 FcϒR111b Rallele was associated with
generalized EOP and was found more in adult patients with disease
reccurence.

50. 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

51. Decreased expression of ANRIL is correlated with decreased expression levels
of ADIPORI, VAMP3 and C11ORF10. [Bochenek et al 2013]
Protein VAMP3 belongs to VAMP/synaptobrevin family and plays a role in
phagocytosis wherein VAMP3 mediates the transfer of TNF to cell surface
[Murray et al 2005]
VAMP3 gene polymorphisms

52. 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.

53. Risk gene of aggressive periodontitis GLT6D1 mapped to
chromosome 9 at 9q34.3 [ Schafer et al 2010].
It encodes for an unknown protein belonging to family of
proteins that is characterized by a glycosyl transferase domain 1 .
Mainly expressed in gingiva and T cells.
GLT6D1 gene polymorphisms

54. PGE2 plays an important role in periodontitis by mediating
pro-inflammatory reactions in periodontal tissues and is
partly responsible for resorption of alveolar bone .
COX 2 is specifically induced by cytokines and specific
expression for gingival tissues in periodontitis.
Polymorphisms within COX 2 are related to various
inflammatory diseases.
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

55. 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 that 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

56. 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.
VDR gene
Bone homeostasis
bone mineral density
Disorders
Osteoporosis, osteoarthritis

57. 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.

58. Disease modifying genes in implant failures

59. 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.

60. 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.

61. 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

62. 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]

64. 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.

65. REFERENCES• Textbook of periodontology 11th edition by newman takei Carranza
chapter : genetic factors associated with periodontitis ;pg 361
• Textbook of periodontology 5th edition by jan lindhe
Chapter : susceptibility pg
• Textbook of periodontology 6th 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.