Genetic Risk Factors for Periodontitis · 2020-05-14 · Twin study of dental caries • 20,839...
Transcript of Genetic Risk Factors for Periodontitis · 2020-05-14 · Twin study of dental caries • 20,839...
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Genetic Risk Factors for Periodontitis
Bryan Michalowicz, D.D.SDivision of Periodontology
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Pathogenic Bacteria
SusceptibleHost
Modifying Environmental Factors
Periodontitis is a COMMOM, COMPLEX, MULTIFACTORIAL disease.
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Periodontitis Diagnoses
• Aggressive Periodontitis (Grade II or III, Stage C under new scheme)– Localized– Generalized
• Chronic (Adult) Periodontitis
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Localized Aggressive Periodontitis
•Incisors and 6-year molars•Saucer-like defects
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Disorder Protein or Tissue Defect
Leukocyte Adhesion Deficiency Type I
CD18 (b-2 integrin chain of the LFA molecule)
Leukocyte Adhesion Deficiency Type II
CD15 (neutrophil ligand for E and P selectins); inborn error in fucose metabolism
Chronic and Cyclic Neutropenias Various
Chediak-Higashi Syndrome Abnormal transport of vesicles to and from neutrophil lysosomes caused by mutations in thelysosomal trafficking regulator gene
Ehler-Danlos Syndrome [types IV & VIII]
Type III collagen for EDS type IV, unknown for EDS type VIII
Papillon-Lefevre Syndrome Cathepsin C (dipeptidyl aminopeptidase I)
Hypophosphatasia Tissue non-specific alkaline phosphatase
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Cyclic Neutropenia
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Leukocyte adhesion deficiency
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Papillon-Lefèvre Syndrome
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Papillon-Lefèvre Syndrome
• several point mutations in the cathepsin C gene are associated with the phenotype
• mutations may be missense, nonsense, insertions or deletions
• almost total loss of enzyme activity in PLS patients (i.e., homozygotes or compound heterozygotes)
• reduced enzyme activity in obligate carriers
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Cathepsin C
• lysosomal protease present in neutrophils and macrophages
• dipeptidyl aminopeptidase I (removes dipeptides from amino terminus of protein)
• chromosomal location: 11q14.1-q14.3
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Approaches to Evaluate Genetic Risk in Humans
• Segregation Analyses• Twin and Family Studies• Association (Case-Control) Studies
– Candidate gene approach– Genome-wide associations (GWAS)
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Segregation Analyses of Aggressive Periodontitis
• AR, AD, and X-linked modes of inheritance have all been proposed
• Largest collection of families to date favors AD inheritance
• Frequency of disease allele greater in blacks than whites
• Highlights genetic heterogeneity
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TWIN STUDY DESIGN• Differences between MZ (identical) twins of a pair are
due to differences in environment.• Differences between DZ twins of a pair are due to
differences in environment plus unshared genes. • Differences (in correlations) between MZ and DZ
twins is due to the effects of one-half the genetic variance (the difference in gene sharing between mzand dz twins)
• Twice this difference [2(rMZ-rDZ)] is heritability
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Classic twin study assumptions
• Twins are representative of non-twins• The environments are similar for MZ and
DZ twins (especially relevant for behavioral studies)
• Genes and environment don’t interact (for estimating heritability as described)
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Reared Together and Apart Twin Correlations for Clinical Measures
00.10.20.30.40.50.60.70.80.9
AL PD Gingivitis
MZTMZADZT
Michalowicz et al., 1991
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Twin Correlations for Presence of Periodontal Pathogens
0
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0.2
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P.i. P.g. A.a. E.c. F.n.
MZ DZ
Michalowicz et al, J Periodontol. 1999;70(3):263-73.
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Conclusions• Approximately 50% of the population variance for
attachment loss and probing depth is attributed to genetic variance
• Genetic factors do not significantly influence levels of plaque or calculus, or the presence of specific bacteria in subgingival plaque
• The family environment does not significantly influence measures of disease in adults
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Nibali et al. J Dent Res. 2019 Jun;98(6):632-641
All twin studies combined
Excluding those where disease was self-reported
Other family studies
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Twin study of dental caries• 20,839 complete twin pairs with known zygosity and caries data
Results of variance decomposition for caries indices and caries trajectories. Each bar represents a caries trait, and the stacked components represent the relative contributions of components A (additive genetic factors), C (shared environmental factors), and E (nonshared environmental factors) to variation in that trait. DMFSa and DFSa refer to proximal surfaces.
J Dent Res. 2020 Mar;99(3):264-270.
• From cross sectional data, heritability ranged from 49 to 63%.
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Association Studies using candidate gene markers
• Case-control study design• Exploit phenomenon that alleles at nearby
loci co-segregate (are in “linkage disequilibrium”)
• Focus on common genetic variations, e.g., single nucleotide polymorphisms (SNPs) with frequencies > 5%
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Candidate Genes for Periodontal Disease
• Cytokines, including interleukin-1• Vitamin D receptor• N-formyl peptide receptor• Class II HLA antigens (DR, DQ, DP)• Cathepsins• Toll-like receptors• MMPs
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Genotype distributions and frequencies of the minor alleles by periodontal diagnosis and race
Polymorphism Genotype Caucasians p Blacks p
Patients Controls Patients ControlsIL6 −174 GG 124 (39.0%) 42 (29.2%) 0.12 81 (90.0%) 38 (84.4%) 0.35
CG 142 (44.7%) 74 (51.4%) 9 (10.0%) 7 (15.6%)
CC 52 (16.4%) 28 (19.4%) 0 (0%) 0 (0%)
IL6 −1363 GG 263 (85.7%) 112 (77.8%) 0.02 88 (98.5%) 43 (95.6%) 0.23
TG 48 (14.0%) 28 (19.4%) 1 (1.1%) 2 (4.4%)
TT 1 (0.3%) 4 (2.8%) 0 (0%) 0 (0%)
For −174, GG vs. CC + CG: p = 0.044 (OR = 1.6, 95% CI = 1.0–2.4)For −1363, GG vs. TT + GT: p = 0.017 (OR = 1.8, 95% CI = 1.1–2.8)
Cytokine, Vol 45 (1), 2009, p50-54
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Genome-wide associations studies (GWAS)
• Uses a case-control study design• No pre-selection of “candidate gene” regions• More informative with larger patient sample sizes and more
polymorphism genetic markers• Typically use SNPs (single nucleotide polymorphisms)• Include SNPs that are both assayed in patient samples and
imputed• Test for SNPs whose alleles are distributed differently in cases
and controls• Must control for false positive findings
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(www.broad.mit.edu/diabetes/scandinavs/type2.html)
Type 2 Diabetes GWAS (>380K SNPs)
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Cases ControlsGWAS 1 141 500GWAS2 142 479Validation sample
155 341
Fine mapping
461 1383
Schaefer AS, et al. A genome-wide association study identifies GLT6D1 as a susceptibility locus for [aggressive]
periodontitis. Hum Mol Genet. 2010;19(3):553
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SNP rs1537415
GWAS1 GWAS2 Validation
P-value 1.8 x 10–4 3.1 x 10–4 5.7 x 10–3
OR (95% CI) 1.67 (1.27–2.18) 1.65 (1.26–2.17) 1.47 (1.12–1.93)
Controls 11 (%) 187 (38.3) 185 (38.6) 128 (37.5)12 (%) 236 (48.4) 233 (48.6) 156 (45.7)
22 (%) 65 (13.3) 61 (12.7) 57 (16.7)
Cases 11 (%) 36 (26.3) 33 (24.6) 38 (25.0)12 (%) 65 (47.4) 70 (52.2) 79 (52.0)
22 (%) 36 (26.3) 31 (23.1) 35 (23.0)
Schaefer, A. S. et al. Hum. Mol. Genet. 2010 19:553-562
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GLT6D1 • Glucosyltransferase• Impairment of a potential GATA-3
transcription factor binding site at rs1537415• Minor (disease-associated)
allele associated with decreased GATA-3 binding
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Genome-wide association study of chronic periodontitis in a general German population (SHIP)
J Clin Periodontol 2013, Vol 40 (11): 977-985
• No genome-wide significant SNP associations
• The proportion of the sex age, and smoking status adjusted variance explained by additive effects of all common SNPs (Heritability) was 23% and 14% for mean PAL (top) and CDC/AAP disease definition (bottom), respectively.
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Divaris K et al. Hum. Mol. Genet. 2013;22:2312-2324
761 had severe disease, 1920 moderate disease and 1823 healthy
Genome-wide association results for severe (A) and moderate (B) chronic periodontitis.
2,135,236 SNPs tested, none reached genome-wide statistical significance
For severe disease, the minor allele [C] of NIN showed a 3.5% enrichment among severe CP patients; OR = 1.89 (P = 3.5 ×10−7).
Heritability for severe disease explained by all SNPs increased from 18 to 52% with the inclusion of a genome-wide interaction term with smoking.
Genome-wide association study of chronic periodontitis in a general US population (D-ARIC)
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Nat Commun. 2019 Jun 24;10(1):2773.
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Genome-wide analysis of dental caries and periodontitis combining clinical and self-reported data
Trait name DMFS DFSS Nteeth Periodontitis
Trait Decayed, missing and filled tooth surfaces # of natural teethPresence or absence of periodontitis
Phenotypic assessment Derived from clinical dental records
Derived from clinical dental records or self-reports
CDC/AAP definitions(4 studies)Two or more tooth surfaces with PD ≥ 5 mm, or at least four tooth surfaces with PD ≥4 mm (1 study)PD ≥5.5 mm in 2 or more sextants (1 study).Self report (1 study)
# of studies in primary analysis
9 9 7
# of participants in primary analysis 26,792 27,949 17,353 cases,
28,210 controls
PD = probing depth
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Caries/Dentures
Periodontitis/Loose teeth
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Summary• For dental caries/dentures, identified 47
significant associations, 45 of which were new
• For periodontitis/loose teeth, only one SNP reached genome-wide significance (an intronic variant within SIGLEC5 (OR for periodontitis = 1.05)
• This same marker was identified in a previous study of aggressive periodontitis
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Conclusions – Aggressive periodontitis
• Familial• Segregation analyses suggest transmission
as an AD disorder, although other modes have been proposed (Genetic heterogeneity)
• Strong environmental component (multi-factorial)
• No major gene identified to date
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Conclusions: Chronic Periodontitis• Genetic factors play a role in defining risk
(Heritability estimated at about 30%)• Using the candidate gene approach, only a
handful of polymorphisms have been validated in other studies (e.g., IL-1, IL-6, FcγR)
• GWAS have not validated previous SNP associations (above)– Risk associated with any one variant likely small,
ORs < 2– One SNP in the SIGLEC5 region appears to confer
a statistically significant but very small increase in risk for disease
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Clinical Utility of Genetic Tests
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Talmud, P. J et al. BMJ 2010;340:b4838
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Positive predictive value increases with prevalenceOR = 2, sensitivity = 0.6
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0.00 0.10 0.20 0.30 0.40 0.50 0.60 0.70Prevalence
PPV
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Clinical implications of genetic epidemiological research
• Focus prevention/early treatment on those most at risk
• Better determine prognosis• Identify new disease pathways/drug targets• Identify individuals who may benefit most
from host-modulating agents (pharmacogenetics)