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Table  2 Summary of contemporary evidence related to periodontal infectogenomics

From: Periodontal Infectogenomics

Authors

Study Design

Ethnicity

Number Of Patients

Clinical Groups

Analysed Gene Polymorphisms

Analysed Microbes

Associations

Complement System (MBL)

 Liukkonen A et al. 2017 [31]

CS

Finnish Study Population

222

Generalised Periodontitis, Localised Periodontitis, Periodontitis free

MBL2 (allele D, allele B, allele C) Grouped as: wild-type A/A, heterozygote A/O homozygote O/O

Aa

P. gingivalis

MBL2 homozygote variant (O/O) type could provoke the virulence of Aa

TLR

 Kinane DF et al. 2006 [34]

In vitro

HGECs from healthy gingival tissues from 6 healthy subjects

Two HGECs from subjects heterozygous for the TLR4 polymorphism and four with the wild-type TLR4.

TLR4 Asp299Gly and Thr399Ile (Mutant type) TLR4 normal (Wild type)

P. gingivalis

Wild type TLR4 (Normal) appears more responsive to P.gingivalis than the mutant type

 Holla LI et al. 2010 [35]

CC

Caucasian

481

CP and H

TLR2 2408G/A, i.e. Arg753Gln and -16934A/T TLR9-1486C/T, -1237C/T and 12848A/G

Aa

P. gingivalis

P. intermedia

T. forsythia

T. denticola

P. micros

F. nucleatum

Not significant

CD14

 Schulz S et al. 2008 [33]

CC

Caucasian

213

AgP, CP and H

CD14 -159C > T, TLR4 Asp299Gly, Thr399Ile

P. gingivalis

P. intermedia

T. forsythia

Aa

T. denticola

CD14 -159TT genotype + patients: < P. intermedia detection

 Gong Y et al. 2013 [32]

CS

204

Renal transplant patients with and without cyclosporine A induced gingival overgrowth

CD14–260C > T

P. gingivalis

P. intermedia

T. forsythia

Aa

T. denticola

Gingival overgrowth patients with CD14–260 CT + TT: > detection of P. gingivalis, T. forsythia,T. denticola and red complex.

FcR

 Kobayashi T et al. 2000 [81]

CC

Japanese

33

CP and H

FcγRIIIb-NA1 and FcγRIIIb-NA2

P.gingivalis

CP patients with both FcγRIIIb-NA1/NA1 and FcγRIIIb-NA2/NA2 genotypes: lower stimulation index for IgG1- and IgG3-mediated phagocytosis in PMNs

 Kaneko S et al. 2004 [41]

CC

Japanese and Caucasian

185

AgP

FcαRI nt324 A → G

P. gingivalis

FcαRI nt324 A/A in AgP: decreased phagocytosis of P. gingivalis

 Wolf DL et al. 2006 [36]

CC

Caucasian

205

CP and H

FcγRIIIb NA1/NA2, FcγIIa 131R/H

19 bacterial stains

Not significant

 Nicu EA et al. 2007 [37]

CS

Mixed

98

CP

FcγRIIa131H/R

Aa

In CP patients with FcγRIIa (H/H): increased phagocytosis, degraulation and elastase release after stimulation with Aa

 Wang Y et al. 2012 [38]

CC

Japanese

119

CP and H (females post delivery)

FcγRIIbnt645 + 25A/G, FcγRIIb-nt646-184A/G,FcγRIIb-1232 T,FcγRIIa-R131H,FcγRIIIaV158F,FcγRIIIb-NA1/NA2

P. gingivalis

P. intermedia

Aa

Not significant

 Sugita N et al. 2012 [39]

CS

Japanese

32

CP and H

FcγRIIb-nt645 + 25A/G

P.gingivalis

FcγRIIb-nt645 + 25AA genotype: < IgG4 levels produced against P. gingivalis sonicate and IgG2 produced against the P. gingivalis 40-kDa outer membrane protein (OMP)

IL-1

 Socransky SS et al. 2000 [42]

CS

108

CP

IL-1A + 4845 and IL-1B + 3954

40 taxa

IL-1genotype + subjects: > counts of T. forsythia, T. denticola, F.nucleatum, F. periodonticum, Campylobacter gracilis, C. showae, Streptococcus constellatus. Streptococcus intermedius, Streptococcus gordonii and 3 Capnocytophage species

 Cullinan MP et al. 2001 [43]

L

Caucasian

295

CP

IL-1a + 4845 and IL-1B + 3954

Aa

P. gingivalis

P. intermedia

Not significant

 Papapanou PN et al. 2001 [45]

CC

Caucasian

205

CP and H

IL-1A + 4845 and IL-1B + 3953

19 bacterial stains

Not significant

 Jansson H et al. 2005 [77]

L

22

Patients with dental implants

IL-1α-889 and IL-1β + 3953

P. gingivalis

P. nigrescens

Aa

Not significant

 Kowalski J et al. 2006 [48]

CS

16

CP

IL-1A-889 and IL-1B + 3953

P. gingivalis

P. intermedia

T. forsythia

Aa

T. denticola

F. nucleatum

E. corrodens

P. micros

C. rectus

IL-1 genotype + subjects: Higher total count of C. Rectus, red complex and orange complex bacteria

IL-1genotype - subjects: Higher mean titre of P. intermedia

 Agerbaek MR et al. 2006 [76]

CS

Caucasian

151

CP in supportive periodontal therapy

IL-1A + 4845 and IL-1B-3954

40 taxa

IL-1 genotype negative subjects: > total bacteria load and > levels of Aa, E. nodatum, P. gingivalis, Streptococcus anginosus

 Kratka Z et al. 2007 [72]

L

20

AgP

IL-1A -889C/T and IL-1B + 3953C/T

P. gingivalis

P. intermedia

T. forsythia

Aa

T. denticola

Not significant

 Ferreira SB et al. 2008 [47]

CC

Mixed

292

CP and H

IL-1β 3954

P. gingivalis

T. forsythia

Aa

T. denticola

Not significant

 Gonçalves L de S et al. 2009 [46]

CC

Mixed

105

CP and H (Grouped into HIV on HARRT and non HIV)

IL-1A + 4845 and IL-1B + 3954

33 bacterial species

Not significant

 Schulz S et al. 2011 [71]

CC

Caucasian

248

AgP, CP and H

IL1α(rs180058),IL-1β (rs16944, rs1143634), IL-1R (rs2234650), and IL-1RA (rs315952)

P. gingivalis

P. intermedia

T. forsythia

Aa

T. denticola

Il-1α rs1800587, Il-1β rs 1,143,634 and composite genotype: > Aa detection in AgP group

 Cantore S et al. 2014 [44]

CC

Italian Caucasian

195

H and CP

IL-1α + 4845 and IL-1β + 3954

Subgingival species

Not significant

 Deppe H et al. 2015 [79]

Prospective

Caucasian

104

Type 2 diabetes mellitus patients and healthy controls

IL-1A, IL-1B and IL-1RN

Red, orange, green, yellow and purple complexes

Not significant

IL-2

 Reichert S et al. 2009 [49]

CC

Caucasian

200

AgP, CP and H

IL-2 -330 T/G and 166 G/T

P. gingivalis

P. intermedia

T. forsythia

Aa

T. denticola

IL-2-330, 166 TT-TT haplotype and 166TT: > detection of P. gingivalis and red complex

IL-2 -330 TG: < P. gingivalis and red complex

IL-4

 Reichert S et al. 2011 [52]

CC

Caucasian

243

AgP, CP and H

IL-4RA Q551R

P. gingivalis

P. intermedia

T. forsythia

Aa

T. denticola

QR + RR polymorphism: Presence of T. forsythia

 Finoti LS et al. 2013 [50]

CC

Caucasian

39

CP and H

IL-4 -590C/T, +33C/T and VNTR

P. gingivalis

T. forsythia

T. denticola

IL-4 TCI/CCI haplotype in CP: higher levels of P. gingivalis, T. forsythia, T. denticola

 Bartova J et al. 2014 [51]

CC

62

CP and H

IL-4 -590c/T and intron 3 VNTR

P. gingivalis

P. intermedia

T. forsythia

Aa

IL-4 -590CC and 11 of IL-4 VNTR: T. forsythia stimulates production of cytokines TNFα, IL-6, IL-10, IFNγ, IL-10, and IL-1β while P. intermedia affects the in vitro production of IL-6 and IL-10 CP.

IL-6

 Nibali L et al. 2007 [68]

CS

Mixed

45

AgP

IL-6 -174, Fcα, FcγRIIa, FcγRIIb, FcγRIIIa, FcγRIIIb, FPR, TNF and VDR

Aa

P. gingivalis

T. forsythia

IL-6- 174GG and Fcγ haplotypes: >Aa detection

 Nibali L et al. 2008 [69]

CS

Mixed

107

AgP and CP

IL-1A -889, IL-1B -511, + 3954

IL-6 -174, − 572, − 1363, −1480, − 6106, TLR4–299,-399,

TNFα − 308

Aa

P. gingivalis

T. forsythia

IL-6 -6106 AA and IL-6 haplotypes (−174G, -572C, − 1363G, -1480C, − 6106A): > detection of Aa

 Nibali L et al. 2010 [57]

CS

Mixed

40

CP

IL-6 -174G > C

Aa

P. gingivalis

IL-6- 174GG: >Aa detection

 Nibali L et al. 2011 [70]

CS

Indian

251

H and with periodontal disease

IL-6 -174, − 572, − 1363, − 6106 and − 1480

40 taxa

IL-6- 174GG: > counts of Aa and detection and counts of C. Sputigena

 Nibali L et al. 2013 [82]

L

Caucasian

12

AgP

IL-6 -1363, − 1480

Aa

IL6 haplotype: >counts of Aa before and after treatment

IL-8

 Linhartova PB et al. 2013 [55]

CC

Caucasian

492

AgP, CP and H

IL-8 -845C/T, −251A/T, + 396 G/T and + 781C/T

P. gingivalis

P. intermedia

T. forsythia

Aa

T. denticola

F. nucleatum

P. micros

IL8 − 251 T in AgP: > A. actinomycetemcomitans detection

CC genotype of IL8 + 781 T/C variant in CP: < T. forsythia detection

In non-periodontitis subjects with T allele of IL8 + 396G/T variant or TT genotype: <F. nucleatum detection.

 Finoti LS et al. 2013 [54]

CS

Mixed

65

CP and H

IL-8 ATC/TTC

P. gingivalis

T. forsythia

T. denticola

Not significant

 Finoti LS et al. 2013 [53]

CS

Mixed

30

CP and H

IL-8 ATC/TTC and AGT/TTC haplotype

P. gingivalis

T. forsythia

T. denticola

The diseased sites of AGT/TTC patients: harbour higher levels of P. gingivalis, T. denticola, T. forsythia, and red complex

IL-10

 Reichert S et al. 2008 [56]

CC

Caucasian

93

AgP, CP and H

IL-10 -1082G > A, -819C > T and -590C > A

P. gingivalis

P. intermedia

T. forsythia

Aa

T. denticola

IL-10 ACC, ATA and ACC/ATA haplotypes: < P. intermedia detection

IL-10 GCC/GCC haplotype: > P. intermedia detection

 Luo Y et al. 2013 [78]

CS

Chinese

202

Renal transplant patients with and without cyclosporine A induced gingival overgrowth

IL-10 -1082, −819 and − 592

P. gingivalis

P. intermedia

T. forsythia

Aa

T. denticola

Gingival overgrowth patients with ATA haplotype: higher detection and count of P. gingivalis and T. denticola

IFN-γ & IL-12

 Takeuchi-Hatanaka K et al., 2008 [73]

CS

Japanese

110

AgP, severe CP, mild CP and H

5′ flanking region of IL12RB2

P. gingivalis

P. intermedia

T. forsythia

Aa

T. denticola

F. nucleatum

E. corrodens

Higher serum IgG titres against periodontopathic bacteria in patients with variant alleles

 Reichert S et al. 2008 [58]

CC

Caucasian

198

AgP, CP and H

IFN-γ 874 T/A

IL-12 1188A/C

P. gingivalis

P. intermedia

T. forsythia

Aa

T. denticola

IFN-γ 874AA: < detection of Aa

IFN-γ 874TA: > detection of P. intermedia

 Holla LI et al. 2011 [59]

CC

Caucasian

498

CP and H

IFN-γ +874A/T

P. gingivalis

P. intermedia

T. forsythia

Aa

T. denticola

F. nucleatum

P. micros

Not significant

TNFα

 Schulz S et al. 2008 [60]

CC

Caucasian

175

AgP, CP and H

TNFα -308G > A and – 238G > A

P. gingivalis

P. intermedia

T. forsythia

Aa

T. denticola

TNFα308GG/238GG haplotype: > P. intermedia detection

 Trombone APF et al. 2009 [62]

CC

Mixed

304

CP and H

TNFα -308G/A

P. gingivalis

T. forsythia

Aa

T. denticola

Not significant

 Schulz S et al. 2012 [61]

CS

Caucasian

942

Cp and H (All Coronary Artery Disease patients)

TNFα 308G > A and – 238G > A

P. gingivalis

P. intermedia

T. forsythia

Aa

T. denticola

P. micros

F. nucleatum

C. rectus

E. nodatum

E. corrodens

C. sputigena

TNFα-308 AG + AA genotype and A-allele: > P. intermedia

detection

HLAII

 Shimomura-Kuroki J et al. 2009 [74]

CC

Japanese

64

AgP, CP and H

IL-1α −889, IL-1α + 4845, IL-1β + 3954

FcγRIIa-H/R131

HLA- DQB1

P. gingivalis

P. intermedia

T. forsythia

Aa

T. denticola

HLADQB1 BamHI sites in patients: > T. forsythia detection

NF-κβ

 Schulz S et al. 2010 [75]

CC

Caucasian

222

AgP, CP and H

TLR2 (Arg753Gln and Arg677Trp)

NF-κβ -94ins/del ATTG

P. gingivalis

P. intermedia

T. forsythia

Aa

T. denticola

NF-κβ-94del/del: > Aa detection

VDR

 Borges et al. 2009 [64]

CC

Caucasian

60

CP and H

VDR TaqI

38 taxa

Not significant

T bet

       

 Cavalla et al. 2015 [63]

CC

Mixed

608

CP, CG and H

TBX21-1993 T/C

P. gingivalis

T. forsythia

T. denticola

Not significant

MMP8

 Holla LI et al. 2012 [65]

CC

Caucasian

619

CP and H

MMP8

(-799C/T and + 17C/G)

P. gingivalis

P. intermedia

T. forsythia

Aa

T. denticola

P. micros

F. nucleatum

Not significant

ApoE

 Linhartova PB et al. 2015 [66]

CC

Caucasian

469

CP and H

ApoE (rs429358C/T and rs7412C/T)

P. gingivalis

P. intermedia

T. forsythia

Aa

T. denticola

P. micros

F. nucleatum

Not significant

PPARγ

 Hirano E et al. 2010 [67]

CS

Japanese

130

CP and H All Pregnant Females Grouped as term birth and preterm birth

PPARγPro12Ala

P. gingivalis

P. intermedia

T. forsythia

Aa

Not significant

GWAS

 Divaris K et al. 2012 [2]

Caucasian and Blacks

1020 white and 123 African American participants

Healthy to severe chronic periodontitis

2,178,777 SNPs

C. rectus

F. nucleatum

P. nigrescens

P. gingivalis

T. forsythia

T. denticola

P. intermedia

Aa

Not a significant genome wide signals.

But 13 loci, including KCNK1, FBXO38, UHRF2, IL33, RUNX2, TRPS1, CAMTA1, and VAMP3, provide an evidence of association for red and orange complex microbiota, but not for Aa.

 Rhodin K et al. 2014 [25]

Caucasian

1020 + 4504 from two previously conducted GWAs

Healthy to severe chronic periodontitis

18,307 genes

C. rectus

F. nucleatum

P. nigrescens

P. gingivalis

T. forsythia

T. denticola

P. intermedia

Aa

Statistically significant association for 6 genes – 4 with severe chronic periodontitis (NIN, ABHD12B, WHAMM, AP3B2) and 2 with high periodontal pathogen colonisation (red complex – KCNK1, P. gingivalis – DAB2IP).

 Offenbacher S et al. 2016 [10]

975 European American For CP in the larger cohort (n = 821 severe CP, 2031 = moderate CP, 1914 = healthy/mild disease) and a German sample of 717 AgP cases and 4210 controls.

Healthy to severe chronic periodontitis and aggressive periodontitis

21,35,235 SNPs

8 periodontal pathogens divided into 6 PCTs with distinct microbial community as PCT1 with high pathogen load (Socransky trait), PCT4 with a mixed infection, PCT3, PCT5 dominated by Aa and P. gingivalis, respectively.

Genome-wide significant signals for PCT1 (CLEC19A, TRA, GGTA2P, TM9SF2, IFI16, RBMS3),

PCT4 (HPVC1) and PCT5 (SLC15A4, PKP2, SNRPN).

Overall, the highlighted loci included genes associated with immune response and epithelial barrier function.

Systematic review

 Nibali L et al. 2016 [80]

43 studies of candidate genes and two GWAS

Healthy to severe chronic periodontitis and aggressive periodontitis

Periodontal Pathogens

No evidence yet that neither IL-1 genetic polymorphisms nor any other investigated genetic polymorphisms are associated with presence and counts of subgingival microbiota.

  1. Aa Aggregatibacter actinomycetemcomitans, AgP Aggressive Periodontitis; CS: Cross Sectional, CC Case Control, H Healthy, CG Chronic Gingivitis, HGECs Human Primary Gingival Epithelial Cultures, CP Chronic Periodontitis, L Longitudinal