Serum antibody levels against microbial biomarkers of periodontitis, Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis, are associated especially with the presence of these species in the oral cavity. We investigated the genetic basis of host antibody responses against these species through a genome-wide association study (GWAS) to identify the genetic determinants of this immune reactivity. Serum immunoglobulin A (IgA) and immunoglobulin G (IgG) antibody levels against A. actinomycetemcomitans and P. gingivalis were determined using multiserotype enzyme-linked immunosorbent assay in 3,719 participants from 4 Finnish cohort studies: FinnTwin, Parogene, FINRISK97, and Health-2000. The associations of genetic polymorphisms and imputed human leukocyte antigen (HLA) alleles with antibody levels were investigated. All antibody levels presented significant increasing trends with periodontitis stage and grade. A. actinomycetemcomitans IgG displayed association with single nucleotide polymorphisms (SNPs) in chromosome 6 with lead SNP rs574581129 (near HLA-DRB1, P = 3.6 × 10−8) and P. gingivalis IgG in chromosome 14 with lead SNP rs146761521 (near NUBPL, 5.5 × 10−8). In addition, all antibody levels presented suggestive associations with several loci. Detailed HLA analyses revealed that A. actinomycetemcomitans IgG was associated with DQA1*01:01, DQB1*05:01, and DRB1*01:01 and P. gingivalis IgG with HLA-A*02:01 alleles. Both IgA and IgG antibody levels against microbial biomarker species of periodontitis increase with periodontitis stage and grade, but genetic variation is also a significant predictor. Specific alleles within the HLA region may influence antibody responses to A. actinomycetemcomitans and P. gingivalis, highlighting potential genetic contributions to the immunological mechanisms underlying periodontitis.
BehleJHSedaghatfarMGDemmerRTWolfDLCelentiRKebschullMBeluskoPBHerrera-AbreuMLallaEPapapanouPN.2009. Heterogeneity of systemic inflammatory responses to periodontal therapy. J Clin Periodontol. 36(4):287–294. https://doi.org/10.1111/j.1600-051x.2009.01382.x
2.
BuhlinKHolmerJGustafssonAHörkköSPockleyAGJohanssonAPajuSKlingeBPussinenPJ. 2015. Association of periodontitis with persistent, pro-atherogenic antibody responses. J Clin Periodontol. 42(11):1006–1014. https://doi.org/10.1111/jcpe.12456
3.
BullonPNewmanHNBattinoM.2014. Obesity, diabetes mellitus, atherosclerosis and chronic periodontitis: a shared pathology via oxidative stress and mitochondrial dysfunction? Periodontol 2000. 64(1):139–153. https://doi.org/10.1111/j.1600-0757.2012.00455.x
4.
ChoiJ-IChungS-WKangH-SRhimB-YParkY-MLimU-SKimS-J.2004. Epitope mapping of Porphyromonas gingivalis heat-shock protein and human heat-shock protein in human atherosclerosis. J Dent Res. 83(12):936–940. https://doi.org/10.1177/154405910408301209
5.
DahlénGLuanW-MDahlgrenUPapapanouPPBaelumVFejerskovO.2016. Subgingival bacterial clusters and serum antibody response as markers of extent and severity of periodontitis in adult Chinese. Eur J Oral Sci. 124(2):179–187. https://doi.org/10.1111/eos.12256
6.
DyeBAChoudharyKSheaSPapapanouPN.2005. Serum antibodies to periodontal pathogens and markers of systemic inflammation. J Clin Periodontol. 32(12):1189–1199. https://doi.org/10.1111/j.1600-051x.2005.00856.x
7.
DyeBAHerrera-AbreuMLerche-SehmJVlachojannisCPikdokenLPretzlBSchwartzAPapapanouPN. 2009. Serum antibodies to periodontal bacteria as diagnostic markers of periodontitis. J Periodontol. 80(4):634–647. https://doi.org/10.1902/jop.2009.080474
8.
EbersoleJLCappelliDSteffenMJ.1992. Characteristics and utilization of antibody measurements in clinical studies of periodontal disease. J Periodontol. 63(suppl 12S):1110–1116. https://doi.org/10.1902/jop.1992.63.12s.1110
9.
EbersoleJLDawsonDAIIIHujaPEPandruvadaSBasuANguyenLZhangYGonzalezOA. 2018. Age and periodontal health - immunological view. Curr Oral Health Rep. 5(4):229–241. https://doi.org/10.1007/s40496-018-0202-2
10.
EsbergAHaworthSKuja-HalkolaRMagnussonPKEJohanssonI.2020. Heritability of oral microbiota and immune responses to oral bacteria. Microorganisms. 8(8):1126. https://doi.org/10.3390/microorganisms8081126
11.
HwangAMStoupelJCelentiRDemmerRTPapapanouPN. 2014. Serum antibody responses to periodontal microbiota in chronic and aggressive periodontitis: a postulate revisited. J Periodontol. 85(4):592–600. https://doi.org/10.1902/jop.2013.130172
12.
JaagoMPupinaNRähniAPihlakASadamHVranaNESinisaloJPussinenPPalmK.2022. Antibody response to oral biofilm is a biomarker for acute coronary syndrome in periodontal disease. Commun Biol. 5(1):205. https://doi.org/10.1038/s42003-022-03122-4
13.
JaziMMSolgiGAsl RoostaHNoshadSMoslemiNSadrimaneshRMoradiB, 2013. HLA-DRB and HLA-DQA/HLA-DQB allele and haplotype frequencies in Iranian patients with aggressive periodontitis. J Periodontal Res. 48(4):533–539. https://doi.org/10.1111/jre.12043
14.
JoshiCBapatRAndersonWDawsonDCherukaraGHijaziK.2021. Serum antibody response against periodontal bacteria and coronary heart disease: systematic review and meta-analysis. J Clin Periodontol. 48(12):1570–1586. https://doi.org/10.1111/jcpe.13550
15.
KaidesojaMAaltonenSBoglLHHeikkiläKKaartinenSKujalaUMKärkkäinenUMasipGMustelinLPalviainenT, et al. 2019. FinnTwin16: a longitudinal study from age 16 of a population-based Finnish twin cohort. Twin Res Hum Genet. 22(6):530–539. https://doi.org/10.1017/thg.2019.106
16.
KallioKAMarchesaniMVlachopoulouEMäntyläPPajuSBuhlinKSuominenALContrerasJKnuuttilaMHernandezM, et al. 2014. Genetic variation on the BAT1-NFKBIL1-LTA region of major histocompatibility complex class III associates with periodontitis. Infect Immun. 82(5):1939–1948. https://doi.org/10.1128/iai.01681-13
17.
KevelamSHRodenburgRJWolfNIFerreiraPLunsingRJNijtmansLGMitchellAArroyoHARatingDVanderverAvan BerkelCGM, et al. 2013. NUBPL mutations in patients with complex I deficiency and a distinct MRI pattern. Neurology. 80(17):1577–1583. https://doi.org/10.1212/wnl.0b013e31828f1914
18.
KönönenEPajuSPussinenPJHyvönenMDi TellaPSuominen-TaipaleLKnuuttilaM.2007. Population-based study of salivary carriage of periodontal pathogens in adults. J Clin Microbiol. 45(8):2446–2451.
19.
LakioLAntinheimoJPajuSBuhlinKPussinenPJAlfthanG.2009. Tracking of plasma antibodies against Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis during 15 years. J Oral Microbiol. 1(1):1979. https://doi.org/10.3402/jom.v1i0.1979
ManzoorMLeskeläJPietiäinenMMartinez-MajanderNYlikotilaPKönönenENiiranenTLahtiLSinisaloJPutaalaJ, et al. 2024. Multikingdom oral microbiome interactions in early-onset cryptogenic ischemic stroke. ISME Commun. 4(1):ycae088. https://doi.org/10.1093/ismeco/ycae088
22.
NishimuraNSasakiT.2009. Rab family small G proteins in regulation of epithelial apical junctions. Front Biosci (Landmark Ed). 14(6):2115–2129. https://doi.org/10.2741/3366
23.
OhyamaHTakashibaSOyaizuKNagaiANaruseTInokoHKuriharaHMurayamaY.1996. HLA Class II genotypes associated with early-onset periodontitis: DQB1 molecule primarily confers susceptibility to the disease. J Periodontol. 67(9):888–894.
24.
PalmFPussinenPJAignerABecherHBuggleFBauerMFGrond-GinsbachCSaferAUrbanekCGrauAJ.2016. Association between infectious burden, socioeconomic status, and ischemic stroke. Atherosclerosis. 254:117–123. https://doi.org/10.1016/j.atherosclerosis.2016.10.008
25.
PapapanouPNNeiderudAMPapadimitriouASandrosJDahlénG.2000. “Checkerboard” assessments of periodontal microbiota and serum antibody responses: a case-control study. J Periodontol. 71(6):885–897. https://doi.org/10.1902/jop.2000.71.6.885
26.
PietiäinenMLiljestrandJMKopraEPussinenPJ. 2018. Mediators between oral dysbiosis and cardiovascular diseases. Eur J Oral Sci. 126(suppl 1):26–36. https://doi.org/10.1111/eos.12423
27.
PussinenPJKönönenEPajuSHyvärinenKGursoyUKHuumonenSKnuuttilaMSuominenAL.2011. Periodontal pathogen carriage, rather than periodontitis, determines the serum antibody levels. J Clin Periodontol. 38(5):405–411. https://doi.org/10.1111/j.1600-051x.2011.01703.x
28.
PussinenPJNyyssönenKAlfthanGSalonenRLaukkanenJASalonenJT., et al. 2005. Serum antibody levels to Actinobacillus actinomycetemcomitans predict the risk for coronary heart disease. Arterioscler Thromb Vasc Biol. 25(4):833–838. https://doi.org/10.1161/01.atv.0000157982.69663.59
29.
PussinenPJPussinenPJAignerABecherHBuggleFBauerMFGrond-GinsbachCSaferAUrbanekCGrauAJ. 2003. Antibodies to periodontal pathogens are associated with coronary heart disease. Arterioscler Thromb Vasc Biol. 23(7):1250–1254. https://doi.org/10.1161/01.atv.0000072969.71452.87
30.
RitariJHyvärinenKClancy JFinnGenPartanenJKoskelaS.2020. Increasing accuracy of HLA imputation by a population-specific reference panel in a FinnGen biobank cohort. NAR Genom Bioinform. 2(2):lqaa030. https://doi.org/10.1093/nargab/lqaa030
31.
SalminenAHyvärinenKRitariJCaetanoAKamburOMäntyläPYilmazMSinisalo JFinnGenPerolaMHavulinnaA, et al. 2025. Genetic loci associated with periodontitis: the FinnGen study based on national health registers. J Clin Periodontol. 52(9):1263–1275. https://doi.org/10.1111/jcpe.14193
32.
ShaddoxLMMorfordLANibaliL.2021. Periodontal health and disease: the contribution of genetics. Periodontol2000. 85(1):161–181. https://doi.org/10.1111/prd.12357
SinghSPHuckOAbrahamNGAmarS.2018. Kavain reduces Porphyromonas gingivalis-induced adipocyte inflammation: role of PGC-1α signaling. J Immunol. 201(5):1491–1499. https://doi.org/10.4049/jimmunol.1800321
35.
TakashibaSOhyamaHOyaizuKKogoe-KatoNMurayamaY.1999. HLA genetics for diagnosis of susceptibility to early-onset periodontitis. J Periodontal Res. 34(7):374–378. https://doi.org/10.1111/j.1600-0765.1999.tb02269.x
36.
TonettiMSGreenwellHKornmanKS. 2018. Staging and grading of periodontitis: framework and proposal of a new classification and case definition. J Clin Periodontol. 45(suppl 20):S149–S161. https://doi.org/10.1111/jcpe.12945
TurunenSPKummuOHarilaKVeneskoskiMSoliymaniRBaumannMPussinenPJHörkköS.2012. Recognition of Porphyromonas gingivalis gingipain epitopes by natural IgM binding to malondialdehyde modified low-density lipoprotein. PLoS One. 7(4):e34910. https://doi.org/10.1371/journal.pone.0034910
39.
VlachojannisCDyeBAHerrera-AbreuMPikdökenLLerche-SehmJPretzlBCelentiRPapapanouPN.2010. Determinants of serum IgG responses to periodontal bacteria in a nationally representative sample of US adults. J Clin Periodontol. 37(8):685–696. https://doi.org/10.1111/j.1600-051x.2010.01592.x
40.
XuTDongQLuoYLiuYGaoLPanYZhangD.2021. Porphyromonas gingivalis infection promotes mitochondrial dysfunction through Drp1-dependent mitochondrial fission in endothelial cells. Int J Oral Sci. 13(1):28. https://doi.org/10.1038/s41368-021-00134-4
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