Abstract
Objective
Cytokines that mediate the immune responses are important in the pathogenesis of periodontitis. The genetic polymorphisms of IL-10, TNFAIP3 (A20), and NF-κB1 (p105/p50) and their association with the risk of periodontitis were investigated.
Method
Venous blood from 102 clinical periodontal healthy participants and 100 patients with periodontitis was collected to genotype the IL-10 (rs1800872), A20 (rs2230926, rs5029937, rs6927127), and NF-κB1 (rs28362491) SNP loci by Sanger technology. Univariable and multivariable logic regression and path analysis model was used to analyze the genotypes and alleles.
Result
Single-gene mutations in the A20 (rs2230926, rs5029937, rs6927127) and IL-10 (rs1800872) genes were not associated with the risk of periodontitis. NF-κΒ1 (rs28362491) gene influenced periodontitis susceptibility by affecting CAL. The combined effect of A20 and IL-10 was related to the risk of periodontitis (ORa = 0.123-0.151). One site mutated in the A20 (rs2230926, rs5029937, rs6927127) gene or IL-10 (rs1800872) gene reduced the risk of periodontitis.
Conclusion
Single gene polymorphisms in A20 and IL-10 genes were not associated with the risk of periodontitis. NF-κB1 gene polymorphism indirectly affects susceptibility to periodontitis. The combined effect of anti-inflammatory gene polymorphisms (A20 and IL-10) correlated with the decreased risk of periodontitis.
Clinical Relevance
This study helps to explore the potential mechanisms underlying the role of anti-inflammatory genes in the progression of periodontal disease and provides a basis for the selection and development of appropriate periodontal treatment strategies based on the genetic profile of the patient.
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Data Availability
The original data presented in the study are included in the article. Further inquiries should be directed to the corresponding authors upon reasonable request.
References
Darveau RP, Curtis MA (2021) Oral biofilms revisited: A novel host tissue of bacteriological origin. Periodontology 2000(86):8–13. https://doi.org/10.1111/prd.12374
Hao T, Zhang R, Zhao T, Wu J, Leung WK, Yang J, Sun W (2022) Porphyromonas gingivalis infection promotes inflammation via inhibition of the AhR signalling pathway in periodontitis. Cell Prolif:e13364. https://doi.org/10.1111/cpr.13364
Loos BG, Van Dyke TE (2020) The role of inflammation and genetics in periodontal disease. Periodontology 2000(83):26–39. https://doi.org/10.1111/prd.12297
Naqvi RA, Gupta M, George A, Naqvi AR (2022) MicroRNAs in sha** the resolution phase of inflammation. Semin Cell Dev Biol 124:48–62. https://doi.org/10.1016/j.semcdb.2021.03.019
Li C, Li B, Dong Z, Gao L, He X, Liao L, Hu C, Wang Q, ** Y (2014) Lipopolysaccharide differentially affects the osteogenic differentiation of periodontal ligament stem cells and bone marrow mesenchymal stem cells through Toll-like receptor 4 mediated nuclear factor κB pathway. Stem Cell Res Ther 5:67. https://doi.org/10.1186/scrt456
Mooney EC, Sahingur SE (2021) The Ubiquitin System and A20: Implications in Health and Disease. J Dent Res 100:10–20. https://doi.org/10.1177/0022034520949486
Han Y, Huang Y, Yang Q, Jia L, Zheng Y, Li W (2022) Long non-coding RNA SNHG5 mediates periodontal inflammation through the NF-κB signalling pathway. J Clin Periodontol 49:1038–1051. https://doi.org/10.1111/jcpe.13684
Cartwright T, Perkins ND, CLW (2016) NFKB1: a suppressor of inflammation, ageing and cancer. FEBS J 283:1812–1822. https://doi.org/10.1111/febs.13627
Martens A, van Loo G (2020) A20 at the Crossroads of Cell Death, Inflammation, and Autoimmunity. Cold Spring Harb Perspect Biol 12. https://doi.org/10.1101/cshperspect.a036418
Crump KE, Oakley JC, **a-Juan X, Madu TC, Devaki S, Mooney EC, Sahingur SE (2017) Interplay of Toll-Like Receptor 9, Myeloid Cells, and Deubiquitinase A20 in Periodontal Inflammation. Infect Immun 85. https://doi.org/10.1128/iai.00814-16
Fu YW, Xu HZ (2021) Expression of deubiquitinases in human gingiva and cultured human gingival fibroblasts. BMC Oral Health 21:290. https://doi.org/10.1186/s12903-021-01655-4
Zhang R, Wu Z, Li M, Yang J, Cheng R, Hu T (2022) Canonical and noncanonical pyroptosis are both activated in periodontal inflammation and bone resorption. J Periodontal Res 57:1183–1197. https://doi.org/10.1111/jre.13055
Li Y, Mooney EC, Holden SE, **a XJ, Cohen DJ, Walsh SW, Ma A, Sahingur SE (2019) A20 Orchestrates Inflammatory Response in the Oral Mucosa through Restraining NF-κB Activity. J Immunol(Baltimore, Md : 1950) 202:2044–2056. https://doi.org/10.4049/jimmunol.1801286
Li Y, Mooney EC, **a XJ, Gupta N, Sahingur SE (2020) A20 Restricts Inflammatory Response and Desensitizes Gingival Keratinocytes to Apoptosis. Front Immunol 11:365. https://doi.org/10.3389/fimmu.2020.00365
Hamidullah CB, Konwar R (2012) Role of interleukin-10 in breast cancer. Breast Cancer Res Treat 133:11–21. https://doi.org/10.1007/s10549-011-1855-x
Liu Y, Yang J, Sun W (2020) Upregulation of IL-10 expression inhibits the proliferation of human periodontal ligament stem cells. Braz Oral Res 34:e030. https://doi.org/10.1590/1807-3107bor-2020.vol34.0030
Chen M, Lin X, Zhang L, Hu X (2022) Effects of nuclear factor-κB signaling pathway on periodontal ligament stem cells under lipopolysaccharide-induced inflammation. Bioengineered 13:7951–7961. https://doi.org/10.1080/21655979.2022.2051690
Brodzikowska A, Górski B (2022) Polymorphisms in Genes Involved in Inflammation and Periodontitis. Narrative Rev Biomol:12. https://doi.org/10.3390/biom12040552
Cheng R, Wu Z, Li M, Shao M, Hu T (2020) Interleukin-1β is a potential therapeutic target for periodontitis: a narrative review. Int J Oral Sci 12:2. https://doi.org/10.1038/s41368-019-0068-8
Yang SL, Huang SJ (2019) Interleukin-10 polymorphisms (rs1800871, rs1800872 and rs1800896) and periodontitis risk: A meta-analysis. Arch Oral Biol 97:59–66. https://doi.org/10.1016/j.archoralbio.2018.10.012
Schulz S, Hierse L, Altermann W, Klapproth J, Zimmermann U, Reichert Y, Gläser C, Kluttig A, Stein JM, Schaller HG, Reichert S (2010) The del/del genotype of the nuclear factor-kappaB -94ATTG polymorphism and its relation to aggressive periodontitis. J Periodontal Res 45:396–403. https://doi.org/10.1111/j.1600-0765.2009.01251.x
Ma A, Malynn BA (2012) A20: linking a complex regulator of ubiquitylation to immunity and human disease. Nat Rev Immunol 12:774–785. https://doi.org/10.1038/nri3313
Zhu L, Wang L, Wang X, Zhou L, Liao Z, Xu L, Wu H, Ren J, Li Z, Yang L, Chen S, Li B, Wu X, Zhou Y, Li Y (2015) Characteristics of A20 gene polymorphisms and clinical significance in patients with rheumatoid arthritis. J Transl Med 13:215. https://doi.org/10.1186/s12967-015-0566-1
Elsby LM, Orozco G, Denton J, Worthington J, Ray DW, Donn RP (2010) Functional evaluation of TNFAIP3 (A20) in rheumatoid arthritis. Clin Exp Rheumatol 28:708–714
Hajishengallis G, Chavakis T (2021) Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities. Nat Rev Immunol 21:426–440. https://doi.org/10.1038/s41577-020-00488-6
Papapanou PN, Sanz M, Buduneli N, Dietrich T, Feres M, Fine DH, Flemmig TF, Garcia R, Giannobile WV, Graziani F, Greenwell H, Herrera D, Kao RT, Kebschull M, Kinane DF, Kirkwood KL, Kocher T, Kornman KS, Kumar PS et al (2018) Periodontitis: Consensus report of workgroup 2 of the 2017 World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions. J Clin Periodontol 45(Suppl 20):S162–s170. https://doi.org/10.1111/jcpe.12946
Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215. https://doi.org/10.1093/nar/16.3.1215
Laine ML, Crielaard W and Loos BG (2012) Genetic susceptibility to periodontitis. Periodontology 58:37–68. https://doi.org/10.1111/j.1600-0757.2011.00415.x
Martens A, Hertens P, Priem D, Rinotas V, Meletakos T, Gennadi M, Van Hove L, Louagie E, Coudenys J, De Muynck A, Gaublomme D, Sze M, van Hengel J, Catrysse L, Hoste E, Zajac JD, Davey RA, Van Hoorebeke L, Hochepied T et al (2022) A20 controls RANK-dependent osteoclast formation and bone physiology. EMBO Rep 23:e55233. https://doi.org/10.15252/embr.202255233
Okada Y, Eyre S, Suzuki A, Kochi Y, Yamamoto K (2019) Genetics of rheumatoid arthritis: 2018 status. Ann Rheum Dis 78:446–453. https://doi.org/10.1136/annrheumdis-2018-213678
Zhang S, Yu N, Arce RM (2020) Periodontal inflammation: Integrating genes and dysbiosis. Periodontology 82:129–142. https://doi.org/10.1111/prd.12267
Elkhawaga SY, Gomaa MH, Elsayed MM, Ebeed AA (2021) NFKB1 promoter -94 insertion/deletion ATTG polymorphism (rs28362491) is associated with severity and disease progression of rheumatoid arthritis through interleukin-6 levels modulation in Egyptian patients. Clin Rheumatol 40:2927–2937. https://doi.org/10.1007/s10067-021-05584-z
Gautam A, Gupta S, Mehndiratta M, Sharma M, Singh K, Kalra OP, Agarwal S, Gambhir JK (2017) Association of NFKB1 gene polymorphism (rs28362491) with levels of inflammatory biomarkers and susceptibility to diabetic nephropathy in Asian Indians. World J Diabetes 8:66–73. https://doi.org/10.4239/wjd.v8.i2.66
Zhou B, Qie M, Wang Y, Yan L, Zhang Z, Liang A, Wang T, Wang X, Song Y, Zhang L (2010) Relationship between NFKB1 -94 insertion/deletion ATTG polymorphism and susceptibility of cervical squamous cell carcinoma risk. Ann Oncol : official J Eur Soc Med Oncol 21:506–511. https://doi.org/10.1093/annonc/mdp507
Luo JY, Liu F, Fang BB, Tian T, Li YH, Zhang T, Li XM, Yang YN (2022) NFKB1 Gene Mutant Was Associated with Prognosis of Coronary Artery Disease and Exacerbated Endothelial Mitochondrial Fission and Dysfunction. Oxidative Med Cell Longev 2022:9494926. https://doi.org/10.1155/2022/9494926
Schulz S, Zielske M, Schneider S, Hofmann B, Schaller HG, Schlitt A, Reichert S (2021) Polymorphism of CD14 Gene Is Associated with Adverse Outcome among Patients Suffering from Cardiovascular Disease. Mediat Inflamm 2021:3002439. https://doi.org/10.1155/2021/3002439
Carvalho BAS, Duarte CAB, Silva JF, Batista W, Douglas-de-Oliveira DW, de Oliveira ES, Soares LG, Galvão EL, Rocha-Gomes G, Glória JCR, Gonçalves PF, Flecha OD (2020) Clinical and radiographic evaluation of the Periodontium with biologic width invasion. BMC Oral Health 20:116. https://doi.org/10.1186/s12903-020-01101-x
Eke PI, Dye BA, Wei L, Thornton-Evans GO, Genco RJ (2012) Prevalence of periodontitis in adults in the United States: 2009 and 2010. J Dent Res 91:914–920. https://doi.org/10.1177/0022034512457373
Kurushima Y, Wells PM, Bowyer RCE, Zoheir N, Doran S, Richardson JP, Sprockett DD, Relman DA, Steves CJ, Nibali L (2022) Host Genotype Links to Salivary and Gut Microbiota by Periodontal Status. J Dental Res:220345221125402. https://doi.org/10.1177/00220345221125402
Wang Z, Li Y, Zhou Y, Qiao Y (2019) Association between the IL-10 rs1800872 polymorphisms and periodontitis susceptibility: A meta-analysis. Medicine 98:e17113. https://doi.org/10.1097/md.0000000000017113
Chatzopoulos G, Doufexi AE, Wolff L, Kouvatsi A (2018) Interleukin-6 and interleukin-10 gene polymorphisms and the risk of further periodontal disease progression. Braz Oral Res 32:e11. https://doi.org/10.1590/1807-3107bor-2018.vol32.0011
Jamshidy L, Tadakamadla SK, Choubsaz P, Sadeghi M, Tadakamadla J (2021) Association of IL-10 and TNF-α Polymorphisms with Dental Peri-Implant Disease Risk: A Meta-Analysis, Meta-Regression, and Trial Sequential Analysis. Int J Environ Res Public Health 18. https://doi.org/10.3390/ijerph18147697
Pereira APL, Trugilo KP, Okuyama NCM, Sena MM, Couto-Filho JD, Watanabe MAE, de Oliveira KB (2020) IL-10 c.-592C>A (rs1800872) polymorphism is associated with cervical cancer. J Cancer Res Clin Oncol 146:1971–1978. https://doi.org/10.1007/s00432-020-03256-0
Helaoui A, Sfar S, Boudhiba N, Dehghanian F, Dehbashi M, Bouchahda H, Hojati Z, Kenani A (2023) Association of xenobiotic-metabolizing genes polymorphisms with cervical cancer risk in the Tunisian population. Mol Biol Rep 50:949–959. https://doi.org/10.1007/s11033-022-07945-6
Liu X, Li YI, Pritchard JK (2019) Trans Effects on Gene Expression Can Drive Omnigenic Inheritance. Cell 177:1022–1034.e6. https://doi.org/10.1016/j.cell.2019.04.014
Funding
This research was supported by the West China Hospital of Stomatology, the National Natural Science Foundation of China (Grant number 81970948 and 72104162), and the Natural Science Foundation of Sichuan Province (Grant No. 2020YFS0178).
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All authors contributed to the study conception and design. Mingming Li prepared the manuscript and collected data. Yuhan Zhang prepared the manuscript, applied the statistical analysis and sample size calculation. Aopeng Zhang prepared the manuscript and organised tables. Rui Zhang contributed to the ethical procedures and patient screening. He Cai revised the manuscript. Ran Cheng and Tao Hu designed the study, edited and revised the manuscript. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
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This study was approved by the Ethics Committee of West China Hospital of Stomatology, Sichuan University (WCHSIRB-D-2019-227). This trial was retrospectively registered in the Chinese Clinical Trial Registry (ChiCTR, Registration number: ChiCTR2200058699). All patients signed an informed consent that their dental and medical history can be used anonymously for research.
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Li, M., Zhang, Y., Zhang, A. et al. Association between polymorphisms of anti-inflammatory gene alleles and periodontitis risk in a Chinese Han population. Clin Oral Invest 27, 6689–6700 (2023). https://doi.org/10.1007/s00784-023-05278-7
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DOI: https://doi.org/10.1007/s00784-023-05278-7