Mixed evidence for the relationship between periodontitis and Alzheimer’s disease: A bidirectional Mendelian randomization study


Autoři: Yi-Qian Sun aff001;  Rebecca C. Richmond aff003;  Yue Chen aff004;  Xiao-Mei Mai aff005
Působiště autorů: Center for Oral Health Services and Research Mid-Norway (TkMidt), Trondheim, Norway aff001;  Department of Clinical and Molecular Medicine (IKOM), NTNU—Norwegian University of Science and Technology, Trondheim, Norway aff002;  School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom aff003;  School of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa, Ottawa, Canada aff004;  Department of Public Health and Nursing, NTNU—Norwegian University of Science and Technology, Trondheim, Norway aff005
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
doi: 10.1371/journal.pone.0228206

Souhrn

Recent experimental studies indicated that a periodontitis-causing bacterium might be a causal factor for Alzheimer’s disease (AD). We applied a two-sample Mendelian randomization (MR) approach to examine the potential causal relationship between chronic periodontitis and AD bidirectionally in the population of European ancestry. We used publicly available data of genome-wide association studies (GWAS) on periodontitis and AD. Five single-nucleotide polymorphisms (SNPs) were used as instrumental variables for periodontitis. For the MR analysis of periodontitis on risk of AD, the causal odds ratio (OR) and 95% confidence interval (CI) were derived from the GWAS of periodontitis (4,924 cases vs. 7,301 controls) and from the GWAS of AD (21,982 cases vs. 41,944 controls). Seven non-overlapping SNPs from another latest GWAS of periodontitis was used to validate the above association. Twenty SNPs were used as instrumental variables for AD. For the MR analysis of liability to AD on risk of periodontitis, the causal OR was derived from the GWAS of AD including 30,344 cases and 52,427 controls and from the GWAS of periodontitis consisted of 12,289 cases and 22,326 controls. We employed multiple methods of MR. Using the five SNPs as instruments of periodontitis, there was suggestive evidence of genetically predicted periodontitis being associated with a higher risk of AD (OR 1.10, 95% CI 1.02 to 1.19, P = 0.02). However, this association was not verified using the seven independent SNPs (OR 0.97, 95% CI 0.87 to 1.08, P = 0.59). There was no association of genetically predicted AD with the risk of periodontitis (OR 1.00, 95% CI 0.96 to 1.04, P = 0.85). In summary, we did not find convincing evidence to support periodontitis being a causal factor for the development of AD. There was also limited evidence to suggest genetic liability to AD being associated with the risk of periodontitis.

Klíčová slova:

Alzheimer's disease – Cognitive impairment – Europe – Genetics of disease – Genome-wide association studies – Instrumental variable analysis – Molecular genetics – Periodontitis


Zdroje

1. Jansen IE, Savage JE, Watanabe K, Bryois J, Williams DM, Steinberg S, et al. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk. Nat Genet. 2019;51(3):404–13. Epub 2019/01/09. doi: 10.1038/s41588-018-0311-9 30617256.

2. Kunkle BW, Grenier-Boley B, Sims R, Bis JC, Damotte V, Naj AC, et al. Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Abeta, tau, immunity and lipid processing. Nat Genet. 2019;51(3):414–30. Epub 2019/03/02. doi: 10.1038/s41588-019-0358-2 30820047.

3. Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet. 2013;45(12):1452–8. Epub 2013/10/29. doi: 10.1038/ng.2802 24162737; PubMed Central PMCID: PMC3896259.

4. Larsson SC, Traylor M, Malik R, Dichgans M, Burgess S, Markus HS. Modifiable pathways in Alzheimer's disease: Mendelian randomisation analysis. BMJ (Clinical research ed). 2017;359:j5375. Epub 2017/12/08. doi: 10.1136/bmj.j5375 29212772; PubMed Central PMCID: PMC5717765 at www.icmje.org/coi_disclosure.pdf and declare: no financial relationships with any organisation that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

5. Zhu Z, Zheng Z, Zhang F, Wu Y, Trzaskowski M, Maier R, et al. Causal associations between risk factors and common diseases inferred from GWAS summary data. Nature communications. 2018;9(1):224. Epub 2018/01/18. doi: 10.1038/s41467-017-02317-2 29335400; PubMed Central PMCID: PMC5768719.

6. Mokry LE, Ross S, Morris JA, Manousaki D, Forgetta V, Richards JB. Genetically decreased vitamin D and risk of Alzheimer disease. Neurology. 2016;87(24):2567–74. Epub 2016/11/20. doi: 10.1212/WNL.0000000000003430 27856775; PubMed Central PMCID: PMC5207000.

7. Dominy SS, Lynch C, Ermini F, Benedyk M, Marczyk A, Konradi A, et al. Porphyromonas gingivalis in Alzheimer's disease brains: Evidence for disease causation and treatment with small-molecule inhibitors. Science advances. 2019;5(1):eaau3333. Epub 2019/02/13. doi: 10.1126/sciadv.aau3333 30746447; PubMed Central PMCID: PMC6357742.

8. Ilievski V, Zuchowska PK, Green SJ, Toth PT, Ragozzino ME, Le K, et al. Chronic oral application of a periodontal pathogen results in brain inflammation, neurodegeneration and amyloid beta production in wild type mice. PLoS One. 2018;13(10):e0204941. Epub 2018/10/04. doi: 10.1371/journal.pone.0204941 30281647; PubMed Central PMCID: PMC6169940.

9. Noble JM, Borrell LN, Papapanou PN, Elkind MS, Scarmeas N, Wright CB. Periodontitis is associated with cognitive impairment among older adults: analysis of NHANES-III. J Neurol Neurosurg Psychiatry. 2009;80(11):1206–11. Epub 2009/05/08. doi: 10.1136/jnnp.2009.174029 19419981; PubMed Central PMCID: PMC3073380.

10. Davey Smith G, Hemani G. Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum Mol Genet. 2014;23(R1):R89–98. Epub 2014/07/30. doi: 10.1093/hmg/ddu328 25064373; PubMed Central PMCID: PMC4170722.

11. Davies NM, Holmes MV, Davey Smith G. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ (Clinical research ed). 2018;362:k601. Epub 2018/07/14. doi: 10.1136/bmj.k601 30002074; PubMed Central PMCID: PMC6041728 interests and declare that we have no competing interests.

12. Munz M, Richter GM, Loos BG, Jepsen S, Divaris K, Offenbacher S, et al. Meta-analysis of genome-wide association studies of aggressive and chronic periodontitis identifies two novel risk loci. Eur J Hum Genet. 2019;27(1):102–13. Epub 2018/09/16. doi: 10.1038/s41431-018-0265-5 30218097; PubMed Central PMCID: PMC6303247.

13. Shungin D, Haworth S, Divaris K, Agler CS, Kamatani Y, Keun Lee M, et al. Genome-wide analysis of dental caries and periodontitis combining clinical and self-reported data. Nature communications. 2019;10(1):2773. Epub 2019/06/27. doi: 10.1038/s41467-019-10630-1 31235808; PubMed Central PMCID: PMC6591304.

14. Verbanck M, Chen CY, Neale B, Do R. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet. 2018;50(5):693–8. Epub 2018/04/25. doi: 10.1038/s41588-018-0099-7 29686387; PubMed Central PMCID: PMC6083837.

15. Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol. 2013;37(7):658–65. Epub 2013/10/12. doi: 10.1002/gepi.21758 24114802; PubMed Central PMCID: PMC4377079.

16. Bowden J, Davey Smith G, Haycock PC, Burgess S. Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator. Genet Epidemiol. 2016;40(4):304–14. Epub 2016/04/12. doi: 10.1002/gepi.21965 27061298; PubMed Central PMCID: PMC4849733.

17. Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. International journal of epidemiology. 2015;44(2):512–25. Epub 2015/06/08. doi: 10.1093/ije/dyv080 26050253; PubMed Central PMCID: PMC4469799.

18. Zhao Q, Wang J, Hemani G, Bowden J, Small DS. Statistical inference in two-sample summary-data Mendelian randomization using robust adjusted profile score. https://arxivorg/abs/180109652 2019.

19. Burgess S, Labrecque JA. Mendelian randomization with a binary exposure variable: interpretation and presentation of causal estimates. Eur J Epidemiol. 2018;33(10):947–52. Epub 2018/07/25. doi: 10.1007/s10654-018-0424-6 30039250; PubMed Central PMCID: PMC6153517.

20. Ide M, Harris M, Stevens A, Sussams R, Hopkins V, Culliford D, et al. Periodontitis and Cognitive Decline in Alzheimer's Disease. PLoS One. 2016;11(3):e0151081. Epub 2016/03/11. doi: 10.1371/journal.pone.0151081 26963387; PubMed Central PMCID: PMC4786266.

21. Kinane DF, Stathopoulou PG, Papapanou PN. Periodontal diseases. Nat Rev Dis Primers. 2017;3:17038–. doi: 10.1038/nrdp.2017.38 28805207.

22. Divaris K, Monda KL, North KE, Olshan AF, Reynolds LM, Hsueh WC, et al. Exploring the genetic basis of chronic periodontitis: a genome-wide association study. Hum Mol Genet. 2013;22(11):2312–24. Epub 2013/03/06. doi: 10.1093/hmg/ddt065 23459936; PubMed Central PMCID: PMC3652417.

23. Schaefer AS, Richter GM, Nothnagel M, Manke T, Dommisch H, Jacobs G, et al. A genome-wide association study identifies GLT6D1 as a susceptibility locus for periodontitis. Hum Mol Genet. 2010;19(3):553–62. Epub 2009/11/06. doi: 10.1093/hmg/ddp508 19897590.

24. G Caton J, Armitage G, Berglundh T, Chapple ILC, Jepsen S, S Kornman K, et al. A new classification scheme for periodontal and peri-implant diseases and conditions—Introduction and key changes from the 1999 classification. J Clin Periodontol. 2018;45 Suppl 20:S1–S8. doi: 10.1111/jcpe.12935 29926489.


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2020 Číslo 1