Angiogenesis, Inflammation & Therapeutics | Online ISSN  2207-872X
REVIEWS   (Open Access)

Saliva as a Diagnostic Medium: Biomarker Identification, Genetic Analysis, and Disease Association

Usha Subbiah1*, Harini Venkata Subbiah1, Sumathi K2, Shenbaga Lalitha S2

+ Author Affiliations

Journal of Angiotherapy 5(2) 1-8 https://doi.org/10.25163/angiotherapy.52221522618181221

Submitted: 26 November 2021  Revised: 28 November 2021  Published: 18 December 2021 

Abstract

Background: Saliva, an exocrine secretion, plays a vital role in maintaining oral and systemic health through its diverse molecular composition, including proteins, nucleic acids, and hormones. As an easily accessible and non-invasive biological fluid, saliva has emerged as a promising tool for diagnostic purposes, offering a potential medium for biomarker identification in various diseases. Methods: This review synthesizes current research on the use of saliva as a diagnostic medium, focusing on its molecular composition, including DNA, RNA, proteins, and noncoding RNAs, and their applications in disease diagnosis. We explore the use of salivary biomarkers in the detection of oral and systemic diseases, such as oral squamous cell carcinoma (OSCC), diabetes mellitus, cardiovascular diseases, and genetic disorders. The review also discusses the role of genetic polymorphisms in salivary proteins and their association with disease risk, as well as the potential of saliva in detecting infectious diseases like COVID-19, dengue, and HIV. Results: Salivary biomarkers, including DNA, mRNA, noncoding RNAs, and proteins, have shown promise in diagnosing a range of diseases. Studies have identified specific salivary mRNAs, such as IL-6 and NGFI-A binding protein 2, as potential biomarkers for OSCC. Noncoding RNAs, including miRNAs and piRNAs, have been implicated in various malignancies and systemic diseases. Proteomic analyses of saliva have revealed disease-specific protein signatures, providing insights into conditions such as Sjögren's syndrome, graft-versus-host disease, and diabetes. Furthermore, genetic polymorphisms in salivary proteins have been associated with oral diseases, such as dental caries and periodontitis, as well as systemic conditions. Conclusion: Saliva represents a valuable and underutilized diagnostic medium with the potential to revolutionize disease detection and monitoring. The identification of salivary biomarkers and genetic polymorphisms linked to disease risk underscores the importance of saliva in personalized medicine. However, further research is needed to standardize saliva collection and processing methods to enhance its diagnostic accuracy and reliability. The integration of salivary diagnostics into clinical practice could significantly improve patient outcomes through early detection and personalized treatment strategies.

Keywords: Salivary biomarkers, Genetic analysis, Non-invasive diagnostics, Oral diseases, Systemic health

References

Adeola, H. A., Holmes, H., & Temilola, D. O. (2020). Diagnostic potential of salivary exosomes in oral cancer. In In Vitro Diagnostics. IntechOpen. https://doi.org/10.5772/intechopen.94192

Adhikari, R., & Soni, A. (2020). Submandibular sialadenitis and sialadenosis. In StatPearls [Internet].

Adriaanse, M. P., Vreugdenhil, A. C., Vastmans, V., Groeneveld, L., & Molenbroeck, S. (2016). HLA typing using buccal swabs as accurate and non-invasive substitute for venipuncture in children at risk for celiac disease. Journal of Gastroenterology and Hepatology. https://doi.org/10.1111/jgh.13331

Badea, V., Grigorian, M., Nuca, C., Amariei, C., Martinescu, A., & Voineagu, L. (2013). Study regarding the use of salivary 8-hydroxideoxyguanosine and interleukin-1 gene polymorphism-as potential biomarkers in the diagnosis of aggressive periodontitis. Revista Româna de Medicina de Laborator, 21(1), 75-82. https://doi.org/10.2478/rrlm-2013-0020

Bahn, J. H., Zhang, Q., Li, F., Chan, T.-M., Lin, X., Kim, Y., et al. (2015). The landscape of microRNA, Piwi-interacting RNA, and circular RNA in human saliva. Clinical Chemistry, 61(1), 221-230. https://doi.org/10.1373/clinchem.2014.230433

Balamane, M., Winters, M. A., Dalai, S. C., Freeman, A. H., Traves, M. W., Israelski, D. M., et al. (2010). Detection of HIV-1 in saliva: Implications for case-identification, clinical monitoring, and surveillance for drug resistance. Open Virology Journal, 4, 88. https://doi.org/10.2174/1874357901004010088

Banavar, S. R., & Vidya, G. S. (2014). Diagnostic efficacy of saliva for dengue-A reality in near future? A piloting initiative. Journal of Clinical and Diagnostic Research, 8(3), 229.

Bassim, C. W., Ambatipudi, K. S., Mays, J. W., Edwards, D. A., Swatkoski, S., Fassil, H., et al. (2012). Quantitative salivary proteomic differences in oral chronic graft-versus-host disease. Journal of Clinical Immunology, 32(6), 1390-1399. https://doi.org/10.1007/s10875-012-9738-4

Buzalaf, M. A. R., Ortiz, A. de C., Carvalho, T. S., Fideles, S. O. M., Araújo, T. T., & Moraes, S. M. (2020). Saliva as a diagnostic tool for dental caries, periodontal disease, and cancer: Is there a need for more biomarkers? Expert Review of Molecular Diagnostics, 20(5), 543-555. https://doi.org/10.1080/14737159.2020.1743686

Cabras, T., Pisano, E., Montaldo, C., Giuca, M. R., Iavarone, F., Zampino, G., et al. (2013). Significant modifications of the salivary proteome potentially associated with complications of Down syndrome revealed by top-down proteomics. Molecular & Cellular Proteomics, 12(7), 1844-1852. https://doi.org/10.1074/mcp.M112.026708

Caseiro, A., Ferreira, R., Padrão, A., Quintaneiro, C., Pereira, A., Marinheiro, R., et al. (2013). Salivary proteome and peptidome profiling in type 1 diabetes mellitus using a quantitative approach. Journal of Proteome Research, 12(4), 1700-1709. https://doi.org/10.1021/pr3010343

Castagnola, M., Scarano, E., Passali, G. C., Messana, I., Cabras, T., Iavarone, F., et al. (2017). Salivary biomarkers and proteomics: Future diagnostic and clinical utilities. Acta Otorhinolaryngologica Italica, 37(2), 94. https://doi.org/10.14639/0392-100X-1598

Czumbel, L. M., Kiss, S., Farkas, N., Mandel, I., Hegyi, A., Nagy, Á., et al. (2020). Saliva as a candidate for COVID-19 diagnostic testing: A meta-analysis. Frontiers in Medicine, 7, 465. https://doi.org/10.3389/fmed.2020.00465

de Souza, F. T. A., Kummer, A., Silva, M. L. V., Amaral, T. M. P., Abdo, E. N., Abreu, M. H. N. G., et al. (2015). The association of openness personality trait with stress-related salivary biomarkers in burning mouth syndrome. Neuroimmunomodulation, 22(4), 250-255. https://doi.org/10.1159/000367714

Dhanya, M., & Hegde, S. (2016). Salivary glucose as a diagnostic tool in type II diabetes mellitus: A case-control study. Nigerian Journal of Clinical Practice, 19(4), 486-490. https://doi.org/10.4103/1119-3077.183314

Dickinson, D. P. (2002). Salivary (SD-type) cystatins: Over one billion years in the making-but to what purpose? Critical Reviews in Oral Biology and Medicine, 13(6), 485-508. https://doi.org/10.1177/154411130201300606

Fliss, M. S., Usadel, H., Caballero, O. L., Wu, L., Buta, M. R., Eleff, S. M., et al. (2017). Facile detection of mitochondrial DNA mutations in tumors and bodily fluids. Science, 287(5460), 2017-2019. https://doi.org/10.1126/science.287.5460.2017

Griffin, T. J. (2015). The human saliva proteome: Overview and emerging methods for characterization. In Advances in Global Health through Sensing Technologies (Vol. 9490, p. 949003). International Society for Optics and Photonics. https://doi.org/10.1117/12.2183316

Hernández-Arenas, Y. Y., Támara-De Ávila, J. J., Isaza-Guzmán, D. M., González-Pérez, L. V., & Tobón-Arroyave, S. I. (2021). Relationship of the XRCC1 rs25487 polymorphism with demographic, behavioral, clinical, and histological parameters in oral potentially malignant disorders and oral squamous cell carcinoma in a Colombian population. Journal of Oral Biosciences, 63(2), 217-223. https://doi.org/10.1016/j.job.2021.02.006

Katsiougiannis, S., & Wong, D. T. W. (2016). The proteomics of saliva in Sjögren's syndrome. Rheumatic Disease Clinics of North America, 42(3), 449-456. https://doi.org/10.1016/j.rdc.2016.03.004

Khurshid, Z., Zafar, M. S., Khan, R. S., Najeeb, S., Slowey, P. D., & Rehman, I. U. (2018). Role of salivary biomarkers in oral cancer detection. Advances in Clinical Chemistry, 86, 23-70. https://doi.org/10.1016/bs.acc.2018.05.002

Kim, D., Moon, J., Shin, Y., Lee, S., Jung, K., Park, K., et al. (2020). Usefulness of saliva for perampanel therapeutic drug monitoring. Epilepsia, 61(6), 1120-1128. https://doi.org/10.1111/epi.16513

Küchler, E. C., Pecharki, G. D., Castro, M. L., Ramos, J., Barbosa Jr, F., Brancher, J. A., et al. (2017). Genes involved in enamel development are associated with calcium and phosphorus levels in saliva. Caries Research, 51(3), 225-230. https://doi.org/10.1159/000450764

Lima, D. P., Diniz, D. G., Moimaz, S. A. S., Sumida, D. H., & Okamoto, A. C. (2010). Saliva: Reflection of the body. International Journal of Infectious Diseases, 14(3), e184-e188. https://doi.org/10.1016/j.ijid.2009.04.022

Lin, X., Lo, H.-C., Wong, D. T. W., & Xiao, X. (2015). Noncoding RNAs in human saliva as potential disease biomarkers. Frontiers in Genetics, 6, 175. https://doi.org/10.3389/fgene.2015.00175

Lips, A., Antunes, L. S., Antunes, L. A., Pintor, A. V. B., Santos, D. A. B. dos, Bachinski, R., et al. (2017). Salivary protein polymorphisms and risk of dental caries: A systematic review. Brazilian Oral Research, 31. https://doi.org/10.1590/1807-3107bor-2017.vol31.0041

Majem, B., Rigau, M., Reventós, J., & Wong, D. T. (2015). Noncoding RNAs in saliva: Emerging biomarkers for molecular diagnostics. International Journal of Molecular Sciences, 16(4), 8676-8698. https://doi.org/10.3390/ijms16048676

Maron, J. L., Johnson, K. L., Rocke, D. M., Cohen, M. G., Liley, A. J., & Bianchi, D. W. (2010). Neonatal salivary analysis reveals global developmental gene expression changes in the premature infant. Clinical Chemistry, 56(3), 409-416. https://doi.org/10.1373/clinchem.2009.136234

Márton, I. J., Horváth, J., Lábiscsák, P., Márkus, B., Dezso, B., Szabó, A., et al. (2019). Salivary IL-6 mRNA is a robust biomarker in oral squamous cell carcinoma. Journal of Clinical Medicine, 8(11), 1958. https://doi.org/10.3390/jcm8111958

Matse, J. H., Yoshizawa, J., Wang, X., Elashoff, D., Bolscher, J. G. M., Veerman, E. C. I., et al. (2013). Discovery and prevalidation of salivary extracellular microRNA biomarkers panel for the noninvasive detection of benign and malignant parotid gland tumors. Clinical Cancer Research, 19(11), 3032-3038. https://doi.org/10.1158/1078-0432.CCR-12-3505

Nandakumar, A., Priyadharsini Nataraj, A. J., & Rajkumar Krishnan, M. K. M. (2020). Estimation of salivary 8-Hydroxydeoxyguanosine (8-OHdG) as a potential biomarker in assessing progression towards malignancy: A case-control study. Asian Pacific Journal of Cancer Prevention, 21(8), 2325. https://doi.org/10.31557/APJCP.2020.21.8.2325

Oh, S. Y., Kang, S.-M., Kang, S. H., Lee, H.-J., Kwon, T.-G., Kim, J.-W., et al. (2020). Potential salivary mRNA biomarkers for early detection of oral cancer. Journal of Clinical Medicine, 9(1), 243. https://doi.org/10.3390/jcm9010243

Özlem, K., & Yarat, A. (2020). Saliva as a diagnostic tool in oral diseases. Experimed, 10(3), 135-139. https://doi.org/10.26650/experimed.2020.0042

Pedersen, A. M. L., Sørensen, C. E., Proctor, G. B., Carpenter, G. H., & Ekström, J. (2018). Salivary secretion in health and disease. Journal of Oral Rehabilitation, 45(9), 730-746. https://doi.org/10.1111/joor.12664

Peres, R. C. R., Camargo, G., Mofatto, L. S., Cortellazzi, K. L., Santos, M., Santos, M. N., et al. (2010). Association of polymorphisms in the carbonic anhydrase 6 gene with salivary buffer capacity, dental plaque pH, and caries index in children aged 7-9 years. Pharmacogenomics Journal, 10(2), 114. https://doi.org/10.1038/tpj.2009.37

Rapado-González, Ó., Martínez-Reglero, C., Salgado-Barreira, Á., Takkouche, B., López-López, R., & Suárez-Cunqueiro, M. M., et al. (2020). Salivary biomarkers for cancer diagnosis: A meta-analysis. Annals of Medicine, 52(3-4), 131-144. https://doi.org/10.1080/07853890.2020.1730431

Salazar-Ruales, C., Arguello, J.-V., López-Cortés, A., Cabrera-Andrade, A., Garcia-Cardenas, J. M., Guevara-Ramirez, P., et al. (2018). Salivary microRNAs for early detection of head and neck squamous cell carcinoma: A case-control study in the high altitude mestizo Ecuadorian population. Biomed Research International. https://doi.org/10.1155/2018/9792730

Sanna, M., Firinu, D., Manconi, P. E., Pisanu, M., Murgia, G., Piras, V., et al. (2015). The salivary proteome profile in patients affected by SAPHO syndrome characterized by a top-down RP-HPLC-ESI-MS platform. Molecular BioSystems, 11(6), 1552-1562. https://doi.org/10.1039/C4MB00719K

Sivadasan, P., Gupta, M. K., Sathe, G. J., Balakrishnan, L., Palit, P., Gowda, H., et al. (2015). Human salivary proteome-a resource of potential biomarkers for oral cancer. Journal of Proteomics, 127, 89-95. https://doi.org/10.1016/j.jprot.2015.05.039

Streckfus, C., Bigler, L., Dellinger, T., Dai, X., Kingman, A., & Thigpen, J. T. (2000). The presence of soluble c-erbB-2 in saliva and serum among women with breast carcinoma: A preliminary study. Clinical Cancer Research, 6(6), 2363-2370.

Subbiah, H. V., Subbiah, U., & Ajith, A. (2021). Association of β-defensin 1 gene polymorphism and dental caries susceptibility in Tamil ethnicity. Research Journal of Pharmacy and Technology, 14(9), 4731-4735. https://doi.org/10.52711/0974-360X.2021.00823

van Veen, E. M., Brentnall, A. R., Byers, H., Harkness, E. F., Astley, S. M., Sampson, S., et al. (2018). Use of single-nucleotide polymorphisms and mammographic density plus classic risk factors for breast cancer risk prediction. JAMA Oncology, 4(4), 476-482. https://doi.org/10.1001/jamaoncol.2017.4881

Vandewoestyne, M., Van Hoofstat, D., Franssen, A., Van Nieuwerburgh, F., & Deforce, D. (2013). Presence and potential of cell-free DNA in different types of forensic samples. Forensic Science International: Genetics, 7(2), 316-320. https://doi.org/10.1016/j.fsigen.2012.12.006

Witsø, E., Stene, L. C., Paltiel, L., Joner, G., & Rønningen, K. S. (2002). DNA extraction and HLA genotyping using mailed mouth brushes from children. Pediatric Diabetes, 3(2), 89-94. https://doi.org/10.1034/j.1399-5448.2002.30205.x

Wong, D. T. W. (2015). Salivary extracellular noncoding RNA: Emerging biomarkers for molecular diagnostics. Clinical Therapeutics, 37(3), 540-551. https://doi.org/10.1016/j.clinthera.2015.02.017

Zahran F, Ghalwash D, Shaker O, Al-Johani K, Scully C 2015. Salivary micro RNA s in oral cancer. Oral Dis.;21(6):739-47.

Zahran, F., Ghalwash, D., Shaker, O., Al-Johani, K., & Scully, C. (2015). Salivary microRNAs in oral cancer. Oral Diseases, 21(6), 739-747. https://doi.org/10.1111/odi.12340

Zhong, L.-P., Chen, G.-F., Xu, Z.-F., Zhang, X., Ping, F.-Y., & Zhao, S.-F. (2005). Detection of telomerase activity in saliva from oral squamous cell carcinoma patients. International Journal of Oral and Maxillofacial Surgery, 34(5), 566-570. https://doi.org/10.1016/j.ijom.2004.10.007

Zimmermann BG, Park NJ, Wong DT 2007. Genomic targets in saliva. Ann N Y Acad Sci.;1098:184.

Zimmermann, B. G., Park, N. J., & Wong, D. T. (2007). Genomic targets in saliva. Annals of the New York Academy of Sciences, 1098, 184. https://doi.org/10.1196/annals.1384.002

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