{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T12:07:09Z","timestamp":1764245229807,"version":"3.46.0"},"reference-count":30,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T00:00:00Z","timestamp":1764201600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The Hispanic Alliance for Clinical Translational Research","award":["U54GM133807"],"award-info":[{"award-number":["U54GM133807"]}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["5P20GM103475-20","#1P20GM156713-01"],"award-info":[{"award-number":["5P20GM103475-20","#1P20GM156713-01"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The National Institute on Minority Health and Health Disparities RCMI","award":["#U54 MD007600"],"award-info":[{"award-number":["#U54 MD007600"]}]},{"name":"NCI AWARD UPR\/MDACC","award":["#2U54CA096297-17"],"award-info":[{"award-number":["#2U54CA096297-17"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objective: Cervical cancer incidence is rising in Puerto Rico (PR) despite being preventable through HPV vaccination, Pap smear screening, and the timely treatment of dysplasia. This study evaluated the presence of single-nucleotide polymorphisms (SNPs) in Toll-like receptors (TLR4 and TLR9) among women with cervical dysplasia and HPV infection, as potential immune-related susceptibility factors. Methods: Cervicovaginal samples from 210 Hispanic women in PR were analyzed for dysplasia severity and HPV genotype. Demographic data were collected. Seven SNPs (four in TLR4, three in TLR9) were examined using PCR-RFLP and AS-PCR. Associations between SNP frequency, dysplasia severity, and high-risk HPV (HR-HPV) were assessed. Results: HR-HPV was found in 64% of severe dysplasia cases versus 46% of mild\/negative cases (p &lt; 0.025). The TLR4 AG (rs4986790) and CT (rs1927911) genotypes were more frequent in severe dysplasia. For TLR9, CT heterozygotes (rs187084) and the TC genotype (rs5743836) were also enriched in severe dysplasia. Conclusions: This first PR-based study shows that TLR4 and TLR9 SNPs significantly correlate with HR-HPV infection and dysplasia severity, supporting further research on their potential as biomarkers for cervical cancer prevention.<\/jats:p>","DOI":"10.3390\/cancers17233795","type":"journal-article","created":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T11:50:13Z","timestamp":1764244213000},"page":"3795","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Association of TLR-4 and TLR-9 Polymorphisms with HPV Infection and Cervical Dysplasia in Hispanic Women"],"prefix":"10.3390","volume":"17","author":[{"given":"Keimari","family":"Mendez","sequence":"first","affiliation":[{"name":"School of Medicine, Medical Sciences Campus, University of Puerto Rico, San Juan, PR 00936, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0028-3202","authenticated-orcid":false,"given":"Ana","family":"Rosario-Santos","sequence":"additional","affiliation":[{"name":"School of Medicine, Medical Sciences Campus, University of Puerto Rico, San Juan, PR 00936, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Magaly","family":"Mart\u00ednez-Ferrer","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, School of Pharmacy, University of Puerto Rico, San Juan, PR 00936, USA"},{"name":"University of Puerto Rico Comprehensive Cancer Center, San Juan, PR 00921, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2878-5308","authenticated-orcid":false,"given":"Naydi","family":"P\u00e9rez-Rios","sequence":"additional","affiliation":[{"name":"Alliance for Clinical and Translational Research-Medical Sciences Campus, University of Puerto Rico, San Juan, PR 00921, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alejandro O.","family":"Rivera-Torres","sequence":"additional","affiliation":[{"name":"University of Puerto Rico Comprehensive Cancer Center, San Juan, PR 00921, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5403-9160","authenticated-orcid":false,"given":"Josefina","family":"Romaguera","sequence":"additional","affiliation":[{"name":"School of Medicine, Medical Sciences Campus, University of Puerto Rico, San Juan, PR 00936, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1880-0498","authenticated-orcid":false,"given":"Filipa","family":"Godoy-Vitorino","sequence":"additional","affiliation":[{"name":"School of Medicine, Medical Sciences Campus, University of Puerto Rico, San Juan, PR 00936, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,27]]},"reference":[{"key":"ref_1","unstructured":"World Heatlh Organization Cervical Cancer. Available online: https:\/\/www.who.int\/health-topics\/cervical-cancer#tab=tab_1."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Zhang, Z., Li, Y., Huang, H., Wei, T., Huang, Y., Qu, X., Xu, Y., Zhang, A., Li, J., and Gong, Z. (2025). Disparities and trends of the incidence and mortality of female-specific cancers in the United States. PLoS ONE, 20.","DOI":"10.1371\/journal.pone.0334128"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Godoy-Vitorino, F., Ortiz-Morales, G., Romaguera, J., Sanchez, M.M., Martinez-Ferrer, M., and Chorna, N. (2018). Discriminating high-risk cervical Human Papilloma Virus infections with urinary biomarkers via non-targeted GC-MS-based metabolomics. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0209936"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"106336","DOI":"10.1016\/j.ypmed.2020.106336","article-title":"Elimination of cervical cancer in U.S. Hispanic populations: Puerto Rico as a case study","volume":"144","author":"Ortiz","year":"2021","journal-title":"Prev. Med."},{"key":"ref_5","first-page":"e00357-23","article-title":"The cervical microbiota of Hispanics living in Puerto Rico is nonoptimal regardless of HPV status","volume":"8","author":"Romaguera","year":"2023","journal-title":"mSystems"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Olusola, P., Banerjee, H.N., Philley, J.V., and Dasgupta, S. (2019). Human Papilloma Virus-Associated Cervical Cancer and Health Disparities. Cells, 8.","DOI":"10.3390\/cells8060622"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1001\/jamaoncol.2020.7488","article-title":"Incidence of Cervical Cancer in Puerto Rico, 2001\u20132017","volume":"7","author":"Ortiz","year":"2021","journal-title":"JAMA Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Salehi, A.M., Shahbazi, F., Garavand, R., Kamkari, S., and Jenabi, E. (2025). Global socioeconomic inequalities in breast, cervical, ovarian, and uterine cancers incidence, mortality, disability-adjusted life year\u2019s rates: A relative concentration index analysis. BMC Women\u2019s Health, 25.","DOI":"10.1186\/s12905-025-03961-3"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Alshammari, A.H., Ishii, H., Hirotsu, T., Hatakeyama, H., Morishita, M., and di Luccio, E. (2024). Bridging the gap in cervical cancer screening for underserved communities: MCED and the promise of future technologies. Front. Oncol., 14.","DOI":"10.3389\/fonc.2024.1407008"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Godoy-Vitorino, F., Romaguera, J., Zhao, C., Vargas-Robles, D., Ortiz-Morales, G., V\u00e1zquez-S\u00e1nchez, F., Sanchez-V\u00e1zquez, M., de la Garza-Casillas, M., Martinez-Ferrer, M., and White, J.R. (2018). Cervicovaginal Fungi and Bacteria Associated with Cervical Intraepithelial Neoplasia and High-Risk Human Papillomavirus Infections in a Hispanic Population. Front. Microbiol., 9.","DOI":"10.3389\/fmicb.2018.02533"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Mitra, A., MacIntyre, D.A., Marchesi, J.R., Lee, Y.S., Bennett, P.R., and Kyrgiou, M. (2016). The vaginal microbiota, human papillomavirus infection and cervical intraepithelial neoplasia: What do we know and where are we going next?. Microbiome, 4.","DOI":"10.1186\/s40168-016-0203-0"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Papamentzelopoulou, M., and Pitiriga, V.C. (2025). Unlocking the Interactions Between the Whole-Body Microbiome and HPV Infection: A Literature Review. Pathogens, 14.","DOI":"10.20944\/preprints202502.1667.v1"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1128\/CMR.16.4.637-646.2003","article-title":"Role of Toll-like receptors in pathogen recognition","volume":"16","author":"Janssens","year":"2003","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1042\/CS20070214","article-title":"Toll-like receptor polymorphisms and susceptibility to human disease","volume":"114","author":"Misch","year":"2008","journal-title":"Clin. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Li, J., Rao, H., Jin, C., and Liu, J. (2017). Involvement of the Toll-Like Receptor\/Nitric Oxide Signaling Pathway in the Pathogenesis of Cervical Cancer Caused by High-Risk Human Papillomavirus Infection. BioMed Res. Int., 2017.","DOI":"10.1155\/2017\/7830262"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Mukherjee, S., Patra, R., Behzadi, P., Masotti, A., Paolini, A., and Sarshar, M. (2023). Toll-like receptor-guided therapeutic intervention of human cancers: Molecular and immunological perspectives. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1244345"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Chauhan, A., Pandey, N., Desai, A., Raithatha, N., Patel, P., Choxi, Y., Kapadia, R., Khandelwal, R., and Jain, N. (2019). Association of TLR4 and TLR9 gene polymorphisms and haplotypes with cervicitis susceptibility. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0220330"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"9127146","DOI":"10.1155\/2018\/9127146","article-title":"The Associations between Toll-Like Receptor 9 Gene Polymorphisms and Cervical Cancer Susceptibility","volume":"2018","author":"Tian","year":"2018","journal-title":"Mediat. Inflamm."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Moura, E.L., Santos, I.F.D., Freitas, P.P., Silva, D.M.D., Santos, A., Lira Neto, A.B., Silva, A., Barbosa, N.R., Nascimento, C.A., and Balliano, T.L. (2022). Polymorphisms in Toll-like receptors genes changes the host\u2019s immune response and is associated with cervical cancer. Immunobiology, 227.","DOI":"10.1016\/j.imbio.2022.152187"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"28","DOI":"10.25259\/CMAS_03_07_2021","article-title":"The Bethesda System for reporting cervical cytology","volume":"19","author":"Pangarkar","year":"2022","journal-title":"Cytojournal"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e00176-18","DOI":"10.1128\/mSphere.00176-18","article-title":"High Rate of Infection by Only Oncogenic Human Papillomavirus in Amerindians","volume":"3","author":"Magris","year":"2018","journal-title":"mSphere"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Vargas-Robles, D., Morales, N., Rodr\u00edguez, I., Nieves, T., Godoy-Vitorino, F., Alcaraz, L.D., P\u00e9rez, M.-E., Ravel, J., Forney, L.J., and Dom\u00ednguez-Bello, M.G. (2020). Changes in the vaginal microbiota across a gradient of urbanization. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-69111-x"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"175","DOI":"10.3758\/BF03193146","article-title":"G*Power 3: A flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behavior Research Methods","volume":"39","author":"Faul","year":"2007","journal-title":"Behav. Res. Methods"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"E31","DOI":"10.1684\/bdc.2014.2037","article-title":"Involvement of Toll-like receptors in cervical cancer susceptibility among Tunisian women","volume":"101","author":"Zidi","year":"2014","journal-title":"Bull. Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Pandey, N.O., Chauhan, A.V., Raithatha, N.S., Patel, P.K., Khandelwal, R., Desai, A.N., Choxi, Y., Kapadia, R.S., and Jain, N.D. (2019). Association of TLR4 and TLR9 polymorphisms and haplotypes with cervical cancer susceptibility. Sci. Rep., 9.","DOI":"10.1038\/s41598-019-46077-z"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Wang, Y., Xia, Y., Chen, Y., Xu, L., Sun, X., Li, J., Huang, G., Li, X., Xie, Z., and Zhou, Z. (2023). Association analysis between the TLR9 gene polymorphism rs352140 and type 1 diabetes. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1030736"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1089\/dna.2011.1427","article-title":"A genetic variant in the promoter region of Toll-like receptor 9 and cervical cancer susceptibility","volume":"31","author":"Chen","year":"2012","journal-title":"DNA Cell Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"8425","DOI":"10.1007\/s11033-012-1695-8","article-title":"Involvement of Toll-like Receptor 9 polymorphism in cervical cancer development","volume":"39","author":"Roszak","year":"2012","journal-title":"Mol. Biol. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Zhang, C., Yang, Z., Luo, P., Li, T., Wang, S., Sun, F., Gong, P., and Mei, B. (2023). Association of TLR4 and TLR9 gene polymorphisms with cervical HR-HPV infection status in Chinese Han population. BMC Infect. Dis., 23.","DOI":"10.1186\/s12879-023-08116-z"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Nieves-Colon, M.A., Ulrich, E.C., Chen, L., Torres Colon, G.A., Clemente, M.R., Copi, C., and Benn Torres, J. (2024). Genetic ancestry in Puerto Rican afro-descendants illustrates diverse histories of African diasporic populations. Am. J. Biol. Anthropol., 185.","DOI":"10.1002\/ajpa.25029"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/23\/3795\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T12:03:39Z","timestamp":1764245019000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/23\/3795"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,27]]},"references-count":30,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["cancers17233795"],"URL":"https:\/\/doi.org\/10.3390\/cancers17233795","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,27]]}}}