{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T20:56:12Z","timestamp":1781124972728,"version":"3.54.1"},"update-to":[{"DOI":"10.1371\/journal.pntd.0009795","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,9,30]],"date-time":"2021-09-30T00:00:00Z","timestamp":1632960000000}}],"reference-count":88,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2021,9,20]],"date-time":"2021-09-20T00:00:00Z","timestamp":1632096000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["404181\/2012-0"],"award-info":[{"award-number":["404181\/2012-0"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004916","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado do Amazonas","doi-asserted-by":"publisher","award":["062.01954\/2015"],"award-info":[{"award-number":["062.01954\/2015"]}],"id":[{"id":"10.13039\/501100004916","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosntds.org"],"crossmark-restriction":false},"short-container-title":["PLoS Negl Trop Dis"],"abstract":"<jats:p><jats:italic>Leishmania<\/jats:italic>are intracellular protozoan parasites that cause a wide spectrum of clinical manifestations in genetically susceptible individuals with an insufficient or balanced Th1 immune response to eliminate the parasite. MiRNAs play important regulatory role in numerous biological processes including essential cellular functions. miR146-a acts as an inhibitor of interleukin 1 receptor associated kinase 1 (IRAK1) and tumour necrosis factor (TNF) receptor associated factor 6 (TRAF6) present in the toll-like receptors pathway while miR499a modulates TGF-\u03b2 and TNF signalling pathways. Here, we investigated whether<jats:italic>MIRNA146A rs2910164 and MIRNA499 rs3746444<\/jats:italic>variants are associated with the development of<jats:italic>L<\/jats:italic>.<jats:italic>guyanensis<\/jats:italic>(<jats:italic>Lg<\/jats:italic>)-cutaneous leishmaniasis (CL). The variants<jats:italic>MIR146A<\/jats:italic>rs2910164 and<jats:italic>MIR499A<\/jats:italic>rs3746444 were assessed in 850 patients with<jats:italic>Lg<\/jats:italic>-CL and 891 healthy controls by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). Plasma cytokines were measured using the BioPlex assay. Carriers of rs2910164 CC genotype have 30% higher odds of developing CL (ORadj<jats:sub>age\/sex<\/jats:sub>= 1.3 [95%CI 0.9\u20131.8]; Padj<jats:sub>age\/sex<\/jats:sub>0.14) compared to individuals with the genotype GG (ORadj<jats:sub>age\/sex<\/jats:sub>= 0.77 [95%CI 0.56\u20131.0]; Padj<jats:sub>age\/sex<\/jats:sub>0.14) if exposed to<jats:italic>Lg<\/jats:italic>-infection. Heterozygous GC individuals also showed lower odds of developing CL (ORadj<jats:sub>age\/sex<\/jats:sub>= 0.77 [95%CI 0.5\u20131.1]; Padj<jats:sub>age\/sex<\/jats:sub>0.09). Homozygosity for the allele C is suggestive of an association with the development of<jats:italic>Lg<\/jats:italic>-CL among exposed individuals to<jats:italic>Lg<\/jats:italic>-infection. However, the odds of developing CL associated with the CC genotype was evident only in male individuals (OR<jats:sub>adjage<\/jats:sub>= 1.3 [95% CI = 0.9\u20132.0]; P<jats:sub>adjage<\/jats:sub>= 0.06). Individuals homozygous for the G allele tend to have higher plasma IL-8 and CCL5. Similarly, for the<jats:italic>MIR499A<\/jats:italic>rs3746444, an association with the G allele was only observed among male individuals (OR = 1.4 [1.0\u20131.9]; P = 0.009). In a dominant model, individuals with the G allele (GG-GA) when compared to the AA genotype reveals that carriers of the G allele have 40% elevated odds of developing<jats:italic>Lg<\/jats:italic>-CL (ORadj<jats:sub>age<\/jats:sub>= 1.4 [1.1\u20131.9]). Individuals with the GG genotype have higher odds of developing<jats:italic>Lg<\/jats:italic>-CL (ORadj<jats:sub>age\/sex<\/jats:sub>= 2.0 [95%CI 0.83\u20135.0]; P<jats:sub>adjage<\/jats:sub>= 0.01. Individuals homozygous for the G allele have higher plasma IL-8. Genetic combinations of both variants revealed that male individuals exposed to<jats:italic>Lg<\/jats:italic>bearing three or four susceptible alleles have higher odds of developing<jats:italic>Lg<\/jats:italic>-CL (OR = 2.3 [95% CI 1.0\u20134.7]; p = 0.017). Both<jats:italic>MIR146A<\/jats:italic>rs2910164 and<jats:italic>MIR499A<\/jats:italic>rs3746444 are associated with the development of<jats:italic>Lg<\/jats:italic>-CL and this association is prevalent in male individuals.<\/jats:p>","DOI":"10.1371\/journal.pntd.0009795","type":"journal-article","created":{"date-parts":[[2021,9,20]],"date-time":"2021-09-20T18:33:08Z","timestamp":1632162788000},"page":"e0009795","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":13,"title":["Variants of MIRNA146A rs2910164 and MIRNA499 rs3746444 are associated with the development of cutaneous leishmaniasis caused by Leishmania guyanensis and with plasma chemokine IL-8"],"prefix":"10.1371","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5896-1005","authenticated-orcid":true,"given":"Tirza Gabrielle Ramos","family":"de Mesquita","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 do Esp\u00edrito Santo","family":"Junior","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thais Carneiro","family":"de Lacerda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krys Layane Guimar\u00e3es Duarte","family":"Queiroz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cl\u00e1udio Marcello da Silveira","family":"J\u00fanior","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2177-7292","authenticated-orcid":true,"given":"Jos\u00e9 Pereira de Moura","family":"Neto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lissianne Augusta Matos","family":"Gomes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4273-2678","authenticated-orcid":true,"given":"Mara L\u00facia Gomes","family":"de Souza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus Vinitius de Farias","family":"Guerra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0538-0773","authenticated-orcid":true,"given":"Rajendranath","family":"Ramasawmy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,9,20]]},"reference":[{"key":"pntd.0009795.ref001","unstructured":"World Health Organization. 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Winter"},{"issue":"7","key":"pntd.0009795.ref049","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1016\/j.humimm.2011.03.004","article-title":"Genetic study of two single nucleotide polymorphisms within corresponding microRNAs and susceptibility to tuberculosis in a Chinese Tibetan and Han population","volume":"72","author":"D Li","year":"2011","journal-title":"Hum Immunol"},{"key":"pntd.0009795.ref050","doi-asserted-by":"crossref","first-page":"e0122055","DOI":"10.1371\/journal.pone.0122055","article-title":"Association between ankylosing spondylitis and the miR-146a and miR-499 polymorphisms","volume":"10","author":"HY Xu","year":"2015","journal-title":"PLoS One"},{"issue":"4","key":"pntd.0009795.ref051","doi-asserted-by":"crossref","first-page":"4571","DOI":"10.1007\/s11033-011-1247-7","article-title":"Has-miR-146a polymorphism (rs2910164) and cancer risk: a meta-analysis of 19 case-control studies","volume":"39","author":"J Wang","year":"2012","journal-title":"Mol Biol 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