{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:05:47Z","timestamp":1792785947965,"version":"4.5.0"},"reference-count":37,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T00:00:00Z","timestamp":1774828800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100004916","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado do Amazonas","doi-asserted-by":"publisher","award":["06200151\/2020"],"award-info":[{"award-number":["06200151\/2020"]}],"id":[{"id":"10.13039\/501100004916","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":["01.02.016301.03393\/2021\u201380"],"award-info":[{"award-number":["01.02.016301.03393\/2021\u201380"]}],"id":[{"id":"10.13039\/501100004916","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":["01.02.016301.01090\/2023-94"],"award-info":[{"award-number":["01.02.016301.01090\/2023-94"]}],"id":[{"id":"10.13039\/501100004916","id-type":"DOI","asserted-by":"publisher"}]},{"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"}]},{"name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de Nivel Superior","id":[{"id":"https:\/\/ror.org\/00x0ma614","id-type":"ROR","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003593","name":"CNPq","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Leishmania guyanensis-associated cutaneous leishmaniasis (CL) is endemic in the Brazilian Amazonas. Despite similar exposure to the pathogen in endemic areas, only a subset of individuals develops disease, suggesting host-genetic control. STAT4 triggers interleukin 12 (IL-12)\u2013dependent Th1 differentiation and interferon-\u03b3 (IFN-\u03b3) production, essential for macrophage-mediated parasite clearance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed a case-control study of 802 patients with L. guyanensis CL and 842 endemic controls (ECs). Eleven STAT4 variants (10 SNVs and 1 insertion\/deletion) were genotyped. Associations were assessed using logistic regression adjusted for age and sex across multiple genetic models, with haplotype analysis adjusted for age and sex via omnibus and likelihood ratio tests.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Two SNVs exerted contrasting associations: the rs1031509 T allele increased susceptibility (adjusted odds ratio [ORadj] = 1.5; 95% CI, 1.3\u20131.7; adjusted P value, Bonferroni correction [Padj-B] = 1.3 \u00d7 10\u22125), while the rs6434435 A allele conferred protection (ORadj = 0.56; 95% CI, .43\u2212.68; Padj-B = 2.6 \u00d7 10\u22128). Omnibus haplotype analysis revealed significant global differences in haplotype distribution between L. guyanensis CL and ECs (omnibus unadjusted \u03c72 = 55.65, df = 13, P = 3.11 \u00d7 10\u22127; likelihood ratio test \u03c72 = 67.81, df = 13, P = 2.02 \u00d7 10\u22129), with a specific high-risk combination (AIGAAAGCTGC) associated with a 9-fold increase in susceptibility (adjusted OR = 9.12; 95% CI, 4.22\u201319.70; P = 1.9 \u00d7 10\u22128; FDR q = 2.4 \u00d7 10\u22127). Genotype-cytokines analyses revealed that carriers of the protected rs6434435 A allele had significantly higher TNF-\u03b1 plasma levels under dominant model (+40.2%, FDR adjusted P = .026) and additive model, with a nominal trend toward elevated IFN-\u03b3.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Haplotypic variation at this locus significantly shapes host inflammatory responses, highlighting STAT4 as a key immunogenetic determinant of resistance to Leishmania infection.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/infdis\/jiag175","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T12:43:15Z","timestamp":1773924195000},"page":"439-448","source":"Crossref","is-referenced-by-count":0,"title":["Contrasting Genetic Effects Within\n                    <i>STAT4<\/i>\n                    Define Susceptibility and Protection in\n                    <i>Leishmania guyanensis<\/i>\n                    Cutaneous Leishmaniasis"],"prefix":"10.1093","volume":"234","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2545-2911","authenticated-orcid":false,"given":"Lener Santos","family":"da Silva","sequence":"first","affiliation":[{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Biodiversidade e Biotecnologia da Amazonia Legal (Rede Bionorte), Universidade do Estado do Amazonas , Manaus ,","place":["Brazil"]},{"name":"Faculdade de Medicina, Universidade Nilton Lins , Manaus, Amazonas ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-0596-8010","authenticated-orcid":false,"given":"Josu\u00e9 Lacerda","family":"de Souza","sequence":"additional","affiliation":[{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Biodiversidade e Biotecnologia da Amazonia Legal (Rede Bionorte), Universidade do Estado do Amazonas , Manaus ,","place":["Brazil"]},{"name":"Faculdade de Medicina, Universidade Nilton Lins , Manaus, Amazonas ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5248-3820","authenticated-orcid":false,"given":"Lizandra Stephanny Fernandes","family":"Menescal","sequence":"additional","affiliation":[{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Imunologia B\u00e1sica e Aplicada, Universidade Federal do Amazonas , Manaus, Amazonas ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00falia","family":"da Costa Torres","sequence":"additional","affiliation":[{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Imunologia B\u00e1sica e Aplicada, Universidade Federal do Amazonas , Manaus, Amazonas ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5717-3759","authenticated-orcid":false,"given":"Ana Vitoria Sena","family":"Gouveia","sequence":"additional","affiliation":[{"name":"Faculdade de Medicina, Universidade Nilton Lins , Manaus, Amazonas ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4706-703X","authenticated-orcid":false,"given":"Eryck Gabriel Rodrigues","family":"Silva","sequence":"additional","affiliation":[{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Imunologia B\u00e1sica e Aplicada, Universidade Federal do Amazonas , Manaus, Amazonas ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1832-0542","authenticated-orcid":false,"given":"Micael Davi Lima","family":"de Oliveira","sequence":"additional","affiliation":[{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Imunologia B\u00e1sica e Aplicada, Universidade Federal do Amazonas , Manaus, Amazonas ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-3930-3838","authenticated-orcid":false,"given":"Marcus Vinitius","family":"de Farias Guerra","sequence":"additional","affiliation":[{"name":"Laboratory of molecular biology, Funda\u00e7\u00e3o de Medicina Tropical Doutor Heitor Vieira Dourado , Manaus, Amazonas ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0173-6266","authenticated-orcid":false,"given":"Mauricio Morishi","family":"Ogusku","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Micobacteriologia, Instituto Nacional de Pesquisas da Amaz\u00f4nia , Manaus, Amazonas ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8950-9011","authenticated-orcid":false,"given":"Landry Erick","family":"Mombo","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Cellular Biology, University of Science and Technology of Masuku , Franceville; \u00a0","place":["Gabon"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5597-7343","authenticated-orcid":false,"given":"Ant\u00f4nio Luiz","family":"Boechat","sequence":"additional","affiliation":[{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Imunologia B\u00e1sica e Aplicada, Universidade Federal do Amazonas , Manaus, Amazonas ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2177-7292","authenticated-orcid":false,"given":"Jose Pereira","family":"de Moura Neto","sequence":"additional","affiliation":[{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Imunologia B\u00e1sica e Aplicada, Universidade Federal do Amazonas , Manaus, Amazonas ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2996-0446","authenticated-orcid":false,"given":"Pritesh","family":"Lalwani","sequence":"additional","affiliation":[{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Imunologia B\u00e1sica e Aplicada, Universidade Federal do Amazonas , Manaus, Amazonas ,","place":["Brazil"]},{"name":"Laboratory of Infectious Diseases, Instituto Le\u00f4nidas e Maria Deane\/Funda\u00e7\u00e3o Oswaldo Cruz Amaz\u00f4nia , Manaus, Amazonas ,","place":["Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aya","family":"Sadahiro","sequence":"additional","affiliation":[{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Imunologia B\u00e1sica e Aplicada, Universidade Federal do Amazonas , Manaus, Amazonas 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Genomic evidence for the Pleistocene and recent population history of Native Americans","volume":"349","author":"Raghavan","year":"2015","journal-title":"Science"},{"key":"2026092314150907900_jiag175-B29","first-page":"974051","article-title":"Distinct chemokine\/cytokine signatures in L. guyanensis infection","volume":"13","author":"de Mesquita","year":"2022","journal-title":"Front Immunol"},{"key":"2026092314150907900_jiag175-B30","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1056\/NEJMoa073003","article-title":"STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus","volume":"357","author":"Remmers","year":"2007","journal-title":"N Engl J Med"},{"key":"2026092314150907900_jiag175-B31","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1136\/annrheumdis-2017-212794","article-title":"The STAT4 SLE risk allele rs7574865[T] is associated with increased IL-12-induced IFN-\u03b3 production in T cells from patients with SLE","volume":"77","author":"Hagberg","year":"2018","journal-title":"Ann Rheum Dis"},{"key":"2026092314150907900_jiag175-B32","doi-asserted-by":"crossref","first-page":"1520","DOI":"10.4049\/jimmunol.165.3.1520","article-title":"Susceptibility of Stat4-deficient mice to Trypanosoma cruzi","volume":"165","author":"Tarleton","year":"2000","journal-title":"J Immunol"},{"key":"2026092314150907900_jiag175-B33","doi-asserted-by":"crossref","first-page":"2524","DOI":"10.1002\/(SICI)1521-4141(199908)29:08<2524::AID-IMMU2524>3.0.CO;2-H","article-title":"STAT4-mediated IL-12 signaling is critical for immunity in CL","volume":"29","author":"Stamm","year":"1999","journal-title":"Eur J Immunol"},{"key":"2026092314150907900_jiag175-B34","doi-asserted-by":"crossref","first-page":"3206","DOI":"10.1002\/1521-4141(200211)32:11<3206::AID-IMMU3206>3.0.CO;2-J","article-title":"Control of new world CL is IL-12-independent but STAT4-dependent","volume":"32","author":"Buxbaum","year":"2002","journal-title":"Eur J Immunol"},{"key":"2026092314150907900_jiag175-B35","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1093\/infdis\/jiu140","article-title":"STAT4 alleles increase risk of pulmonary tuberculosis in Morocco","volume":"210","author":"Sabri","year":"2014","journal-title":"J Infect Dis"},{"key":"2026092314150907900_jiag175-B36","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1093\/cid\/ciz810","article-title":"A single IFNG haplotype associated with low IFN-\u03b3 and susceptibility to CL caused by L. guyanensis","volume":"71","author":"da Silva","year":"2020","journal-title":"Clin Infect Dis"},{"key":"2026092314150907900_jiag175-B37","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1093\/infdis\/jiab320","article-title":"IL-23R variant rs11805303 and susceptibility to CL caused by L. guyanensis","volume":"225","author":"Santos da Silva","year":"2022","journal-title":"J Infect Dis"}],"container-title":["The Journal of Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jid\/advance-article-pdf\/doi\/10.1093\/infdis\/jiag175\/67637980\/jiag175.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jid\/article-pdf\/234\/3\/439\/67637980\/jiag175.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jid\/article-pdf\/234\/3\/439\/67637980\/jiag175.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T18:15:17Z","timestamp":1790187317000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jid\/article\/234\/3\/439\/8555662"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,30]]},"references-count":37,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,3,30]]},"published-print":{"date-parts":[[2026,9,23]]}},"URL":"https:\/\/doi.org\/10.1093\/infdis\/jiag175","relation":{},"ISSN":["0022-1899","1537-6613"],"issn-type":[{"value":"0022-1899","type":"print"},{"value":"1537-6613","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,9,15]]},"published":{"date-parts":[[2026,3,30]]}}}