{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T09:22:15Z","timestamp":1781256135255,"version":"3.54.1"},"reference-count":39,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2019,11,13]],"date-time":"2019-11-13T00:00:00Z","timestamp":1573603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Brazilian Council for Scientific and Technological Development","award":["404181\/2012-0"],"award-info":[{"award-number":["404181\/2012-0"]}]},{"DOI":"10.13039\/501100004916","name":"Funda\u00e7\u00e3o de Amparo a Pesquisa do Estado do Amazonas","doi-asserted-by":"crossref","award":["06201954\/2015"],"award-info":[{"award-number":["06201954\/2015"]}],"id":[{"id":"10.13039\/501100004916","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,7,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Interferon-\u03b3 (IFN-\u03b3) plays an important role in the control of Leishmania infection. Blockade of IFN-\u03b3 signaling in mice increases lesion size and parasite load. In endemic areas of Leishmaniasis, only a fraction of the population develop the disease. This suggest that host genetics may play a role in this response. We investigated whether single nucleotide polymorphisms (SNPs) in IFNG may be associated with elevated or decrease risk in the development of cutaneous leishmaniasis (CL).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We assessed 9 SNP and cytosine-adenine (CA) repeats in IFNG by nucleotide sequencing in 647 patients with CL caused by Leishmania guyanensis and 629 controls. Circulating plasma IFN-\u03b3 levels were also assayed in 400 patients with CL and 400 controls.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>The rs2069705TT genotype is associated with elevated risk of developing CL compared with the rs2069705CC genotype (OR, 1.7; 95% CI, 1.3\u20132.4; P = .0008). There is a 70% chance that this genotype raises the risk of developing CL. In a dominant model, carriers of the rs2069705T allele compared with the rs2069705CC genotype showed a 50% (range, 20\u2013100%) increased risk of developing CL (OR, 1.5; 95% CI, 1.2\u20132.0; P = .0004). Haplotype analysis showed 1 haplotype (H1) associated with low levels of IFN-\u03b3 presented an increased risk of 60% of developing CL (OR, 1.6; 95% CI, 1.3\u20131.9; P = 5 \u00d7 10\u22125) compared with non-H1.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>IFNG variant rs2069705 seems to be a genetic modifier of clinical outcome of Leishmania infection; individuals with the H1 haplotype, associated with low levels of IFN-\u03b3, have a 60% risk of developing CL.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cid\/ciz810","type":"journal-article","created":{"date-parts":[[2019,8,22]],"date-time":"2019-08-22T19:34:17Z","timestamp":1566502457000},"page":"274-281","source":"Crossref","is-referenced-by-count":20,"title":["A Single Haplotype of IFNG Correlating With Low Circulating Levels of Interferon-\u03b3 Is Associated With Susceptibility to Cutaneous Leishmaniasis Caused by Leishmania guyanensis"],"prefix":"10.1093","volume":"71","author":[{"given":"George A V","family":"da Silva","sequence":"first","affiliation":[{"name":"Programa de Pos-Gradua\u00e7\u00e3o em Imunologia B\u00e1sica e Aplicada, Universidade Federal do Amazonas, Amazonas, Manaus, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tirza G","family":"Mesquita","sequence":"first","affiliation":[{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Medicina Tropical, Universidade do Estado do Amazonas, Amazonas, Manaus, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor C","family":"Souza","sequence":"first","affiliation":[{"name":"Instituto Le\u00f4nidas e Maria Deane, FIOCRUZ Amaz\u00f4nia, Amazonas, Manaus, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 do Esp\u00edrito Santo","family":"Junior","sequence":"first","affiliation":[{"name":"Programa de Pos-Gradua\u00e7\u00e3o em Imunologia B\u00e1sica e Aplicada, Universidade Federal do Amazonas, Amazonas, Manaus, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mara L\u00facia","family":"Gomes de Souza","sequence":"first","affiliation":[{"name":"Funda\u00e7\u00e3o de Medicina Tropical Doutor Heitor Vieira Dourado, Manaus, Amazonas, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anette Chrusciak","family":"Talhari","sequence":"first","affiliation":[{"name":"Funda\u00e7\u00e3o de Medicina Tropical Doutor Heitor Vieira Dourado, Manaus, Amazonas, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sin\u00e9sio","family":"Talhari","sequence":"first","affiliation":[{"name":"Funda\u00e7\u00e3o de Medicina Tropical Doutor Heitor Vieira Dourado, Manaus, Amazonas, Brazil"},{"name":"Faculdade de Medicina, Universidade Nilton Lins, Amazonas, Manaus, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felipe G","family":"Naveca","sequence":"first","affiliation":[{"name":"Instituto Le\u00f4nidas e Maria Deane, FIOCRUZ Amaz\u00f4nia, Amazonas, Manaus, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajendranath","family":"Ramasawmy","sequence":"first","affiliation":[{"name":"Programa de Pos-Gradua\u00e7\u00e3o em Imunologia B\u00e1sica e Aplicada, Universidade Federal do Amazonas, Amazonas, Manaus, Brazil"},{"name":"Funda\u00e7\u00e3o de Medicina Tropical Doutor Heitor Vieira Dourado, Manaus, Amazonas, Brazil"},{"name":"Faculdade de Medicina, Universidade Nilton Lins, Amazonas, Manaus, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,11,13]]},"reference":[{"key":"2020071109145544800_CIT0001","doi-asserted-by":"crossref","first-page":"177","DOI":"10.4103\/0974-777X.62881","article-title":"Leishmaniasis vaccine: where are we today?","volume":"2","author":"Kedzierski","year":"2010","journal-title":"J Glob Infect Dis"},{"key":"2020071109145544800_CIT0002","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1084\/jem.179.4.1367","article-title":"CD4+ effector cells default to the Th2 pathway in interferon gamma-deficient mice infected with Leishmania major","volume":"179","author":"Wang","year":"1994","journal-title":"J Exp Med"},{"key":"2020071109145544800_CIT0003","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1084\/jem.181.3.961","article-title":"Mice from a genetically resistant background lacking the interferon gamma receptor are susceptible to infection with Leishmania major but mount a polarized T helper cell 1-type CD4+ T cell response","volume":"181","author":"Swihart","year":"1995","journal-title":"J Exp Med"},{"key":"2020071109145544800_CIT0004","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1084\/jem.185.7.1231","article-title":"Intracellular antimicrobial activity in the absence of interferon-gamma: effect of interleukin-12 in experimental visceral leishmaniasis in interferon-gamma gene-disrupted mice","volume":"185","author":"Taylor","year":"1997","journal-title":"J Exp Med"},{"key":"2020071109145544800_CIT0005","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1111\/j.1365-3083.2005.01686.x","article-title":"Immune response in human visceral Leishmaniasis: analysis of the correlation between innate immunity cytokine profile and disease outcome","volume":"62","author":"Peruhype-Magalh\u00e3es","year":"2005","journal-title":"Scand J Immunol"},{"key":"2020071109145544800_CIT0006","doi-asserted-by":"crossref","first-page":"2244","DOI":"10.1128\/IAI.71.4.2244-2246.2003","article-title":"Th2 responses predominate during the early phases of infection in patients with localized cutaneous leishmaniasis and precede the development of Th1 responses","volume":"71","author":"Bourreau","year":"2003","journal-title":"Infect Immun"},{"key":"2020071109145544800_CIT0007","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1111\/j.1365-3024.2009.01125.x","article-title":"Recruitment of CD8(+) T cells expressing granzyme A is associated with lesion progression in human cutaneous leishmaniasis","volume":"31","author":"Faria","year":"2009","journal-title":"Parasite Immunol"},{"key":"2020071109145544800_CIT0008","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1590\/S0074-02762007005000069","article-title":"T-cell responses associated with resistance to Leishmania infection in individuals from endemic areas for Leishmania (Viannia) braziliensis","volume":"102","author":"Bittar","year":"2007","journal-title":"Mem Inst Oswaldo Cruz"},{"key":"2020071109145544800_CIT0009","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1002\/ddr.20449","article-title":"Immunoregulatory and effector activities in human cutaneous and mucosal leishmaniasis: understanding mechanisms of pathology","volume":"72","author":"Dutra","year":"2011","journal-title":"Drug Dev Res"},{"key":"2020071109145544800_CIT0010","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1590\/0074-0276140539","article-title":"Single nucleotide polymorphisms in the interferon gamma gene are associated with distinct types of retinochoroidal scar lesions presumably caused by Toxoplasma gondii infection","volume":"109","author":"Peixe","year":"2014","journal-title":"Mem Inst Oswaldo Cruz"},{"key":"2020071109145544800_CIT0011","doi-asserted-by":"crossref","first-page":"1794","DOI":"10.1097\/MIB.0000000000000172","article-title":"IFNG rs1861494 polymorphism is associated with IBD disease severity and functional changes in both IFNG methylation and protein secretion","volume":"20","author":"Gonsky","year":"2014","journal-title":"Inflamm Bowel Dis"},{"key":"2020071109145544800_CIT0012","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1046\/j.1365-2370.1999.00122.x","article-title":"In vitro production of IFN-gamma correlates with CA repeat polymorphism in the human IFN-gamma gene","volume":"26","author":"Pravica","year":"1999","journal-title":"Eur J Immunogenet"},{"key":"2020071109145544800_CIT0013","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1016\/S0198-8859(00)00167-1","article-title":"A single nucleotide polymorphism in the first intron of the human IFN-gamma gene: absolute correlation with a polymorphic CA microsatellite marker of high IFN-gamma production","volume":"61","author":"Pravica","year":"2000","journal-title":"Hum Immunol"},{"key":"2020071109145544800_CIT0014","doi-asserted-by":"crossref","first-page":"3147","DOI":"10.1128\/JCM.41.7.3147-3153.2003","article-title":"Identification and differentiation of Leishmania species in clinical samples by PCR amplification of the miniexon sequence and subsequent restriction fragment length polymorphism analysis","volume":"41","author":"Marfurt","year":"2003","journal-title":"J Clin Microbiol"},{"key":"2020071109145544800_CIT0015","doi-asserted-by":"crossref","first-page":"2294","DOI":"10.1128\/JCM.42.5.2294-2297.2004","article-title":"Culture-independent species typing of neotropical Leishmania for clinical validation of a PCR-based assay targeting heat shock protein 70 genes","volume":"42","author":"Garcia","year":"2004","journal-title":"J Clin Microbiol"},{"key":"2020071109145544800_CIT0016","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/S0076-6879(80)65044-7","article-title":"Fractionation of DNA fragments by polyethylene glycol induced precipitation","volume":"65","author":"Lis","year":"1980","journal-title":"Methods Enzymol"},{"key":"2020071109145544800_CIT0017","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1093\/nar\/19.6.1346","article-title":"Precipitation of DNA by polyethylene glycol and ethanol","volume":"19","author":"Paithankar","year":"1991","journal-title":"Nucleic Acids Res"},{"key":"2020071109145544800_CIT0018","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1016\/j.micinf.2005.07.007","article-title":"Infection-induced respiratory burst in BALB\/c macrophages kills Leishmania guyanensis amastigotes through apoptosis: possible involvement in resistance to cutaneous leishmaniasis","volume":"2","author":"Sousa-Franco","year":"2006","journal-title":"Microbes Infect"},{"key":"2020071109145544800_CIT0019","doi-asserted-by":"crossref","first-page":"3874","DOI":"10.1128\/IAI.70.7.3874-3880.2002","article-title":"Hierarchy of susceptibility of dendritic cell subsets to infection by Leishmania major: inverse relationship to interleukin-12 production","volume":"70","author":"Henri","year":"2002","journal-title":"Infect Immun"},{"key":"2020071109145544800_CIT0020","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1084\/jem.20102318","article-title":"Langerhans cells are negative regulators of the anti-Leishmania response","volume":"208","author":"Kautz-Neu","year":"2011","journal-title":"J Exp Med"},{"key":"2020071109145544800_CIT0021","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1038\/nri.2016.72","article-title":"Cutaneous leishmaniasis: immune responses in protection and pathogenesis","volume":"16","author":"Scott","year":"2016","journal-title":"Nat Rev Immunol"},{"key":"2020071109145544800_CIT0022","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1086\/319249","article-title":"Interleukin (IL)-13 is the predomiant Th2 cytokine in localized cutaneous Leishmania lesions and renders specific CD+T cells unresponsive to IL-12","volume":"183","author":"Bourreaeu","year":"2001","journal-title":"J Infect Dis"},{"key":"2020071109145544800_CIT0023","doi-asserted-by":"crossref","first-page":"1034","DOI":"10.1016\/j.micinf.2007.04.009","article-title":"IL-10 producing CD8+ T cells in human infection with Leishmania guyanensis","volume":"9","author":"Bourreau","year":"2007","journal-title":"Microbes Infect"},{"key":"2020071109145544800_CIT0024","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s12936-015-0548-z","article-title":"IL10A genotypic association with decreased IL-10 circulating levels in malaria infected individuals from endemic area of the Brazilian Amazon","volume":"14","author":"Pereira","year":"2015","journal-title":"Malaria J"},{"key":"2020071109145544800_CIT0025","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.meegid.2014.10.030","article-title":"Interferon-\u03b3 (IFNG) microsatellite repeat and single nucleotide polymorphism haplotypes of IFN-\u03b1 receptor (IFNAR1) associated with enhanced malaria susceptibility in Indian populations","volume":"29","author":"Kanchan","year":"2015","journal-title":"Infect Genet Evol"},{"key":"2020071109145544800_CIT0026","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2016\/5168363","article-title":"Frequency of TNFA, IFNG, and IL10 gene polymorphisms and their association with malaria vivax and genomic ancestry","author":"Furini","year":"2016","journal-title":"Mediators Inflammat"},{"key":"2020071109145544800_CIT0027","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/1471-2334-7-33","article-title":"IFNG +874 T\/A polymorphism is not associated with American tegumentarleishmaniasis susceptibility but can influence Leishmania induced IFN-gamma production","volume":"7","author":"Matos","year":"2007","journal-title":"BMC Infect Dis"},{"key":"2020071109145544800_CIT0028","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1038\/sj.gene.6364353","article-title":"IFNG and IFNGR1 gene polymorphisms and susceptibility to post-kala-azar dermal leishmaniasis in Sudan","volume":"8","author":"Salih","year":"2007","journal-title":"Genes Immun"},{"key":"2020071109145544800_CIT0029","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1111\/ahg.12180","article-title":"Comprehensive candidate gene analysis for symptomatic or asymptomatic outcomes of Leishmania infantum infection in Brazil","volume":"81","author":"Weirather","year":"2018","journal-title":"Ann Hum Genet"},{"key":"2020071109145544800_CIT0030","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1016\/j.meegid.2010.03.009","article-title":"Role of the IFNG +874T\/A polymorphism in Chagas disease in a Colombian population","volume":"10","author":"Torres","year":"2010","journal-title":"Infect Genet Evol"},{"key":"2020071109145544800_CIT0031","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.cyto.2006.07.016","article-title":"Cytokine gene polymorphisms and susceptibility to cutaneous leishmaniasis in Iranian patients","volume":"35","author":"Kamali-Sarvestani","year":"2006","journal-title":"Cytokine"},{"key":"2020071109145544800_CIT0032","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1186\/1475-2875-10-264","article-title":"Increased interleukin-10 and interferon-\u03b3 levels in Plasmodium vivax malaria suggest a reciprocal regulation which is not altered by IL-10 gene promoter polymorphism","volume":"10","author":"Medina","year":"2011","journal-title":"Malar J"},{"key":"2020071109145544800_CIT0033","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/j.cyto.2012.04.043","article-title":"IFN-\u03b3 +875 microsatellite polymorphism as a potential protection marker for leprosy patients from Amazonas state, Brazil","volume":"60","author":"Silva","year":"2012","journal-title":"Cytokine"},{"key":"2020071109145544800_CIT0034","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1186\/1475-2875-13-314","article-title":"IFN-gamma and TNF associated with severe falciparum malaria infection in Saudi pregnant women","volume":"13","author":"Nasr","year":"2014","journal-title":"Malar J"},{"key":"2020071109145544800_CIT0035","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1038\/sj.gene.6364214","article-title":"Investigation of malaria susceptibility determinants in the IFNG\/IL26\/IL22 genomic region","volume":"6","author":"Koch","year":"2005","journal-title":"Genes Immun"},{"key":"2020071109145544800_CIT0036","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1111\/j.0105-2896.2004.00198.x","article-title":"The development of effector and memory T cells in cutaneous leishmaniasis: the implications for vaccine development","volume":"201","author":"Scott","year":"2004","journal-title":"Immunol Rev"},{"key":"2020071109145544800_CIT0037","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1515\/bmc-2018-0007","article-title":"Interferon-gamma (IFN-\u03b3): exploring its implications in infectious diseases","volume":"9","author":"Kak","year":"2018","journal-title":"Biomol Concepts"},{"key":"2020071109145544800_CIT0038","doi-asserted-by":"crossref","first-page":"216","DOI":"10.7326\/0003-4819-123-3-199508010-00009","article-title":"Interferon-gamma in the management of infectious diseases","volume":"123","author":"Gallin","year":"1995","journal-title":"Ann Intern Med"},{"key":"2020071109145544800_CIT0039","doi-asserted-by":"crossref","first-page":"2529","DOI":"10.3389\/fimmu.2018.02529","article-title":"Macrophage polarization in Leishmaniasis: broadening horizons","volume":"9","author":"Tomiotto-Pellissier","year":"2018","journal-title":"Front Immunol"}],"container-title":["Clinical Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/cid\/advance-article-pdf\/doi\/10.1093\/cid\/ciz810\/30699551\/ciz810.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/cid\/article-pdf\/71\/2\/274\/33486212\/ciz810.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/cid\/article-pdf\/71\/2\/274\/33486212\/ciz810.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,7,11]],"date-time":"2020-07-11T13:15:37Z","timestamp":1594473337000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/cid\/article\/71\/2\/274\/5625012"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,13]]},"references-count":39,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2019,11,13]]},"published-print":{"date-parts":[[2020,7,11]]}},"URL":"https:\/\/doi.org\/10.1093\/cid\/ciz810","relation":{},"ISSN":["1058-4838","1537-6591"],"issn-type":[{"value":"1058-4838","type":"print"},{"value":"1537-6591","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,7,15]]},"published":{"date-parts":[[2019,11,13]]}}}