{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T23:54:04Z","timestamp":1791071644492,"version":"4.1.0"},"reference-count":65,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2013,11,27]],"date-time":"2013-11-27T00:00:00Z","timestamp":1385510400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"DOI":"10.1371\/journal.pone.0081071","type":"journal-article","created":{"date-parts":[[2013,11,27]],"date-time":"2013-11-27T18:55:01Z","timestamp":1385578501000},"page":"e81071","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":43,"title":["Association of Cytokine and Toll-Like Receptor Gene Polymorphisms with Severe Malaria in Three Regions of Cameroon"],"prefix":"10.1371","volume":"8","author":[{"given":"Tobias O.","family":"Apinjoh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith K.","family":"Anchang-Kimbi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clarisse","family":"Njua-Yafi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Regina N.","family":"Mugri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andre N.","family":"Ngwai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirk A.","family":"Rockett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Mbunwe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard N.","family":"Besingi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taane G.","family":"Clark","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominic P.","family":"Kwiatkowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric A.","family":"Achidi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"in collaboration with The MalariaGEN Consortium","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2013,11,27]]},"reference":[{"key":"ref1","article-title":"World Malaria Report 2012","year":"2012"},{"key":"ref2","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1038\/nature07632","article-title":"A global network for investigating the genomic epidemiology of malaria","volume":"456","author":"GEN Malaria","year":"2008","journal-title":"Nature"},{"key":"ref3","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1038\/nri1311","article-title":"Innate immunity to malaria","volume":"4","author":"MM Stevenson","year":"2004","journal-title":"Nat Rev Immunol"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"e340","DOI":"10.1371\/journal.pmed.0020340","article-title":"Heritability of malaria in Africa","volume":"2","author":"MJ Mackinnon","year":"2005","journal-title":"PLoS Med"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1038\/ni.f.205","article-title":"Immunity to malaria: more questions than answers","volume":"9","author":"J Langhorne","year":"2008","journal-title":"Nat Immunol"},{"key":"ref6","doi-asserted-by":"crossref","first-page":"1753","DOI":"10.1086\/315077","article-title":"The cytokine balance in severe malarial anemia","volume":"180","author":"JA Kurtzhals","year":"1999","journal-title":"J Infect Dis"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1086\/314548","article-title":"A low interleukin-10 tumor necrosis factor-alpha ratio is associated with malaria anemia in children residing in a holoendemic malaria region in western Kenya","volume":"179","author":"C Othoro","year":"1999","journal-title":"J Infect Dis"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1007\/s00439-008-0578-5","article-title":"Haplotypes of IL-10 promoter variants are associated with susceptibility to severe malarial anemia and functional changes in IL-10 production","volume":"124","author":"C Ouma","year":"2008","journal-title":"Hum Genet"},{"key":"ref9","first-page":"103","article-title":"Plasma Levels of Tumour Necrosis Factor-Alpha, Interleukin-10, Interleukin-12, Macrophage Inhibition Factor and Transforming Growth Factor-Beta in Children with Severe and Uncomplicated Falciparum Malaria","volume":"1","author":"EA Achidi","year":"2013","journal-title":"J Trop Dis"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1111\/j.1365-3156.2004.01312.x","article-title":"iNOS promoter variants and severe malaria in Ghanaian children","volume":"9","author":"JP Cramer","year":"2004","journal-title":"Trop Med Int Health"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1038\/sj.gene.6364055","article-title":"Is there a future for TNF promoter polymorphisms?","volume":"5","author":"JP Bayley","year":"2004","journal-title":"Genes Immun"},{"key":"ref12","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.humimm.2006.12.002","article-title":"Immunogenetic control of antibody responsiveness in a malaria endemic area","volume":"68","author":"D Carpenter","year":"2007","journal-title":"Hum Immunol"},{"key":"ref13","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1038\/9649","article-title":"A polymorphism that affects OCT-1 binding to the TNF promoter region is associated with severe malaria","volume":"22","author":"JC Knight","year":"1999","journal-title":"Nat Genet"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1086\/314533","article-title":"Severe malarial anemia and cerebral malaria are associated with different tumor necrosis factor promoter alleles","volume":"179","author":"W McGuire","year":"1999","journal-title":"J Infect Dis"},{"key":"ref15","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1086\/596320","article-title":"Tumor Necrosis Factor and Lymphotoxin-Alpha Polymorphisms and Severe Malaria in African Populations","volume":"199","author":"TG Clark","year":"2009","journal-title":"J Infect Dis"},{"key":"ref16","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1007\/s00439-008-0597-2","article-title":"A genetic association study in The Gambia using tagging polymorphisms in the major histocompatibility complex (MHC) class III region implicates a HLA-B associated transcript 2 (BAT2) polymorphism in severe malaria susceptibility","volume":"125","author":"M Diakite","year":"2009","journal-title":"Hum Genet"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1038\/sj.gene.6364008","article-title":"Complex haplotypic structure of the central MHC region flanking TNF in a West African population","volume":"4","author":"HC Ackerman","year":"2003","journal-title":"Genes Immun"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1086\/432519","article-title":"How malaria has affected the human genome and what human genetics can teach us about malaria","volume":"77","author":"DP Kwiatkowski","year":"2005","journal-title":"Am J Hum Genet"},{"key":"ref19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1365-2370.1997.tb00001.x","article-title":"An investigation of polymorphism in the interleukin-10 gene promoter","volume":"24","author":"DM Turner","year":"1997","journal-title":"Eur J Immunogenet"},{"key":"ref20","doi-asserted-by":"crossref","first-page":"3915","DOI":"10.4049\/jimmunol.166.6.3915","article-title":"Novel single nucleotide polymorphisms in the distal IL-10 promoter affect IL-10 production and enhance the risk of systemic lupus erythematosus","volume":"66","author":"AW Gibson","year":"2001","journal-title":"J Immunol"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1038\/sj.gene.6364227","article-title":"Analysis of IL10 haplotypic associations with severe malaria","volume":"6","author":"JN Wilson","year":"2005","journal-title":"Genes Immun"},{"key":"ref22","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1038\/90868","article-title":"Optimizing human fertility and survival","volume":"7","author":"RG Westendorp","year":"2001","journal-title":"Nat Med"},{"key":"ref23","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":"O Koch","year":"2005","journal-title":"Genes Immun"},{"key":"ref24","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1038\/sj.ejhg.5201084","article-title":"Interleukin-1 gene cluster polymorphisms and susceptibility to clinical malaria in a Gambian case-control study","volume":"12","author":"AJ Walley","year":"2004","journal-title":"Eur J Hum Genet"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"8606","DOI":"10.1074\/jbc.M413541200","article-title":"Induction of proinflammatory responses in macrophages by the glycosylphosphatidylinositols of Plasmodium falciparum: cell signaling receptors, glycosylphosphatidylinositol (GPI) structural requirement, and regulation of GPI activity","volume":"280","author":"G Krishnegowda","year":"2005","journal-title":"J Biol Chem"},{"key":"ref26","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1073\/pnas.0506803102","article-title":"Toll-like receptor (TLR) polymorphisms in African children: Common TLR-4 variants predispose to severe malaria","volume":"103","author":"FP Mockenhaupt","year":"2006","journal-title":"Proc Natl Acad Sciences U_S_A"},{"key":"ref27","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1086\/505152","article-title":"Common polymorphisms of toll-like receptors 4 and 9 are associated with the clinical manifestation of malaria during pregnancy","volume":"194","author":"FP Mockenhaupt","year":"2006","journal-title":"J Infect Dis"},{"key":"ref28","doi-asserted-by":"crossref","first-page":"4926","DOI":"10.4049\/jimmunol.172.8.4926","article-title":"Malaria blood stage parasites activate human plasmacytoid dendritic cells and murine dendritic cells through a Toll-like receptor 9-dependent pathway","volume":"172","author":"S Pichyangkul","year":"2004","journal-title":"J Immunol"},{"key":"ref29","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1084\/jem.20041836","article-title":"Toll-like receptor 9 mediates innate immune activation by the malaria pigment haemozoin","volume":"201","author":"C Coban","year":"2005","journal-title":"J Exp Med"},{"key":"ref30","doi-asserted-by":"crossref","first-page":"2496","DOI":"10.4049\/jimmunol.180.4.2496","article-title":"Malaria Parasites Require TLR9 Signaling for Immune Evasion by Activating Regulatory T Cells","volume":"180","author":"H Hisaeda","year":"2008","journal-title":"J Immunol"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/S1473-3099(05)70023-2","article-title":"Single nucleotide polymorphisms of Toll-like receptors and susceptibility to infectious disease","volume":"5","author":"NWJ Schr\u00f6der","year":"2005","journal-title":"Lancet Infect Dis"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1038\/76048","article-title":"TLR4 mutations are associated with endotoxin hyporesponsiveness in humans","volume":"25","author":"NC Arbour","year":"2000","journal-title":"Nat Genet"},{"key":"ref33","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1038\/ni1116","article-title":"Toll-like receptors in the pathogenesis of human disease","volume":"5","author":"DN Cook","year":"2004","journal-title":"Nat Immunol"},{"key":"ref34","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1001\/archinte.162.9.1028","article-title":"Relevance of mutations in the TLR4 receptor in patients with gram-negative septic shock","volume":"162","author":"E Lorenz","year":"2002","journal-title":"Arch Intern Med"},{"key":"ref35","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1086\/322798","article-title":"A functional polymorphism of toll-like receptor 4 is not associated with likelihood or severity of meningococcal disease","volume":"184","author":"RC Read","year":"2001","journal-title":"J Infect Dis"},{"key":"ref36","doi-asserted-by":"crossref","first-page":"6075","DOI":"10.1073\/pnas.1031605100","article-title":"Assay of locus-specific genetic load implicates rare Toll-like receptor 4 mutations in meningococcal susceptibility","volume":"100","author":"I Smirnova","year":"2003","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref37","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.ejogrb.2004.02.010","article-title":"Relationship between a toll-like receptor-4 gene polymorphism, bacterial vaginosis-related flora and vaginal cytokine responses in pregnant women","volume":"116","author":"MR Genc","year":"2004","journal-title":"Eur J Obstet Gynecol Reprod Biol"},{"key":"ref38","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/S0888-7543(02)00022-8","article-title":"Single-nucleotide polymorphisms in the Toll-like receptor 9 gene (TLR9): frequencies, pairwise linkage disequilibrium, and haplotypes in three U.S. ethnic groups and exploratory case-control disease association studies","volume":"81","author":"R Lazarus","year":"2003","journal-title":"Genomics"},{"key":"ref39","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1053\/j.gastro.2004.05.051","article-title":"Crohn&apos;s disease is associated with a toll-like receptor-9 polymorphism","volume":"127","author":"HP T\u00f6r\u00f6k","year":"2004","journal-title":"Gastroenterology"},{"key":"ref40","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1086\/590440","article-title":"Variants in the Toll-Like Receptor Signaling Pathway and Clinical Outcomes of Malaria","volume":"198","author":"FM Leoratti","year":"2008","journal-title":"J Infect Dis"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1186\/1475-2875-8-44","article-title":"TLR9 polymorphisms in African populations: no association with severe malaria, but evidence of cis-variants acting on gene expression","volume":"8","author":"S Campino","year":"2009","journal-title":"Malar J"},{"key":"ref42","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1038\/ng.388","article-title":"Genome-wide and fine-resolution association analysis of malaria in West Africa","volume":"41","author":"M Jallow","year":"2009","journal-title":"Nat Genet"},{"key":"ref43","doi-asserted-by":"crossref","first-page":"e43987","DOI":"10.1371\/journal.pone.0043987","article-title":"Candidate Polymorphisms and Severe Malaria in a Malian","volume":"7","author":"O Toure","year":"2012","journal-title":"Population - PLOS ONE"},{"key":"ref44","doi-asserted-by":"crossref","first-page":"e47463","DOI":"10.1371\/journal.pone.0047463","article-title":"Candidate Human Genetic Polymorphisms and Severe Malaria in a Tanzanian","volume":"7","author":"A Manjurano","year":"2012","journal-title":"Population - PLOS ONE"},{"key":"ref45","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1179\/136485908X252287","article-title":"Febrile status, malarial parasitaemia and gastro-intestinal helminthiases in school children resident at different altitudes, in south\u2013western Cameroon","volume":"102","author":"EA Achidi","year":"2008","journal-title":"Ann Trop Med Parasitol"},{"key":"ref46","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1186\/1475-2875-11-215","article-title":"Severe and uncomplicated falciparum malaria in children from three regions and three ethnic groups in Cameroon: prospective study","volume":"11","author":"EA Achidi","year":"2012","journal-title":"Malar J"},{"key":"ref47","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1016\/S0035-9203(00)90300-6","article-title":"Severe falciparum malaria","volume":"94","year":"2000","journal-title":"Trans R Soc Trop Med Hyg"},{"key":"ref48","doi-asserted-by":"crossref","first-page":"309","DOI":"10.4269\/ajtmh.1991.45.309","article-title":"<italic>Plasmodium<\/italic> <italic>falciparum<\/italic> reinfection in children from a holoendemic area in relation to seroreactivities against oligopeptides from different malarial antigens","volume":"45","author":"I Rooth","year":"1991","journal-title":"Am J Trop Med Hyg"},{"key":"ref49","doi-asserted-by":"crossref","first-page":"5847","DOI":"10.1073\/pnas.89.13.5847","article-title":"Whole genome amplification from a single cell: implications for genetic analysis","volume":"89","author":"L Zhang","year":"1992","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref50","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1038\/4328","article-title":"High level multiplex genotyping by MALDI-TOF mass spectrometry","volume":"16","author":"P Ross","year":"1998","journal-title":"Nat Biotechnol"},{"key":"ref51","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1111\/j.1469-1809.2007.00356.x","article-title":"On the usage of HWE for identifying genotyping errors","volume":"71","author":"YY Teo","year":"2007","journal-title":"Ann Hum Genet"},{"key":"ref52","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1086\/301967","article-title":"Malaria in humans: <italic>Plasmodium<\/italic> <italic>falciparum<\/italic> blood infection levels are linked to chromosome 5q31-q33","volume":"63","author":"P Rihet","year":"1998","journal-title":"Am J Hum Genet"},{"key":"ref53","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1111\/j.1365-2249.2004.02590.x","article-title":"Allelic polymorphisms in the repeat and promoter regions of the interleukin-4 gene and malaria severity in Ghanaian children","volume":"138","author":"BA Gyan","year":"2004","journal-title":"Clin Exp Immunol"},{"key":"ref54","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1038\/sj.gene.6363630","article-title":"An IL-13 promoter polymorphism associated with increased risk of allergic asthma","volume":"1","author":"TC van der Pouw Kraan","year":"1999","journal-title":"Genes Immun"},{"key":"ref55","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1038\/sj.gene.6363896","article-title":"Chronic obstructive pulmonary disease is associated with the -1055 IL-13 promoter polymorphism","volume":"3","author":"TC van der Pouw Kraan","year":"2002","journal-title":"Genes Immun"},{"key":"ref56","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1038\/sj.gene.6364010","article-title":"A single-nucleotide substitution from C to T at position -1055 in the IL-13 promoter is associated with protection from severe malaria in Thailand","volume":"4","author":"J Ohashi","year":"2003","journal-title":"Genes Immun"},{"key":"ref57","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1365-2370.1997.tb00001.x","article-title":"An investigation of polymorphism in the interleukin-10 gene promoter","volume":"24","author":"DM Turner","year":"1997","journal-title":"Eur J Immunogenet"},{"key":"ref58","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.immuni.2004.07.007","article-title":"IL-22 increases the innate immunity of tissues","volume":"21","author":"K Wolk","year":"2004","journal-title":"Immunity"},{"key":"ref59","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1097\/QAD.0b013e3280ef6ae1","article-title":"Polymorphisms in IRF-1 associated with resistance to HIV-1 infection in highly exposed uninfected Kenyan sex workers","volume":"21","author":"TB Ball","year":"2007","journal-title":"AIDS"},{"key":"ref60","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1038\/sj.gene.6364456","article-title":"Interferon regulatory factor-1 polymorphisms are associated with the control of Plasmodium falciparum infection","volume":"9","author":"VD Mangano","year":"2008","journal-title":"Genes Immun"},{"key":"ref61","doi-asserted-by":"crossref","first-page":"e4206","DOI":"10.1371\/journal.pone.0004206","article-title":"Lack of association of interferon regulatory factor 1 with severe malaria in affected child-parental trio studies across three African populations","volume":"4","author":"VD Mangano","year":"2009","journal-title":"PLOS ONE"},{"key":"ref62","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1086\/522865","article-title":"Toll-like receptor modulation of murine cerebral malaria is dependent on the genetic background of the host","volume":"196","author":"JW Griffith","year":"2007","journal-title":"J Infect Dis"},{"key":"ref63","doi-asserted-by":"crossref","first-page":"6093","DOI":"10.1038\/sj.onc.1210424","article-title":"Downregulation of Sef, an inhibitor of receptor tyrosine kinase signaling, is common to a variety of human carcinomas","volume":"26","author":"S Zisman-Rozen","year":"2007","journal-title":"Oncogene"},{"key":"ref64","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1186\/1475-2875-6-147","article-title":"Cerebrospinal fluid and serum biomarkers of cerebral malaria mortality in Ghanaian children","volume":"6","author":"HB Armah","year":"2007","journal-title":"Malar J"},{"key":"ref65","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1186\/1475-2875-7-83","article-title":"Plasma IP-10, apoptotic and angiogenic factors associated with fatal cerebral malaria in India","volume":"7","author":"V Jain","year":"2008","journal-title":"Malar J"}],"container-title":["PLoS ONE"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/dx.plos.org\/10.1371\/journal.pone.0081071","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,5,8]],"date-time":"2020-05-08T23:37:45Z","timestamp":1588981065000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0081071"}},"subtitle":[],"editor":[{"given":"Nicholas\u00a0M","family":"Pajewski","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2013,11,27]]},"references-count":65,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2013,11,27]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0081071","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,11,27]]}}}