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Variants within the Fc gamma receptors (Fc\u03b3Rs) mediate immunity through engagement of immunoglobulin G and other immune mediators, such as gamma interferon (IFN-\u03b3), resulting in erythrophagocytosis and production of inflammatory cytokines in severe malarial anemia (SMA). The Toll-like receptors (TLRs) trigger transcription of proinflammatory cytokines and induce adaptive immune responses. Therefore, these receptors may condition malaria disease pathogenesis through alteration in adaptive and innate immune responses. To further delineate the impacts of Fc\u03b3RIIIA and TLR9 in SMA pathogenesis, the associations between Fc\u03b3RIIIA \u2212176F\/V and TLR9 \u22121237T\/C variants, SMA (hemoglobin [Hb] &lt; 6.0 g\/dl), and circulating IFN-\u03b3 levels were investigated in children (<jats:italic>n<\/jats:italic>= 301) from western Kenya with acute malaria. Multivariate logistic regression analysis (controlling for potential confounders) revealed that children with the Fc\u03b3RIIIA \u2212176V\/TLR9 \u22121237C (VC) variant combination had 64% reduced odds of developing SMA (odds ratio [OR], 0.36; 95% confidence interval [CI], 0.20 to 0.64;<jats:italic>P<\/jats:italic>= 0.001), while carriers of the Fc\u03b3RIIIA \u2212176V\/TLR9 \u22121237T (VT) variant combination were twice as susceptible to SMA (OR, 2.04; 95% CI, 1.19 to 3.50;<jats:italic>P<\/jats:italic>= 0.009). Children with SMA had higher circulating IFN-\u03b3 levels than non-SMA children (<jats:italic>P<\/jats:italic>= 0.008). Hemoglobin levels were negatively correlated with IFN-\u03b3 levels (<jats:italic>r<\/jats:italic>= \u22120.207,<jats:italic>P<\/jats:italic>= 0.022). Consistently, the Fc\u03b3RIIIA \u2212176V\/TLR9 \u22121237T (VT) carriers had higher levels of circulating IFN-\u03b3 (<jats:italic>P<\/jats:italic>= 0.011) relative to noncarriers, supporting the observation that higher IFN-\u03b3 levels are associated with SMA. These results demonstrate that Fc\u03b3RIIIA-176F\/V and TLR9 \u22121237T\/C variants condition susceptibility to SMA and functional changes in circulating IFN-\u03b3 levels.<\/jats:p>","DOI":"10.1128\/iai.00945-12","type":"journal-article","created":{"date-parts":[[2012,10,9]],"date-time":"2012-10-09T05:29:22Z","timestamp":1349760562000},"page":"4435-4443","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":13,"title":["Polymorphisms in the Fc Gamma Receptor IIIA and Toll-Like Receptor 9 Are Associated with Protection against Severe Malarial Anemia and Changes in Circulating Gamma Interferon Levels"],"prefix":"10.1128","volume":"80","author":[{"given":"Elly O.","family":"Munde","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, School of Public Health and Community Development, Maseno University, Maseno, Kenya"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Winnie 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