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Although largely unexplored in children with SMA, interleukin-18 (IL-18) is important for regulating innate and acquired immunity in inflammatory and infectious diseases. As such, we selected two functional single-nucleotide polymorphisms (SNPs) in the IL-18 promoter (\u2212137G\u2192C [rs187238] and \u2212607C\u2192A [rs1946518]) whose haplotypes encompass significant genetic variation due to the presence of strong linkage disequilibrium among these variants. The relationship between the genotypes\/haplotypes, SMA (hemoglobin [Hb], &lt;5.0 g\/dl], and longitudinal clinical outcomes were then investigated in Kenyan children (<jats:italic>n<\/jats:italic>= 719). Multivariate logistic regression analyses controlling for age, gender, sickle cell trait, glucose-6-phosphate dehydrogenase (G6PD) deficiency, HIV-1, and bacteremia revealed that carriage of the \u2212607AA genotype was associated with protection against SMA (odds ratio [OR] = 0.440 [95% confidence interval {CI} = 0.21 to 0.90],<jats:italic>P<\/jats:italic>= 0.031) in children with acute infection. In contrast, carriers of the \u2212137G\/\u2212607C (GC) haplotype had increased susceptibility to SMA (OR = 2.050 [95% CI = 1.04 to 4.05],<jats:italic>P<\/jats:italic>= 0.039). Measurement of IL-18 gene expression in peripheral blood leukocytes demonstrated that elevated IL-18 transcripts were associated with reduced hemoglobin concentrations (\u03c1 = \u22120.293,<jats:italic>P<\/jats:italic>= 0.010) and that carriers of the \u201csusceptible\u201d GC haplotype had elevated IL-18 transcripts (<jats:italic>P<\/jats:italic>= 0.026). Longitudinal investigation of clinical outcomes over a 3-year follow-up period revealed that carriers of the rare CC haplotype (\u223c1% frequency) had 5.76 times higher mortality than noncarriers (<jats:italic>P<\/jats:italic>= 0.001). Results presented here demonstrate that IL-18 promoter haplotypes that condition elevated IL-18 gene products during acute infection are associated with increased risk of SMA. Furthermore, carriage of the rare CC haplotype significantly increases the risk of childhood mortality.<\/jats:p>","DOI":"10.1128\/iai.05601-11","type":"journal-article","created":{"date-parts":[[2011,10,4]],"date-time":"2011-10-04T03:47:52Z","timestamp":1317700072000},"page":"4923-4932","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":21,"title":["Functional Promoter Haplotypes of Interleukin-18 Condition Susceptibility to Severe Malarial Anemia and Childhood Mortality"],"prefix":"10.1128","volume":"79","author":[{"given":"Samuel B.","family":"Anyona","sequence":"first","affiliation":[{"name":"University of New Mexico\/Kenya Medical Research Institute, Laboratories of Parasitic and Viral Diseases, Centre for Global Health Research, Kisumu, Kenya"},{"name":"Department of Biochemistry and Biotechnology, Kenyatta University, Nairobi, Kenya"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prakasha","family":"Kempaiah","sequence":"additional","affiliation":[{"name":"Center for Global Health, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evans","family":"Raballah","sequence":"additional","affiliation":[{"name":"University of New Mexico\/Kenya Medical Research Institute, Laboratories of Parasitic and Viral Diseases, Centre for Global Health Research, Kisumu, Kenya"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Collins","family":"Ouma","sequence":"additional","affiliation":[{"name":"University of New Mexico\/Kenya Medical Research Institute, Laboratories of Parasitic and Viral Diseases, Centre for Global Health Research, Kisumu, Kenya"},{"name":"Department of Biomedical Sciences and Technology, Maseno University, Maseno, Kenya"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"Were","sequence":"additional","affiliation":[{"name":"University of New Mexico\/Kenya Medical Research Institute, Laboratories of Parasitic and Viral Diseases, Centre for Global Health Research, Kisumu, Kenya"},{"name":"Department of Pathology, School of Health Sciences, Kenyatta University, Nairobi, Kenya"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory C.","family":"Davenport","sequence":"additional","affiliation":[{"name":"Center for Global Health, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen N.","family":"Konah","sequence":"additional","affiliation":[{"name":"University of New Mexico\/Kenya Medical Research Institute, Laboratories of Parasitic and Viral Diseases, Centre for Global Health Research, Kisumu, Kenya"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John M.","family":"Vulule","sequence":"additional","affiliation":[{"name":"Centre for Global Health Research, Kenya Medical Research Institute, Kisumu, Kenya"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James B.","family":"Hittner","sequence":"additional","affiliation":[{"name":"Department of Psychology, College of Charleston, Charleston, South Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charity W.","family":"Gichuki","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biotechnology, Kenyatta University, Nairobi, Kenya"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John M.","family":"Ong'echa","sequence":"additional","affiliation":[{"name":"University of New Mexico\/Kenya Medical Research Institute, Laboratories of Parasitic and Viral Diseases, Centre for Global Health Research, Kisumu, Kenya"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas J.","family":"Perkins","sequence":"additional","affiliation":[{"name":"University of New Mexico\/Kenya Medical Research Institute, Laboratories of Parasitic and Viral Diseases, Centre for Global Health Research, Kisumu, Kenya"},{"name":"Center for Global Health, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","first-page":"36","article-title":"Image processing with ImageJ","volume":"11","author":"Abramoff M. 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