title: DDX39B (BAT1), TNF and IL6 gene polymorphisms and association with clinical outcomes of patients with Plasmodium vivax malaria.
abstract: BACKGROUND
  DDX39B (BAT1) encodes an RNA helicase known to regulate expression of TNF and IL-6. Elevated levels of these two cytokines are associated with increased severity of clinical malaria. The aim of this study was to investigate the relationship between single nucleotide polymorphisms (SNPs) in the DDX39B, TNF and IL6 genes and the clinical outcomes of patients with Plasmodium vivax malaria.
  
  
  METHODS
  Cross-sectional investigations were carried out in two regions of the Brazilian Amazon where several studies on the pathogenesis of vivax malaria had been performed. Individuals were categorized according to infection status as well as clinical presentation into the following groups: uninfected, asymptomatic infection, mild infection, or complicated infection. Polymorphisms were identified using PCR restriction fragment-length polymorphism analysis and the restriction enzymes NlaIII or NcoI. The plasma levels of cytokines were determined using ELISA.
  
  
  RESULTS
  The G allele of DDX39B-22C > G was associated with absent or decreased manifestations of malaria and the C allele was a risk factor for disease complications. Study participants heterozygous for TNF-308 (GA) and DDX39B-348 (CT) had higher TNF levels than wild-type participants. Haplotypes that included DDX39B (-22C > G and -348C > T) and TNF polymorphisms were not directly associated with mild or complicated malaria infections; however, haplotypes AGC, ACC, GGT, AGT and ACT were associated with increased TNF levels. Participants with genotype combinations GC/CC/GG/GG and GG/CT/GG/GG (DDX39B-22/DDX39B-348/TNF-308/IL6-176) had decreased and increased risk of mild malaria, respectively, compared with asymptomatic and uninfected participants. GC/CC/GG/GG was linked to decreased TNF and IL-6 levels.
  
  
  CONCLUSIONS
  This is the first study to describe patients with DDX39B and IL6 SNPs who had vivax malaria. These findings support the postulation that a set of mutations in immune-related genes is associated with inflammatory mediators and the clinical outcomes of patients with malaria.
authors.forename: Vitor R R
authors.initials: VR
authors.lastname: Mendonça
authors.forename: Ligia C L
authors.initials: LC
authors.lastname: Souza
authors.forename: Gabriela C
authors.initials: GC
authors.lastname: Garcia
authors.forename: Belisa M L
authors.initials: BM
authors.lastname: Magalhães
authors.forename: Marcus V G
authors.initials: MV
authors.lastname: Lacerda
authors.forename: Bruno B
authors.initials: BB
authors.lastname: Andrade
authors.forename: Marilda S
authors.initials: MS
authors.lastname: Gonçalves
authors.affiliation: Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz (FIOCRUZ), Salvador, Brazil. mbarral@bahia.fiocruz.br.
authors.forename: Manoel
authors.initials: M
authors.lastname: Barral-Netto
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D000740:Anemia / Q000209:etiology; D001938:Brazil; D002648:Child; D002675:Child, Preschool; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D053487:DEAD-box RNA Helicases / Q000235:genetics* / Q000502:physiology; D060467:Disease Resistance / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D006932:Hyperbilirubinemia / Q000209:etiology; D007223:Infant; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics*; D016780:Malaria, Vivax / Q000150:complications / Q000235:genetics* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D012131:Respiratory Insufficiency / Q000209:etiology; D012306:Risk; D012640:Seizures / Q000209:etiology; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000235:genetics*; D055815:Young Adult
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; C487886:DDX39B protein, human; D053487:DEAD-box RNA Helicases