DDX39B (BAT1), TNF and IL6 gene polymorphisms and association with clinical outcomes of patients with Plasmodium vivax malaria.

Vitor Rr Mendonça,Gabriela C Garcia,Ligia Cl Souza,Belisa Ml Magalhães,Bruno B Andrade,Marcus Vg Lacerda,Manoel Barral-Netto,Marilda S Gonçalves

doi:10.1186/1475-2875-13-278

Abstract

BackgroundDDX39B (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.MethodsCross-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.ResultsThe 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.ConclusionsThis 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.

Highlights

DEAD [Asp-Glu-Ala-Asp] box polypeptide 39B (DDX39B) (BAT1) encodes an Ribonucleic acid (RNA) helicase known to regulate expression of Tumor necrosis factor (TNF) and Interleukin 6 (IL-6)
The results reported here revealed that a combination of DDX39B, TNF and IL6 host genotypes were associated with manifestations of malaria, mainly by altering plasma levels of TNF and IL-6
Exclusion criteria included conditions known to interfere with the parameters evaluated in this report, such as coinfections and chronic diseases: P. falciparum infection confirmed by nested Polymerase chain reaction (PCR); documented or referred viral hepatitis; chronic alcoholism; human immunodeficiency virus (HIV) infection; yellow fever; dengue; leptospirosis; tuberculosis; Hansen disease; visceral leishmaniasis; cancer and/or other chronic degenerative disease; sickle cell trait; and the use of hepatotoxic and immunosuppressant drugs

Summary

Introduction

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. The clinical outcomes of patients with vivax malaria range from asymptomatic infection to complicated, and potentially lethal disease [2]. The nuclear protein HLA-B-associated transcript 1 (BAT1) is an RNA helicase encoded by the DDX39B gene (DEAD [Asp-Glu-Ala-Asp] box polypeptide 39B, known as BAT1). The hypothesis that DDX39B may have an effect on the clinical presentation of malaria by its modulation of the expression of proinflammatory cytokines involved in the pathogenesis of the disease is appealing, but has not yet been tested

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