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

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.

Frequency ofTNFA,INFG, andIL10Gene Polymorphisms and Their Association with MalariaVivaxand Genomic Ancestry

“…Contradictory results were observed for malaria, with the TNFA-308A allele associated with higher susceptibility/severity [62–64], without alterations [39] or with resistance to P. falciparum malaria [65]. Regarding vivax malaria, which was the focus of the present study, our results were in agreement with other studies, including those in the Brazilian Amazon that did not observe any associations between the TNFA-308G>A SNP and susceptibility or clinical manifestations due to P. vivax infection [10, 19, 66]. …”

“…One hypothesis for the lack of association of the evaluated SNPs is that malaria can occur due to possible linkage disequilibrium of the SNPs in TNFA with the human leukocyte antigens (HLAs), which can cause nonfunctional mutations [65, 66]. The A allele (-308) is described as having a strong linkage disequilibrium with HLA-Bw53 and DRB1 ∗ 1302-DQB1 ∗ 0501, whereas the A allele at the -238 position of the TNFA gene appears to be linked to HLA-B53 but with different immune characteristics [62].…”

Synthetic Antigens Derived from Plasmodium falciparum Sporozoite, Liver, and Blood Stages: Naturally Acquired Immune Response and Human Leukocyte Antigen Associations in Individuals Living in a Brazilian Endemic Area

“…Asymptomatic and or paucisymptomatic infections by P. falciparum and Plasmodium vivax were detected in epidemiological studies in the states of Rondônia (RO) and Amazonas, which likely indicates a pattern of clinical immunity in both populations. [24][25][26][27][28] Seropidemiological studies investigating the type of immune responses elicited in naturally exposed populations to several malaria vaccine candidates in Brazilian populations provide important information on whether immune responses specific to these antigens are generated in natural infections and their immunogenic potential as vaccine candidates.…”

The Branched-chain Amino Acid Transaminase 1 -23C/G Polymorphism Confers Protection Against Acute Coronary Syndrome

“…In addition, Gnjec et al reported that the -23 GG genotype of BAT1 -23 C/G was associated with reduced risk of Alzheimer's disease in Caucasian population (OR = 0.43) 23 . On the other hand, Mendonça et al reported in patients infected with Plasmodium vivax that the -23 G allele was associated with reduced clinical manifestations of malaria in Brazilian populations 14 .…”

“…The BAT1, NFKBIL1, and LTA genes are located in the 6p21.3 region. BAT1 encodes a nuclear protein is called HLA-B-associated transcript 1, which negatively regulates the expression of interleukin (IL)-1, tumor necrosis factor (TNF), and IL-6 13,14 ; NFKBIL1 encodes a protein homologous to IκB (κB inhibitors), which regulates the expression of nuclear factor-kappa B transcription factor, TNF, IL-1, and IL-6 15 ; and LTA encodes a protein involved in the inflammatory and immunological response 16 . LTA binds to their cognates, TNF receptors (TNFR1) and TNFR2, and regulates the expression of anti-apoptotic proteins to prevent cell death, inflammatory response, and cell differentiation 17 .…”