Genetic association of Toll-like-receptor 4 and tumor necrosis factor-α polymorphisms with Plasmodium falciparum blood infection levels

Basu, Madhumita; Maji, Ardhendu Kumar; Chakraborty, Arindom; Banerjee, Rahul; Mullick, Shrabanee; Saha, Pabitra; Das, Sonali; Kanjilal, Sumana Datta; Sengupta, Sanghamitra

doi:10.1016/j.meegid.2010.03.008

Cited by 44 publications

(36 citation statements)

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“…Basu et al (32) investigated five TNFA SNPs (−1031T/C, −857C/T, −308G/A, −238G/A and intronic variant 489G/A (rs1800610)) in malaria patients in India. They found that the TNFA −1031C allele and CC genotype were risk factors for more severe clinical indices.…”

Section: Discussionmentioning

confidence: 99%

TNF-alpha gene (TNFA) variants increase risk for multi-organ dysfunction syndrome (MODS) in acute pancreatitis

et al. 2012

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Background/Objectives Acute pancreatitis (AP) is a complex inflammatory syndrome with unpredictable progression to systemic inflammation and multi-organ dysfunction syndrome (MODS). Tumor necrosis factor alpha (TNF–α) is a cytokine that may link inflammation to the systemic inflammatory response syndrome (SIRS), which usually precedes MODS. Small genetic cohort studies of the TNFA promoter in AP produced ambiguous results. We performed a comprehensive evaluation of TNFA promoter variants to assess both susceptibility to AP and risk of progression to MODS. Methods We prospectively ascertained 401 controls and 211 patients with AP that were assessed for persistent SIRS (>48 hours) and MODS. MODS was defined as failure of ≥2 organ systems (cardiovascular, pulmonary, and/or renal) persisting more than 48 hours. Subjects were genotyped by DNA sequencing and analyzed for SNPs at −1031 C/T (rs1799964), −863 A/C (rs1800630), −857 C/T (rs1799724), −308 A/G (rs1800629), and −238 A/G (rs361525). Results Twenty-three of 211 AP patients (11%) developed MODS. TNFA promoter variants were not associated with susceptibility to AP, but progression to MODS was associated with the minor allele at −1031C (56.5% vs. 32.4% P=0.022, OR: 2.7; 95%CI: 1.12–6.51) and −863A (43.5% vs. 21.8% P=0.022, OR: 2.76; 95%CI: 1.12–6.74). Conclusion TNFA promoter variants do not alter susceptibility to AP, but rather the TNF–α expression-enhancing −1031C and −863A alleles significantly increased the risk of AP progression to MODS. These data, within the context of previous studies, clarify the risk of specific genetic variants in TNFA and therefore the role of TNF–α in the overall AP syndrome.

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Section: Discussionmentioning

confidence: 99%

TNF-alpha gene (TNFA) variants increase risk for multi-organ dysfunction syndrome (MODS) in acute pancreatitis

et al. 2012

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“…For instance, polymorphisms in TLR1 , TLR4 and TLR9 are associated with an aggravated clinical status of malaria during pregnancy [10], [11]. Polymorphisms in TLR4 are also reported to play a role in controlling the parasitemia level in malaria [12]. Furthermore, in malaria, alleles associated with sickle-cell anemia, thalassemias, and glucose-6-phosphate dehydrogenase deficiency confer protective effects, whereas polymorphisms in the TNF-α gene have been linked to increased risk of cerebral malaria (CM) [13].…”

Section: Introductionmentioning

confidence: 99%

Insufficiently Defined Genetic Background Confounds Phenotypes in Transgenic Studies As Exemplified by Malaria Infection in Tlr9 Knockout Mice

et al. 2011

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The use of genetically modified mice, i.e. transgenic as well as gene knockout (KO) and knock-in mice, has become an established tool to study gene function in many animal models for human diseases . However, a gene functions in a particular genomic context. This implies the importance of a well-defined homogenous genetic background for the analysis and interpretation of phenotypes associated with genetic mutations. By studying a Plasmodium chabaudi chabaudi AS (PcAS) malaria infection in mice bearing a TLR9 null mutation, we found an increased susceptibility to infection, i.e. higher parasitemia levels and increased mortality. However, this was not triggered by the deficient TLR9 gene itself. Instead, this disease phenotype was dependent on the heterogeneous genetic background of the mice, which appeared insufficiently defined as determined by single nucleotide polymorphism (SNP) analysis. Hence, it is of critical importance to study gene KO phenotypes on a homogenous genetic background identical to that of their wild type (WT) control counterparts. In particular, to avoid problems related to an insufficiently defined genetic background, we advocate that for each study involving genetically modified mice, at least a detailed description of the origin and genetic background of both the WT control and the altered strain of mice is essential.

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“…In addition, our recent observation of opposing associations of the -1237C allele with different sub-clinical severe malarial phenotypes such as single organ dysfunction (SOD) vs. multi-organ dysfunction (MODS) 2 suggests that phenotype misclassification in malaria could also lead to a reduction in the power to detect the contribution of this variant. This may explain the lack of observed associations between the T-1237C variant and susceptibility or resistance to malaria 22,27,29,30 , in addition to other factors. Therefore, future studies examining large sample sizes of malaria-infected patients categorized into required phenotype classes from different ethnic populations and belonging to different age groups are eagerly awaited for confirmation.…”

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confidence: 98%

A meta-analysis of TLR4 and TLR9 SNPs implicated in severe malaria

Dhangadamajhi

Kar

Rout

et al. 2017

Rev. Soc. Bras. Med. Trop.

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Toll-like receptors (TLRs) are critical mediators of the inflammatory response to malarial infection, and gene polymorphisms affecting TLR function may be partially responsible for inter-individual variation in disease manifestation. However, there are inconsistencies in the associations of common genetic variants of TLR4 (D299G) and TLR9 (T-1237C and T-1486C) with malaria outcome. A comprehensive search was conducted to identify relevant and independent Plasmodium falciparum-infected casecontrol studies, and meta-analysis including six studies for each SNP was performed to obtain more precise estimates of the pooled effects of these variants. The results showed significant associations of the -1486C allele with the risk of severe malaria in allele contrast (T vs. C, p = 0.004, OR = 1.26) and homozygous (TT vs. CC, p = 0.03, OR = 1.51) genetic models. There was no association between the D299G or T-1237C variants and uncomplicated or severe malaria using any of the genetic models tested. However, in stratified analysis, -1237C was associated with the risk of severe malaria in Indian adults (TT vs. TC, p = 0.06, OR = 2.13; TT vs. TC+CC, p <0.00001, OR = 2.65), suggesting that our results must be considered preliminary. The robustness of -1486C as a risk factor warrants investigation into its functionality in malaria pathogenesis. Further, the lack of an association with the T-1237C variant was weak, and future studies examining more detailed individual data from different ethnic groups are essential for confirmation of its genetic contribution to malaria.

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Genetic association of Toll-like-receptor 4 and tumor necrosis factor-α polymorphisms with Plasmodium falciparum blood infection levels

Cited by 44 publications

References 51 publications

TNF-alpha gene (TNFA) variants increase risk for multi-organ dysfunction syndrome (MODS) in acute pancreatitis

TNF-alpha gene (TNFA) variants increase risk for multi-organ dysfunction syndrome (MODS) in acute pancreatitis

Insufficiently Defined Genetic Background Confounds Phenotypes in Transgenic Studies As Exemplified by Malaria Infection in Tlr9 Knockout Mice

A meta-analysis of TLR4 and TLR9 SNPs implicated in severe malaria

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