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Tumor necrosis factor and lymphotoxin-alpha polymorphisms and severe malaria in African populations.

ABSTRACT: The tumor necrosis factor gene (TNF) and lymphotoxin-alpha gene (LTA) have long attracted attention as candidate genes for susceptibility traits for malaria, and several of their polymorphisms have been found to be associated with severe malaria (SM) phenotypes. In a large study involving >10,000 individuals and encompassing 3 African populations, we found evidence to support the reported associations between the TNF -238 polymorphism and SM in The Gambia. However, no TNF/LTA polymorphisms were found to be associated with SM in cohorts in Kenya and Malawi. It has been suggested that the causal polymorphisms regulating the TNF and LTA responses may be located some distance from the genes. Therefore, more-detailed mapping of variants across TNF/LTA genes and their flanking regions in the Gambian and allied populations may need to be undertaken to find any causal polymorphisms.

SUBMITTER: Clark TG

PROVIDER: S-EPMC2742199 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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Tumor necrosis factor and lymphotoxin-alpha polymorphisms and severe malaria in African populations.

Clark Taane G TG Diakite Mahamadou M Auburn Sarah S Campino Susana S Fry Andrew E AE Green Angela A Richardson Anna A Small Kerrin K Teo Yik Y YY Wilson Jonathan J Jallow Muminatou M Sisay-Joof Fatou F Pinder Margaret M Griffiths Michael J MJ Peshu Norbert N Williams Thomas N TN Marsh Kevin K Molyneux Malcolm E ME Taylor Terrie E TE Rockett Kirk A KA Kwiatkowski Dominic P DP

The Journal of infectious diseases 20090201 4

The tumor necrosis factor gene (TNF) and lymphotoxin-alpha gene (LTA) have long attracted attention as candidate genes for susceptibility traits for malaria, and several of their polymorphisms have been found to be associated with severe malaria (SM) phenotypes. In a large study involving >10,000 individuals and encompassing 3 African populations, we found evidence to support the reported associations between the TNF -238 polymorphism and SM in The Gambia. However, no TNF/LTA polymorphisms were ...[more]

PMID: 19281305

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Project description:To investigate the significance of functional polymorphisms of inflammatory response genes by analysis of a large population of patients, both with and without severe sepsis, and representative of the diverse populations (geographic diversity, physician diversity, clinical treatment diversity) that would be encountered in critical care clinical practice.: Collaborative case-control study conducted from July 2001 to December 2005.A heterogeneous population of patients from 12 U.S. intensive care units represented by the Genetic Predisposition to Severe Sepsis archive.A total of 854 patients with severe sepsis and an equal number of mortality, age, gender, and race-matched patients also admitted to the intensive care unit without evidence of any infection (matched nonseptic controls).We developed assays for six functional single nucleotide polymorphisms present before the first codon of tumor necrosis factor at -308, IL1B at -511, IL6 at -174, IL10 at -819, and CD14 at -159, and in the first intron of LTA (also known as tumor necrosis factor-B) at +252 (LTA[+252]). The Project IMPACT critical care clinical database information management system developed by the Society of Critical Care Medicine and managed by Tri-Analytics and Cerner Corporation was utilized. Template-directed dye-terminator incorporation assay with fluorescence polarization detection was used as a high-throughput genotyping strategy. Fifty-three percent of the patients were male with 87.3% and 6.4% of Caucasian and African American racial types, respectively. Overall mortality was 35.1% in both severe sepsis and matched nonseptic control patients group. Average ages (standard deviation) of the severe sepsis and matched nonseptic control patients were 63.0 (16.05) and 65.0 (15.58) yrs old, respectively. Among the six single nucleotide polymorphisms, LTA (+252) was most overrepresented in the septic patient group (% severe sepsis; AA 45.6: AG 51.1: GG 56.7, p = .005). Furthermore, the genetic risk effect was most pronounced in males, age >60 yrs (p = .005).LTA(+252) may influence predisposition to severe sepsis, a predisposition that is modulated by gender and age. Although the genetic influences can be overwhelmed by both comorbid factors and acute illness in individual cases, population studies suggest that this is an influential biological pathway modulating risk of critical illnesses.

Project description:The multifactorial pathogenesis of severe malaria is partly attributed to host genes, such as those encoding cytokines involved in complex inflammatory reactions, namely tumor necrosis factor-alpha (TNF-α). However, the relationship between TNF-α -308G >A gene polymorphism (rs1800629) and the severity of Plasmodium falciparum (P. falciparum) malaria remains unclear, which prompts a meta-analysis to obtain more precise estimates. The present meta-analysis aimed to better understand this correlation and provide insight into its association in populations with different ethnicities. Literature search outcomes included eight eligible articles in which TNF-α -308G >A polymorphism was determined in uncomplicated malaria (UM) and severe malaria (SM) of P. falciparum as represented in the case and control groups. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated in standard homozygous, recessive, dominant, and codominant genetic models. Subgroup analysis was based on ethnicity, i.e., Africans and Asians. The analyses included overall and the modified outcomes; the latter was obtained without the studies that deviated from the Hardy-Weinberg Equilibrium. The significant data also underwent sensitivity treatment but not publication bias tests because the number of studies was less than ten. Interaction tests were applied to differential outcomes between the subgroups. Overall and HWE-compliant analyses showed no significant association between the TNF-α -308G >A polymorphism and susceptibility to P. falciparum SM (ORs = 1.10-1.52, 95%CIs = 0.68-2.79; Pa = 0.24-0.68). Stratification by ethnicity revealed that two significant associations were found only in the Asians favoring SM for dominant (OR = 1.95, 95% CI = 1.06-3.61, Pa = 0.03) and codominant (OR = 1.83, 95% CI = 1.15-2.92, Pa = 0.01) under the random-effects model, but not among the African populations. The two significant Asian associations were improved with a test of interaction with P-value of0.02-0.03. The significant core outcomes were robust. Results of the meta-analysis suggest that TNF-α -308G >A polymorphism might affect the risk of P. falciparum SM, particularly in individuals of Asian descent. This supports ethnicity as one of the dependent factors of the TNF-α -308G >A association with the clinical severity of malaria. Further large and well-designed genetic studies are needed to confirm this conclusion.

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Tumor necrosis factor and lymphotoxin-alpha polymorphisms and severe malaria in African populations.

Publications

Tumor necrosis factor and lymphotoxin-alpha polymorphisms and severe malaria in African populations.

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