Dataset Information

A study of the TNF/LTA/LTB locus and susceptibility to severe malaria in highland papuan children and adults.

ABSTRACT: Severe malaria (SM) syndromes caused by Plasmodium falciparum infection result in major morbidity and mortality each year. However, only a fraction of P. falciparum infections develop into SM, implicating host genetic factors as important determinants of disease outcome. Previous studies indicate that tumour necrosis factor (TNF) and lymphotoxin alpha (LT?) may be important for the development of cerebral malaria (CM) and other SM syndromes.An extensive analysis was conducted of single nucleotide polymorphisms (SNPs) in the TNF, LTA and LTB genes in highland Papuan children and adults, a population historically unexposed to malaria that has migrated to a malaria endemic region. Generated P-values for SNPs spanning the LTA/TNF/LTB locus were corrected for multiple testing of all the SNPs and haplotype blocks within the region tested through 10,000 permutations. A global P-value of < 0.05 was considered statistically significant.No associations between SNPs in the TNF/LTA/LTB locus and susceptibility to SM in highland Papuan children and adults were found.These results support the notion that unique selective pressure on the TNF/LTA/LTB locus in different populations has influenced the contribution of the gene products from this region to SM susceptibility.

SUBMITTER: Randall LM

PROVIDER: S-EPMC2978234 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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A study of the TNF/LTA/LTB locus and susceptibility to severe malaria in highland papuan children and adults.

Randall Louise M LM Randall Louise M LM Kenangalem Enny E Lampah Daniel A DA Tjitra Emiliana E Mwaikambo Esther D ED Handojo Tjandra T Piera Kim A KA Zhao Zhen Z ZZ de Labastida Rivera Fabian F Zhou Yonghong Y McSweeney Karli M KM Le Lien L Amante Fiona H FH Haque Ashraful A Stanley Amanda C AC Woodberry Tonia T Salwati Ervi E Granger Donald L DL Hobbs Maurine R MR Price Ric N RN Weinberg J Brice JB Montgomery Grant W GW Anstey Nicholas M NM Engwerda Christian R CR

Malaria journal 20101029

<h4>Background</h4>Severe malaria (SM) syndromes caused by Plasmodium falciparum infection result in major morbidity and mortality each year. However, only a fraction of P. falciparum infections develop into SM, implicating host genetic factors as important determinants of disease outcome. Previous studies indicate that tumour necrosis factor (TNF) and lymphotoxin alpha (LTα) may be important for the development of cerebral malaria (CM) and other SM syndromes.<h4>Methods</h4>An extensive analysi ...[more]

PMID: 21029472

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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.

Dataset Information

A study of the TNF/LTA/LTB locus and susceptibility to severe malaria in highland papuan children and adults.

Publications

A study of the TNF/LTA/LTB locus and susceptibility to severe malaria in highland papuan children and adults.

Similar Datasets

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