Tumor necrosis factor SNP haplotypes are associated with iron deficiency anemia in West African children

Abstract

Plasma levels of tumor necrosis factor-alpha (TNF-alpha) are significantly raised in malaria infection and TNF-alpha is thought to inhibit intestinal iron absorption and macrophage iron release. This study investigated putative functional single nucleotide polymorphisms (SNPs) and haplotypes across the major histocompatibility complex (MHC) class III region, including TNF and its immediate neighbors nuclear factor of kappa light polypeptide gene enhancer in B cells (lkappaBL), inhibitor-like 1 and lymphotoxin alpha (LTA), in relation to nutritional iron status and anemia, in a cohort of 780 children across a malaria season. The prevalence of iron deficiency anemia (IDA) increased over the malaria season (P < .001). The TNF(-308) AA genotype was associated with an increased risk of iron deficiency (adjusted OR 8.1; P = .001) and IDA (adjusted OR 5.1; P = .01) at the end of the malaria season. No genotypes were associated with IDA before the malaria season. Thus, TNF appears to be a risk factor for iron deficiency and IDA in children in a malaria-endemic environment and this is likely to be due to a TNF-alpha-induced block in iron absorption.

Figure 1

The TNF gene locus. The haplotype-tagging SNPs span a 25-kb region across the IκBL, LTA and TNF loci (rs numbers are from NCBI dbSNP build 129 released June 18, 2008, www.ncbi.nlm.nih.gov/projects/SNP/). The SNPs are designated according to the nucleotide position relative to the transcriptional starting site of TNF. Filled boxes represent exons.

Figure 2

Percentage of children with iron deficiency anemia at the start and end of the malaria season by TNF single nucleotide polymorphisms. (A) Start of the malaria season. (B) End of the malaria season. Iron deficiency anemia was defined as a ferritin of less than 12 μg/L, zinc protoporphyrin more than 80 μmol/mol hemoglobin and hemoglobin concentration less than 110 g/L in children with a full dataset for ferritin, hemoglobin concentration, zinc protoporphyrin, α₁-antichymotrypsin, and malaria blood film. Too few children had the genotypes TNF₋₁₀₃₁CC (n = 9), TNF₋₂₃₈AA (n = 4), and TNF₊₈₅₁GG (n = 10) to allow for meaningful interpretation. Significance values were derived from multimarker logistic regression models including as dependent variable iron deficiency anemia at the start or end of the malaria season and adjusted for village, age (grouped by year), malaria parasite positivity, α₁-antichymotrypsin level (a marker of inflammation), hemoglobin type (HbAA, HbAS), and G6PD deficiency (A type) genotype.