Abstract
Background: Anaemia is a major public health concern especially in African children living in malaria-endemic regions. Interferon-gamma (IFN-γ) is elevated during malaria infection and is thought to influence erythropoiesis and iron status. Genetic variants in the IFN-γ gene (IFNG) are associated with increased IFN-γ production. We investigated putative functional single nucleotide polymorphisms (SNPs) and haplotypes of IFNG in relation to nutritional iron status and anaemia in Gambian children over a malaria season. Methods: We used previously available data from Gambian family trios to determine informative SNPs and then used the Agena Bioscience MassArray platform to type five SNPs from the IFNG gene in a cohort of 780 Gambian children aged 2-6 years. We also measured haemoglobin and biomarkers of iron status and inflammation at the start and end of a malaria season. Results: We identified five IFNG haplotype-tagging SNPs ( IFNG-1616 [rs2069705], IFNG+874 [rs2430561], IFNG+2200 [rs1861493], IFNG+3234 [rs2069718] and IFNG+5612 [rs2069728]). The IFNG+2200C [rs1861493] allele was associated with reduced haemoglobin concentrations (adjusted β -0.44 [95% CI -0.75, -0.12]; Bonferroni adjusted P = 0.03) and a trend towards iron deficiency compared to wild-type at the end of the malaria season in multivariable models adjusted for potential confounders. A haplotype uniquely identified by IFNG+2200C was similarly associated with reduced haemoglobin levels and trends towards iron deficiency, anaemia and iron deficiency anaemia at the end of the malaria season in models adjusted for age, sex, village, inflammation and malaria parasitaemia. Conclusion: We found limited statistical evidence linking IFNG polymorphisms with a risk of developing iron deficiency and anaemia in Gambian children. More definitive studies are needed to investigate the effects of genetically influenced IFN-γ levels on the risk of iron deficiency and anaemia in children living in malaria-endemic areas.
Highlights
Malaria and iron deficiency are major public health problems for children living in sub-Saharan Africa
We found that hepcidin and hepcidin/ferritin ratio decreased while the Transferrin saturation (TSAT)/hepcidin ratio increased across the malaria season in keeping with the need for increased erythropoiesis and increased rates of iron absorption at the end of the malaria season
We hypothesized that IFN-γ, a pro-inflammatory cytokine induced during malaria infection13, might play a role in influencing the risk of iron deficiency (ID) and anaemia in children exposed to malaria
Summary
Malaria and iron deficiency are major public health problems for children living in sub-Saharan Africa. The majority (94%) of the 405,000 global deaths due to malaria in 2018 occurred in sub-Saharan Africa, where up to 24% of the population have malaria parasitaemia at any given time1,2 In this region, iron deficiency (ID) and anaemia are highly prevalent, and may lead to impaired brain development, while iron deficiency anaemia (IDA) is a leading cause of years lived with disability in African children. IFN-γ has been reported to increase the expression of hepcidin, and divalent metal transporter 1 (DMT1), while suppressing ferroportin, ferritin, and transferrin receptors19,20 This regulation of iron proteins may be aimed at starving invading pathogens of iron, a critical nutrient for pathogen growth, but could play an important role in the pathogenesis of ID and IDA.
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