IRON STATUS AND THE RISK OF SEVERE INFECTION IN AFRICAN CHILDREN

John MURIUKI1, Alex MENTZER2, Alison ELLIOTT3,4, Thomas WILLIAMS1,5, George DAVEY SMITH6, Sarah ATKINSON1,7

1KEMRI-Wellcome Trust Research Programme, Nairobi, Kenya
2Centre for Clinical Vaccinology and Tropical Medicine and the Jenner Institute Laboratories, University of Oxford, Oxford, United Kingdom
3MRC/UVRI Uganda Research Unit on AIDS, Entebbe, Uganda
4London School of Hygiene & Tropical Medicine, London, United Kingdom
5Department of Medicine, Imperial College, London, United Kingdom
6MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom
7Department of Paediatrics, University of Oxford, Oxford, United Kingdom

Background: Iron status may influence susceptibility to infection since pathogens require iron to proliferate and iron is critical for host immunity. However, causality is difficult to establish due to confounding bias and reverse causality in epidemiological studies. In this study, we applied Mendelian randomization (MR) to infer whether iron status is causally associated with the risks of severe infections.

Methods: To identify genetic variants for use as instrumental variables (IVs) in MR analyses, we conducted a genome wide association study (GWAS) of iron status in 3928 children in five African countries. We then identified the IVs in large case-control GWAS studies of severe malaria (n=7957 cases and 7746 controls), bacteraemia (1970 cases and 4013 controls), and tuberculosis (3525 cases and 3424 controls) and performed MR analyses.

Results: We found that African-specific genetic loci influenced iron status and risk of severe infection. GTF3C5, a locus implicated in transferrin endocytosis, was associated with a 12% and 15% reduced risk of severe malaria and bacteraemia, respectively. SDR16C5, a locus involved in retinol metabolism influenced hepcidin levels and a unit increase in genetically determined hepcidin level was associated with 33% protection against overall bacteraemia and 78% protection against Klebsiella pneumoniae bacteraemia. The FREM3 locus, within the malaria protective Dantu region altered soluble transferrin receptor (sTfR) levels, and a unit increase in genetically determined sTfR level was associated with 70% and 37% protection against severe malaria and bacteraemia, respectively.

Conclusion: MR analyses suggest an important link between iron status and severe infection in African children.