African-specific genetic loci determine iron status and risk of severe malaria and bacteremia in African children

Iron is an essential trace element for both humans and pathogens, but its genetic determinants are understudied in Africa where iron deficiency and infectious diseases are highly prevalent. We conducted genome-wide association studies for six iron-related biomarkers in 3928 children from five sites across Africa with replication in 2868 African American adults. We identified previously unreported loci for transferrin in GTF3C5, a gene regulating cellular iron-uptake; for soluble transferrin receptor in FREM3, the Dantu locus; and for hepcidin in CHCHD7/SDR16C5. The lead GTF3C5 (rs2905094) and FREM3 (rs141274959) variants were both associated with protection against severe malaria and against bacteremia in large case-control studies. The CHCHD7/SDR16C5 lead variant, rs73596248, increased hepcidin concentrations and protected against bacteremia. We report limited transferability of polygenic risk scores derived from European ancestry studies to African populations. Our findings advance the understanding of the genetics of iron status in Africa and suggest an important link between iron and infection.