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

Iron is essential for both humans and pathogens, yet its genetic regulation remains understudied in African populations. 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 and investigated associations with severe malaria and bacteremia. We identified previously unreported loci at genome-wide significance, for transferrin in GTF3C5, a gene regulating cellular iron-uptake, and for hepcidin in CHCHD7/SDR16C5. Variants tagging the DUP4 haplotype, encoding the Dantu blood group, were associated with soluble transferrin receptor levels. Variants at GTF3C5 (rs2905094) and DUP4 (rs141274959) conferred protection against severe malaria and bacteremia. The CHCHD7/SDR16C5 variant (rs73596248) increased hepcidin levels and protected against risk of bacteremia. Polygenic risk scores derived from European data showed limited transferability. Our findings advance understanding of the genetics of iron status in Africa and highlight the importance of iron in the battle between host and pathogen.