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

John Muthii Muriuki; Alexander J Mentzer; Gavin Band; Amanda Y Chong; Alex W Macharia; Reagan M Mogire; Kelvin Mokaya Abuga; Ruth Mitchell; James J Gilchrist; Emily L Webb; Francis M Ndungu; Laura M Raffield; Lynette Ekunwe; Amy R Bentley; Sodiomon B Sirima; Shabir A Madhi; Adrian V S Hill; Andrew M Prentice; Philip Bejon; Gibran Hemani; George Davey Smith; Manjinder S Sandhu; Alison M Elliott; Thomas N Williams; Adebowale Adeyemo; Sarah H Atkinson

doi:10.1038/s41467-026-71567-w

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

John Muthii Muriuki^*, Alexander J Mentzer, Gavin Band, Amanda Y Chong, Alex W Macharia, Reagan M Mogire, Kelvin Mokaya Abuga, Ruth Mitchell, James J Gilchrist, Emily L Webb, Francis M Ndungu, Laura M Raffield, Lynette Ekunwe, Amy R Bentley, Sodiomon B Sirima, Shabir A Madhi, Adrian V S Hill, Andrew M Prentice, Philip Bejon, Gibran HemaniGeorge Davey Smith, Manjinder S Sandhu, Alison M Elliott, Thomas N Williams, Adebowale Adeyemo, Sarah H Atkinson

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

Abstract

Iron is essential for both humans and pathogens, yet its genetic regulation remains understudied in African populations. Here, we report genome-wide association studies of six iron-related biomarkers in 3928 children from five sites across Africa, with replication in 2868 African American adults and investigate associations with severe malaria and bacteremia. We identify previously unreported loci at genome-wide significance, for transferrin at GTF3C5, and for hepcidin at CHCHD7/SDR16C5. Variants tagging the DUP4 haplotype, encoding the Dantu blood group (rs552439837) are associated with soluble transferrin receptor levels. Variants at GTF3C5 (rs2905094) and DUP4 confer protection against severe malaria and bacteremia. The CHCHD7/SDR16C5 variant (rs73596248) increases hepcidin levels and is associated with reduced risk of Klebsiella pneumoniae and Staphylococcus aureus bacteremia. Polygenic risk scores derived from European data show limited transferability to African populations. In this work, we demonstrate new genetic insights into iron regulation and highlight iron's role in host-pathogen interactions.

Original language	English
Journal	Nature Communications
Early online date	7 Apr 2026
DOIs	https://doi.org/10.1038/s41467-026-71567-w
Publication status	E-pub ahead of print - 7 Apr 2026

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Publisher Copyright:
© The Author(s) 2026.

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This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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Bristol Population Health Science Institute

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Integrative Epidemiology Unit
Davey Smith, G. (Principal Investigator)
1/04/23 → 31/03/28
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Muriuki, J. M., Mentzer, A. J., Band, G., Chong, A. Y., Macharia, A. W., Mogire, R. M., Abuga, K. M., Mitchell, R., Gilchrist, J. J., Webb, E. L., Ndungu, F. M., Raffield, L. M., Ekunwe, L., Bentley, A. R., Sirima, S. B., Madhi, S. A., Hill, A. V. S., Prentice, A. M., Bejon, P., ... Atkinson, S. H. (2026). African-specific genetic loci determine iron status and risk of severe malaria and bacteremia in African children. Nature Communications. Advance online publication. https://doi.org/10.1038/s41467-026-71567-w

@article{b9dba1021d004a87b0e82059311f93ba,

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

abstract = "Iron is essential for both humans and pathogens, yet its genetic regulation remains understudied in African populations. Here, we report genome-wide association studies of six iron-related biomarkers in 3928 children from five sites across Africa, with replication in 2868 African American adults and investigate associations with severe malaria and bacteremia. We identify previously unreported loci at genome-wide significance, for transferrin at GTF3C5, and for hepcidin at CHCHD7/SDR16C5. Variants tagging the DUP4 haplotype, encoding the Dantu blood group (rs552439837) are associated with soluble transferrin receptor levels. Variants at GTF3C5 (rs2905094) and DUP4 confer protection against severe malaria and bacteremia. The CHCHD7/SDR16C5 variant (rs73596248) increases hepcidin levels and is associated with reduced risk of Klebsiella pneumoniae and Staphylococcus aureus bacteremia. Polygenic risk scores derived from European data show limited transferability to African populations. In this work, we demonstrate new genetic insights into iron regulation and highlight iron's role in host-pathogen interactions.",

author = "Muriuki, \{John Muthii\} and Mentzer, \{Alexander J\} and Gavin Band and Chong, \{Amanda Y\} and Macharia, \{Alex W\} and Mogire, \{Reagan M\} and Abuga, \{Kelvin Mokaya\} and Ruth Mitchell and Gilchrist, \{James J\} and Webb, \{Emily L\} and Ndungu, \{Francis M\} and Raffield, \{Laura M\} and Lynette Ekunwe and Bentley, \{Amy R\} and Sirima, \{Sodiomon B\} and Madhi, \{Shabir A\} and Hill, \{Adrian V S\} and Prentice, \{Andrew M\} and Philip Bejon and Gibran Hemani and Smith, \{George Davey\} and Sandhu, \{Manjinder S\} and Elliott, \{Alison M\} and Williams, \{Thomas N\} and Adebowale Adeyemo and Atkinson, \{Sarah H\}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2026. ",

year = "2026",

month = apr,

day = "7",

doi = "10.1038/s41467-026-71567-w",

language = "English",

journal = "Nature Communications",

issn = "2041-1723",

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Muriuki, JM, Mentzer, AJ, Band, G, Chong, AY, Macharia, AW, Mogire, RM, Abuga, KM, Mitchell, R, Gilchrist, JJ, Webb, EL, Ndungu, FM, Raffield, LM, Ekunwe, L, Bentley, AR, Sirima, SB, Madhi, SA, Hill, AVS, Prentice, AM, Bejon, P, Hemani, G , Smith, GD, Sandhu, MS, Elliott, AM, Williams, TN, Adeyemo, A & Atkinson, SH 2026, 'African-specific genetic loci determine iron status and risk of severe malaria and bacteremia in African children', Nature Communications. https://doi.org/10.1038/s41467-026-71567-w

TY - JOUR

T1 - African-specific genetic loci determine iron status and risk of severe malaria and bacteremia in African children

AU - Muriuki, John Muthii

AU - Mentzer, Alexander J

AU - Band, Gavin

AU - Chong, Amanda Y

AU - Macharia, Alex W

AU - Mogire, Reagan M

AU - Abuga, Kelvin Mokaya

AU - Mitchell, Ruth

AU - Gilchrist, James J

AU - Webb, Emily L

AU - Ndungu, Francis M

AU - Raffield, Laura M

AU - Ekunwe, Lynette

AU - Bentley, Amy R

AU - Sirima, Sodiomon B

AU - Madhi, Shabir A

AU - Hill, Adrian V S

AU - Prentice, Andrew M

AU - Bejon, Philip

AU - Hemani, Gibran

AU - Smith, George Davey

AU - Sandhu, Manjinder S

AU - Elliott, Alison M

AU - Williams, Thomas N

AU - Adeyemo, Adebowale

AU - Atkinson, Sarah H

PY - 2026/4/7

Y1 - 2026/4/7

N2 - Iron is essential for both humans and pathogens, yet its genetic regulation remains understudied in African populations. Here, we report genome-wide association studies of six iron-related biomarkers in 3928 children from five sites across Africa, with replication in 2868 African American adults and investigate associations with severe malaria and bacteremia. We identify previously unreported loci at genome-wide significance, for transferrin at GTF3C5, and for hepcidin at CHCHD7/SDR16C5. Variants tagging the DUP4 haplotype, encoding the Dantu blood group (rs552439837) are associated with soluble transferrin receptor levels. Variants at GTF3C5 (rs2905094) and DUP4 confer protection against severe malaria and bacteremia. The CHCHD7/SDR16C5 variant (rs73596248) increases hepcidin levels and is associated with reduced risk of Klebsiella pneumoniae and Staphylococcus aureus bacteremia. Polygenic risk scores derived from European data show limited transferability to African populations. In this work, we demonstrate new genetic insights into iron regulation and highlight iron's role in host-pathogen interactions.

AB - Iron is essential for both humans and pathogens, yet its genetic regulation remains understudied in African populations. Here, we report genome-wide association studies of six iron-related biomarkers in 3928 children from five sites across Africa, with replication in 2868 African American adults and investigate associations with severe malaria and bacteremia. We identify previously unreported loci at genome-wide significance, for transferrin at GTF3C5, and for hepcidin at CHCHD7/SDR16C5. Variants tagging the DUP4 haplotype, encoding the Dantu blood group (rs552439837) are associated with soluble transferrin receptor levels. Variants at GTF3C5 (rs2905094) and DUP4 confer protection against severe malaria and bacteremia. The CHCHD7/SDR16C5 variant (rs73596248) increases hepcidin levels and is associated with reduced risk of Klebsiella pneumoniae and Staphylococcus aureus bacteremia. Polygenic risk scores derived from European data show limited transferability to African populations. In this work, we demonstrate new genetic insights into iron regulation and highlight iron's role in host-pathogen interactions.

U2 - 10.1038/s41467-026-71567-w

DO - 10.1038/s41467-026-71567-w

M3 - Article (Academic Journal)

C2 - 41946712

SN - 2041-1723

JO - Nature Communications

JF - Nature Communications

ER -

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

Abstract

Bibliographical note

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Projects

Integrative Epidemiology Unit

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