FLT1 and other candidate fetal haemoglobin modifying loci in sickle cell disease in African ancestries

Ambroise Wonkam (), Kevin Esoh, Rachel M. Levine, Valentina Josiane Ngo Bitoungui, Khuthala Mnika, Nikitha Nimmagadda, Erin A. D. Dempsey, Siana Nkya, Raphael Z. Sangeda, Victoria Nembaware, Jack Morrice, Fujr Osman, Michael A. Beer, Julie Makani, Nicola Mulder, Guillaume Lettre, Martin H. Steinberg, Rachel Latanich, James F. Casella, Daiana Drehmer, Dan E. Arking, Emile R. Chimusa, Jonathan S. Yen, Gregory A. Newby and Stylianos E. Antonarakis
Additional contact information
Ambroise Wonkam: Johns Hopkins University School of Medicine
Kevin Esoh: Johns Hopkins University School of Medicine
Rachel M. Levine: St. Jude Children’s Research Hospital
Valentina Josiane Ngo Bitoungui: University of Dschang
Khuthala Mnika: University of Cape Town
Nikitha Nimmagadda: St. Jude Children’s Research Hospital
Erin A. D. Dempsey: St. Jude Children’s Research Hospital
Siana Nkya: Muhimbili University of Health and Allied Sciences
Raphael Z. Sangeda: Muhimbili University of Health and Allied Sciences
Victoria Nembaware: University of Cape Town
Jack Morrice: University of Cape Town
Fujr Osman: Johns Hopkins University School of Medicine
Michael A. Beer: Johns Hopkins University School of Medicine
Julie Makani: Muhimbili University of Health & Allied Sciences (MUHAS)
Nicola Mulder: University of Cape Town
Guillaume Lettre: Université de Montréal
Martin H. Steinberg: Boston University Chobanian & Avedisian School of Medicine
Rachel Latanich: Johns Hopkins University School of Medicine
James F. Casella: The Johns Hopkins University School of Medicine
Daiana Drehmer: Johns Hopkins University School of Medicine
Dan E. Arking: Johns Hopkins University School of Medicine
Emile R. Chimusa: Northumbria University
Jonathan S. Yen: St. Jude Children’s Research Hospital
Gregory A. Newby: Johns Hopkins University School of Medicine
Stylianos E. Antonarakis: University of Geneva

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract Known fetal haemoglobin (HbF)-modulating loci explain 10–24% variation of HbF level in Africans with Sickle Cell Disease (SCD), compared to 50% among Europeans. Here, we report fourteen candidate loci from a genome-wide association study (GWAS) of HbF level in patients with SCD from Cameroon, Tanzania, and the United States of America. We present results of cell-based experiments for FLT1 candidate, demonstrating expression in early haematopoiesis and a possible involvement in hypoxia associated HbF induction. Our study employed genotyping arrays that capture a broad range of African and non-African genetic variation and replicated known loci (BCL11A and HBS1L-MYB). We estimated the heritability of HbF level in SCD at 94%, higher than estimated in unselected Europeans, and suggesting a robust capture of HbF-associated loci by these arrays. Our approach, which involved genotype imputation against six reference haplotype panels and association analysis with each of the panels, proved superior over selecting a best-performing panel, evidenced by a substantial proportion of panel-specific (up to 18%) and a low proportion of shared (28%) imputed variants across the panels.

Date: 2025
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DOI: 10.1038/s41467-025-57413-5

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