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

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

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 Cameroo...

Full description

Saved in:
Bibliographic Details
Main Authors: 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, Stylianos E. Antonarakis
Format: Article
Language:English
Published: Nature Portfolio 2025-03-01
Series:Nature Communications
Online Access:https://doi.org/10.1038/s41467-025-57413-5
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:2041-1723

Similar Items