FLT1 and other candidate fetal haemoglobin modifying loci in sickle cell disease in African ancestries.
Journal: Nature communications
Volume: 16
Issue: 1
Year of Publication: 2025
Affiliated Institutions:
McKusick-Nathans Institute and Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. awonkam@jhmi.edu.
McKusick-Nathans Institute and Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Microbiology, Haematology and Immunology, University of Dschang, Dschang, Cameroon.
Division of Human Genetics, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
Department of Biochemistry and Molecular Biology, Muhimbili University of Health and Allied Sciences, Dar Es Salaam, Tanzania.
Department of Pharmaceutical Microbiology, Muhimbili University of Health and Allied Sciences, Dar Es Salaam, Tanzania.
Sickle Cell Programme, Department of Haematology and Blood Transfusion, Muhimbili University of Health & Allied Sciences (MUHAS), Dar Es Salaam, Tanzania.
Computational Biology Division, Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, CIDRI-Africa Wellcome Trust Centre, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
Montreal Heart Institute, Université de Montréal, Montreal, QC, Canada.
Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
Department of Pediatrics, Division of Hematology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Armstrong Oxygen Biology Research Center, Institute for Cell Engineering, and Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, Newcastle, Tyne and Wear, UK.
Department of Genetic Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
Abstract summary
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.
Authors & Co-authors:
Wonkam Ambroise A
Esoh Kevin K
Levine Rachel M RM
Ngo Bitoungui Valentina Josiane VJ
Mnika Khuthala K
Nimmagadda Nikitha N
Dempsey Erin A D EAD
Nkya Siana S
Sangeda Raphael Z RZ
Nembaware Victoria V
Morrice Jack J
Osman Fujr F
Beer Michael A MA
Makani Julie J
Mulder Nicola N
Lettre Guillaume G
Steinberg Martin H MH
Latanich Rachel R
Casella James F JF
Drehmer Daiana D
Arking Dan E DE
Chimusa Emile R ER
Yen Jonathan S JS
Newby Gregory A GA
Antonarakis Stylianos E SE
Study Outcome
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