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...
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Nature Portfolio
2025-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-57413-5 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Ambroise Wonkam |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-13ffb070a5ad4a389539cc449f5fc78f |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-13ffb070a5ad4a389539cc449f5fc78f2025-08-20T03:03:58ZengNature PortfolioNature Communications2041-17232025-03-0116112110.1038/s41467-025-57413-5FLT1 and other candidate fetal haemoglobin modifying loci in sickle cell disease in African ancestriesAmbroise Wonkam0Kevin Esoh1Rachel M. Levine2Valentina Josiane Ngo Bitoungui3Khuthala Mnika4Nikitha Nimmagadda5Erin A. D. Dempsey6Siana Nkya7Raphael Z. Sangeda8Victoria Nembaware9Jack Morrice10Fujr Osman11Michael A. Beer12Julie Makani13Nicola Mulder14Guillaume Lettre15Martin H. Steinberg16Rachel Latanich17James F. Casella18Daiana Drehmer19Dan E. Arking20Emile R. Chimusa21Jonathan S. Yen22Gregory A. Newby23Stylianos E. Antonarakis24McKusick-Nathans Institute and Department of Genetic Medicine, Johns Hopkins University School of MedicineMcKusick-Nathans Institute and Department of Genetic Medicine, Johns Hopkins University School of MedicineDepartment of Hematology, St. Jude Children’s Research HospitalDepartment of Microbiology, Haematology and Immunology, University of DschangDivision of Human Genetics, Faculty of Health Sciences, University of Cape TownDepartment of Hematology, St. Jude Children’s Research HospitalDepartment of Hematology, St. Jude Children’s Research HospitalDepartment of Biochemistry and Molecular Biology, Muhimbili University of Health and Allied SciencesDepartment of Pharmaceutical Microbiology, Muhimbili University of Health and Allied SciencesDivision of Human Genetics, Faculty of Health Sciences, University of Cape TownDivision of Human Genetics, Faculty of Health Sciences, University of Cape TownMcKusick-Nathans Institute and Department of Genetic Medicine, Johns Hopkins University School of MedicineMcKusick-Nathans Institute and Department of Genetic Medicine, Johns Hopkins University School of MedicineSickle Cell Programme, Department of Haematology and Blood Transfusion, Muhimbili University of Health & Allied Sciences (MUHAS)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 TownMontreal Heart Institute, Université de MontréalDepartment of Medicine, Boston University Chobanian & Avedisian School of MedicineMcKusick-Nathans Institute and Department of Genetic Medicine, Johns Hopkins University School of MedicineDepartment of Pediatrics, Division of Hematology, The Johns Hopkins University School of MedicineArmstrong Oxygen Biology Research Center, Institute for Cell Engineering, and Department of Genetic Medicine, Johns Hopkins University School of MedicineMcKusick-Nathans Institute and Department of Genetic Medicine, Johns Hopkins University School of MedicineDepartment of Applied Sciences, Faculty of Health and Life Sciences, Northumbria UniversityDepartment of Hematology, St. Jude Children’s Research HospitalMcKusick-Nathans Institute and Department of Genetic Medicine, Johns Hopkins University School of MedicineDepartment of Genetic Medicine, Faculty of Medicine, University of GenevaAbstract 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.https://doi.org/10.1038/s41467-025-57413-5 |
| spellingShingle | 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 FLT1 and other candidate fetal haemoglobin modifying loci in sickle cell disease in African ancestries Nature Communications |
| title | FLT1 and other candidate fetal haemoglobin modifying loci in sickle cell disease in African ancestries |
| title_full | FLT1 and other candidate fetal haemoglobin modifying loci in sickle cell disease in African ancestries |
| title_fullStr | FLT1 and other candidate fetal haemoglobin modifying loci in sickle cell disease in African ancestries |
| title_full_unstemmed | FLT1 and other candidate fetal haemoglobin modifying loci in sickle cell disease in African ancestries |
| title_short | FLT1 and other candidate fetal haemoglobin modifying loci in sickle cell disease in African ancestries |
| title_sort | flt1 and other candidate fetal haemoglobin modifying loci in sickle cell disease in african ancestries |
| url | https://doi.org/10.1038/s41467-025-57413-5 |
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