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<p>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 <i>FLT1</i> 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 (<i>BCL11A</i> and <i>HBS1L-MYB</i>). 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月1日

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  • 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

摘要

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.