| 著者 |
Wonkam A, Esoh K, Levine RM, Ngo Bitoungui VJ, Mnika K, Nimmagadda N, Dempsey EAD, Nkya S, Sangeda RZ, Nembaware V, Morrice J, Osman F, Beer MA, Makani J, Mulder N, Lettre G, Steinberg MH, Latanich R, Casella JF, Drehmer D, Arking DE, Chimusa ER, Yen JS, Newby GA, Antonarakis SE.
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| 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.
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