title: Association between Variants at BCL11A Erythroid-Specific Enhancer and Fetal Hemoglobin Levels among Sickle Cell Disease Patients in Cameroon: Implications for Future Therapeutic Interventions.
abstract: Variants in BCL11A were previously associated with fetal hemoglobin (HbF) levels among Cameroonian sickle cell disease (SCD) patients, however explaining only ∼2% of the variance. In the same patients, we have investigated the relationship between HbF and two SNPs in a BCL11A erythroid-specific enhancer (N=626). Minor allele frequencies in rs7606173 and rs1427407 were 0.42 and 0.24, respectively. Both variants were significantly associated with HbF levels (p=3.11e-08 and p=6.04e-06, respectively) and explained 8% and 6.2% variations, respectively. These data have confirmed a stronger effect on HbF of genomic variations at the BCL11A erythroid-specific enhancer among patients with SCD in Cameroon, the first report on a West African population. The relevance of these findings is of prime importance because the disruption of this enhancer would alter BCL11A expression in erythroid precursors and thus HbF expression, while sparing the induced functional challenges of any alterations on the expression of this transcription factor in non-erythroid lineages, thus providing an attractive approach for new treatment strategies of SCD.
authors.affiliation: 1 Division of Human Genetics, Department of Medicine, Faculty of Health Sciences, University of Cape Town , Cape Town, South Africa .
authors.forename: Gift Dineo
authors.initials: GD
authors.lastname: Pule
authors.affiliation: 2 Faculty of Medicine and Biomedical Sciences, University of Yaoundé, Cameroon .
authors.forename: Valentina Josiane
authors.initials: VJ
authors.lastname: Ngo Bitoungui
authors.affiliation: 2 Faculty of Medicine and Biomedical Sciences, University of Yaoundé, Cameroon .
authors.forename: Bernard
authors.initials: B
authors.lastname: Chetcha Chemegni
authors.affiliation: 3 Non-Communicable Diseases Research Unit, South African Medical Research Council , Cape Town, South Africa .
authors.forename: Andre Pascal
authors.initials: AP
authors.lastname: Kengne
authors.affiliation: 4 Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva , Switzerland .
authors.forename: Stylianos
authors.initials: S
authors.lastname: Antonarakis
authors.affiliation: 1 Division of Human Genetics, Department of Medicine, Faculty of Health Sciences, University of Cape Town , Cape Town, South Africa .
authors.forename: Ambroise
authors.initials: A
authors.lastname: Wonkam
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D000755:Anemia, Sickle Cell / Q000235:genetics* / Q000473:pathology; D002163:Cameroon; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005319:Fetal Hemoglobin / Q000235:genetics*; D015870:Gene Expression; D005787:Gene Frequency; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012097:Repressor Proteins
chemical_list: C486563:BCL11A protein, human; D002352:Carrier Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D005319:Fetal Hemoglobin