Menzel, S., Garner, C., Gut, I., Matsuda, F., Yamaguchi, M., Heath, S. et al. A QTL influencing F cell production maps to a gene encoding a zinc-finger protein on chromosome 2p15. Nat. Genet. 39, 1197-1199

King's College London School of Medicine, Division of Gene and Cell Based Therapy, King's Denmark Hill Campus, London SE5 9PJ, UK.
Nature Genetics (Impact Factor: 29.35). 11/2007; 39(10):1197-9. DOI: 10.1038/ng2108
Source: PubMed


F cells measure the presence of fetal hemoglobin, a heritable quantitative trait in adults that accounts for substantial phenotypic diversity of sickle cell disease and beta thalassemia. We applied a genome-wide association mapping strategy to individuals with contrasting extreme trait values and mapped a new F cell quantitative trait locus to BCL11A, which encodes a zinc-finger protein, on chromosome 2p15. The 2p15 BCL11A quantitative trait locus accounts for 15.1% of the trait variance.

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Available from: Simon Charles Heath, Oct 09, 2015
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    • "As a result, significant knowledge regarding the molecular mechanisms underlying HbF regulation has been uncovered. For instance, gene linkage studies associated BCL11A, HSB1L-MYB and HBB regions in the genome with increased HbF expression in adults [6]–[9], and suppression of BCL11A causes an increase in HbF levels and reverses the SCD phenotype in model systems [10], [11]. "
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    ABSTRACT: Induction of fetal hemoglobin (HbF) has therapeutic importance for patients with sickle cell disease (SCD) and the beta-thalassemias. It was recently reported that increased expression of LIN28 proteins or decreased expression of its target let-7 miRNAs enhances HbF levels in cultured primary human erythroblasts from adult healthy donors. Here LIN28A effects were studied further using erythrocytes cultured from peripheral blood progenitor cells of pediatric subjects with SCD. Transgenic expression of LIN28A was accomplished by lentiviral transduction in CD34(+) sickle cells cultivated ex vivo in serum-free medium. LIN28A over-expression (LIN28A-OE) increased HbF, reduced beta (sickle)-globin, and strongly suppressed all members of the let-7 family of miRNAs. LIN28A-OE did not affect erythroblast differentiation or prevent enucleation, but it significantly reduced or ameliorated the sickling morphologies of the enucleated erythrocytes.
    PLoS ONE 09/2014; 9(9):e106924. DOI:10.1371/journal.pone.0106924 · 3.23 Impact Factor
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    • "As HbF levels in non-anemic individuals are below the dynamic range of the HPLC detection system, the trait is represented in the twins by the fraction of red blood cells that carries HbF ( " F cells " ) enumerated by flow cytometry after anti-HbF staining (Thorpe et al., 1994). HbF and F cells are closely related traits that are influenced by the same set of genes (Menzel et al., 2007a; Uda et al., 2008). "
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    ABSTRACT: HMIP-2 is a human quantitative trait locus affecting peripheral numbers, size and hemoglobin composition of red blood cells, with a marked effect on the persistence of the fetal form of hemoglobin, HbF, in adults. The locus consists of multiple common variants in an enhancer region for MYB (chr 6q23.3), which encodes the hematopoietic transcription factor cMYB. Studying a European population cohort and four African-descended groups of patients with sickle cell anemia, we found that all share a set of two spatially separate HbF-promoting alleles at HMIP-2, termed “A” and “B.” These typically occurred together (“A–B”) on European chromosomes, but existed on separate homologous chromosomes in Africans. Using haplotype signatures for “A” and “B,” we interrogated public population datasets. Haplotypes carrying only “A” or “B” were typical for populations in Sub-Saharan Africa. The “A–B” combination was frequent in European, Asian, and Amerindian populations. Both alleles were infrequent in tropical regions, possibly undergoing negative selection by geographical factors, as has been reported for malaria with other hematological traits. We propose that the ascertainment of worldwide distribution patterns for common, HbF-promoting alleles can aid their further genetic characterization, including the investigation of gene–environment interaction during human migration and adaptation.
    Annals of Human Genetics 07/2014; 78(6). DOI:10.1111/ahg.12077 · 2.21 Impact Factor
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    • "Mapping genetic variants associated with SCD clinical phenotypes have largely been limited to candidate gene approaches and genome-wide association studies (Adams et al., 2003; Menzel et al., 2007; Lettre et al., 2008; Sebastiani et al., 2010; Solovieff et al., 2010; Thein, 2011; Steinberg and Sebastiani, 2012). One of the most characterized modulators of clinical expression of SCD is fetal hemoglobin (HbF). "
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    ABSTRACT: Sickle cell disease (SCD) is a congenital blood disease, affecting predominantly children from sub-Saharan Africa, but also populations world-wide. Although the causal mutation of SCD is known, the sources of clinical variability of SCD remain poorly understood, with only a few highly heritable traits associated with SCD having been identified. Phenotypic heterogeneity in the clinical expression of SCD is problematic for follow-up (FU), management, and treatment of patients. Here we used the joint analysis of gene expression and whole genome genotyping data to identify the genetic regulatory effects contributing to gene expression variation among groups of patients exhibiting clinical variability, as well as unaffected siblings, in Benin, West Africa. We characterized and replicated patterns of whole blood gene expression variation within and between SCD patients at entry to clinic, as well as in follow-up programs. We present a global map of genes involved in the disease through analysis of whole blood sampled from the cohort. Genome-wide association mapping of gene expression revealed 390 peak genome-wide significant expression SNPs (eSNPs) and 6 significant eSNP-by-clinical status interaction effects. The strong modulation of the transcriptome implicates pathways affecting core circulating cell functions and shows how genotypic regulatory variation likely contributes to the clinical variation observed in SCD.
    Frontiers in Genetics 02/2014; 5:26. DOI:10.3389/fgene.2014.00026
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