Post GWAS analysis of a BCL11A intronic region to define its role in regulating HbF levels (Comunicazione a convegno)

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  • Post GWAS analysis of a BCL11A intronic region to define its role in regulating HbF levels (Comunicazione a convegno) (literal)
Anno
  • 2013-01-01T00:00:00+01:00 (literal)
Alternative label
  • 1Francesca Anedda, 1Sonia Sanna, 1Isadora Asunis, 1 Gianluca Usala, 2Danjou Fabrice, 1Cristian Antonio Caria, 1Luciana Perseu, 1Alessia Loi1, Annalisa Cabriolu, 1Loredana Porcu, 1Maria Giuseppina Marini, 1Maria Franca Marongiu, 3,4Carlo Sidore, 3,5Riccardo Berutti, 3Mauro Pala, 1,5Angius Andrea, 1Fabio Busonero,1,4Andrea Maschio, 2Stefania Satta, 2Francarosa Demartis, 2Liliana Maccioni, 6Ramaiah Nagaraja, 4Goncalo Abecasis, 6David Schlessinger, 1Maria Serafina Ristaldi, 2Renzo Galanello, 2Paolo Moi 1,3Francesco Cucca, 1Serena Sanna, 1Uda Manuela. (2013)
    Post GWAS analysis of a BCL11A intronic region to define its role in regulating HbF levels
    in ESHG, Parigi 2013
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • 1Francesca Anedda, 1Sonia Sanna, 1Isadora Asunis, 1 Gianluca Usala, 2Danjou Fabrice, 1Cristian Antonio Caria, 1Luciana Perseu, 1Alessia Loi1, Annalisa Cabriolu, 1Loredana Porcu, 1Maria Giuseppina Marini, 1Maria Franca Marongiu, 3,4Carlo Sidore, 3,5Riccardo Berutti, 3Mauro Pala, 1,5Angius Andrea, 1Fabio Busonero,1,4Andrea Maschio, 2Stefania Satta, 2Francarosa Demartis, 2Liliana Maccioni, 6Ramaiah Nagaraja, 4Goncalo Abecasis, 6David Schlessinger, 1Maria Serafina Ristaldi, 2Renzo Galanello, 2Paolo Moi 1,3Francesco Cucca, 1Serena Sanna, 1Uda Manuela. (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni
  • 1 Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche (CNR), Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy; 2 Clinica Pediatrica 2a, Dipartimento di Scienze Biomediche e Biotecnologie - Università di Cagliari, Ospedale Regionale Microcitemie ASL8, Cagliari, Italy; 3 Dipartimento di Scienze Biomediche, Università di Sassari, Sassari, Italy; 4 Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA; 5 Center for Advanced Studies, Research, and Development in Sardinia (CRS4), AGCT Program, Parco Scientifico e tecnologico della Sardegna, Pula, Italy; 6 Laboratory of Genetics, National Institute on Aging, Baltimore, Maryland, USA. (literal)
Titolo
  • Post GWAS analysis of a BCL11A intronic region to define its role in regulating HbF levels (literal)
Abstract
  • Association studies identified BCL11A transcription factor as the master regulator of fetal hemoglobin (HbF) expression as well as a key modifier of both ?-thalassemia and sickle cell anemia (SCA) phenotypes. Recently, we refined the association signal at this locus by GWAS on 5903 individuals from the SardiNIA project, integrating, with imputation procedure, DNA microarray data and low pass whole-genome sequencing of 2120 Sardinians. Our results revealed two independent SNPs within intron 2 of the BCL11A gene, leading the strongest haplotypic signals and fully accounting for the association observed at this locus. Given that intron 2 shows chromatin signatures of genomic elements with a potential regulatory activity, we carried out functional and expression analysis to asses the specific impact of associated variants in gene action. Preliminary luciferase reporter assays on erythroleukemia cell lines (K562, HEL) have shown a promoter/enhancer activity embedded in the regions encompassing two of them. Notably for one SNP, EMSA on human primary erythroid cells (BFUe) also detected a differential binding pattern showing developmental stage and allele specificity. Furthermore, RT-qPCR and allelic specific expression assays (ASE) conducted on BFUe cells derived from ?-thalassemia patients suggest that the associated SNPs, might function as cis-acting regulatory variants, affecting its expression in a temporal and tissue specific manner. Overall our results support that genetic variants at intron 2 of BCL11A play a crucial role in modulating its function controlling HbF levels with consequent amelioration of ?-thalassemia severity. (literal)
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