Please use this identifier to cite or link to this item: http://repositorio.unicamp.br/jspui/handle/REPOSIP/62404
Type: Artigo de periódico
Title: DNA polymorphisms at the BCL11A, HBS1L-MYB, and beta-globin loci associate with fetal hemoglobin levels and pain crises in sickle cell disease
Author: Lettre, G
Sankaran, VG
Bezerra, MAC
Araujo, AS
Uda, M
Sanna, S
Cao, A
Schlessinger, D
Costa, FF
Hirschhorn, JN
Orkin, SH
Abstract: Sickle cell disease (SCD) is a debilitating monogenic blood disorder with a highly variable phenotype characterized by severe pain crises, acute clinical events, and early mortality. Interindividual variation in fetal hemoglobin (HbF) expression is a known and potentially heritable modifier of SCD severity. High HbF levels are correlated with reduced morbidity and mortality. Common single nucleotide polymorphisms (SNPs) at the BCL11A and HBS1L-MYB loci have been implicated previously in HbF level variation in nonanemic European populations. We recently demonstrated an association between a BCL11A SNP and HbF levels in one SCD cohort [Uda M, et al. (2008)Proc Natl Acad Sci USA 105:1620-1625]. Here, we genotyped additional BCL11A SNIPS, HBS1L-MYB SNIPS, and an SNP upstream of (G)gamma-globin (HBG2; the Xmnl polymorphism), in two independent SCD cohorts: the African American Cooperative Study of Sickle Cell Disease (CSSCD) and an SCD cohort from Brazil. We studied the effect of these SNIPS on HbF levels and on a measure of SCD-related morbidity (pain crisis rate). We strongly replicated the association between these SNPs and HbF level variation (in the CSSCD, P values range from 0.04 to 2 x 10(-42)). Together, common SNIPS at the BCL11A, HBS1L-MYB, and beta-globin (HBB) loci account for >20% of the variation in HbF levels in SCD patients. We also have shown that HbF-associated SNPs associate with pain crisis rate in SCD patients. These results provide a clear example of inherited common sequence variants modifying the severity of a monogenic disease.
Subject: genetic modifier
single nucleotide polymorphism
globin gene regulation
Country: EUA
Editor: Natl Acad Sciences
Rights: fechado
Identifier DOI: 10.1073/pnas.0804799105
Date Issue: 2008
Appears in Collections:Unicamp - Artigos e Outros Documentos

Files in This Item:
File Description SizeFormat 
WOS000258723800052.pdf378.56 kBAdobe PDFView/Open


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.