title: DNA polymorphisms at the BCL11A, HBS1L-MYB, and beta-globin loci associate with fetal hemoglobin levels and pain crises in sickle cell disease.
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 SNPs, HBS1L-MYB SNPs, and an SNP upstream of (G)gamma-globin (HBG2; the XmnI 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 SNPs 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 SNPs 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.
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. lettre@broad.mit.edu
authors.forename: Guillaume
authors.initials: G
authors.lastname: Lettre
authors.forename: Vijay G
authors.initials: VG
authors.lastname: Sankaran
authors.forename: Marcos André C
authors.initials: MA
authors.lastname: Bezerra
authors.forename: Aderson S
authors.initials: AS
authors.lastname: Araújo
authors.forename: Manuela
authors.initials: M
authors.lastname: Uda
authors.forename: Serena
authors.initials: S
authors.lastname: Sanna
authors.forename: Antonio
authors.initials: A
authors.lastname: Cao
authors.forename: David
authors.initials: D
authors.lastname: Schlessinger
authors.forename: Fernando F
authors.initials: FF
authors.lastname: Costa
authors.forename: Joel N
authors.initials: JN
authors.lastname: Hirschhorn
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Orkin
mesh_terms: D000293:Adolescent; D000755:Anemia, Sickle Cell / Q000150:complications / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D015331:Cohort Studies; D005260:Female; D005319:Fetal Hemoglobin / Q000235:genetics / Q000378:metabolism*; D020570:Genes, myb / Q000235:genetics; D005838:Genotype; D005914:Globins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010146:Pain / Q000150:complications / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012097:Repressor Proteins
chemical_list: C486563:BCL11A protein, human; D002352:Carrier Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D005914:Globins; D005319:Fetal Hemoglobin