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Proc Natl Acad Sci U S A DOI:10.1073/pnas.0804799105

DNA polymorphisms at the BCL11A, HBS1L-MYB, and beta-globin loci associate with fetal hemoglobin levels and pain crises in sickle cell disease.

Publication TypeJournal Article
Year of Publication2008
AuthorsLettre, G, Sankaran, VG, Bezerra, MAndré C, Araújo, AS, Uda, M, Sanna, S, Cao, A, Schlessinger, D, Costa, FF, Hirschhorn, JN, Orkin, SH
JournalProc Natl Acad Sci U S A
Date Published2008 Aug 19
KeywordsAdolescent, Anemia, Sickle Cell, Carrier Proteins, Cohort Studies, Female, Fetal Hemoglobin, Genes, myb, Genotype, Globins, Humans, Male, Nuclear Proteins, Pain, Polymorphism, Single Nucleotide

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.


Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID18667698
PubMed Central IDPMC2491485
Grant List / / Howard Hughes Medical Institute / United States