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

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 s...

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Published in:Proceedings of the National Academy of Sciences - PNAS Vol. 105; no. 33; p. 11869
Main Authors: Lettre, Guillaume, Sankaran, Vijay G, Bezerra, Marcos André C, Araújo, Aderson S, Uda, Manuela, Sanna, Serena, Cao, Antonio, Schlessinger, David, Costa, Fernando F, Hirschhorn, Joel N, Orkin, Stuart H
Format: Journal Article
Language:English
Published: United States 19.08.2008
Subjects:
Adolescent
Anemia, Sickle Cell - complications
Anemia, Sickle Cell - epidemiology
Anemia, Sickle Cell - genetics
Anemia, Sickle Cell - metabolism
Carrier Proteins - genetics
Carrier Proteins - metabolism
Cohort Studies
Female
Fetal Hemoglobin - genetics
Fetal Hemoglobin - metabolism
Genes, myb - genetics
Genotype
Globins - genetics
Globins - metabolism
Humans
Male
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
Pain - complications
Pain - epidemiology
Pain - genetics
Pain - metabolism
Polymorphism, Single Nucleotide - genetics
ISSN:1091-6490, 1091-6490
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Summary: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.
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ISSN:1091-6490
1091-6490
DOI:10.1073/pnas.0804799105