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: Guillaume Lettre, Vijay G Sankaran, Marcos André C Bezerra, Aderson S Araújo, Manuela Uda, Serena Sanna, Antonio Cao, David Schlessinger, Fernando F Costa, Joel N Hirschhorn, Stuart H Orkin
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 105 Issue 33 Pg. 11869-74 (Aug 19 2008) ISSN: 1091-6490 [Electronic] United States
• PMID: 18667698 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• BCL11A protein, human
• Carrier Proteins
• Nuclear Proteins
• Repressor Proteins
• Globins
• Fetal Hemoglobin

Topics

• Adolescent
• Anemia, Sickle Cell (complications, epidemiology, genetics, metabolism)
• Carrier Proteins (genetics, metabolism)
• Cohort Studies
• Female
• Fetal Hemoglobin (genetics, metabolism)
• Genes, myb (genetics)
• Genotype
• Globins (genetics, metabolism)
• Humans
• Male
• Nuclear Proteins (genetics, metabolism)
• Pain (complications, epidemiology, genetics, metabolism)
• Polymorphism, Single Nucleotide (genetics)
• Repressor Proteins