DNA polymorphisms at the BCL11A, HBS1L-MYB, and β-globin loci associate with fetal hemoglobin levels and pain crises in sickle cell disease
- 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*,†,§, and
- Stuart H. Orkin§,¶,‖
- *Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142;
- †Divisions of Genetics and Endocrinology and Program in Genomics and
- ¶Division of Hematology/Oncology, Children's Hospital Boston, Boston, MA 02115;
- ‖Department of Pediatric Oncology, Dana–Farber Cancer Institute, Boston, MA 02115;
- **Fundação de Hematologia e Hemoterapia de Pernambuco, Hemope, 52011-000 Recife, Brazil;
- ††Istituto di Neurogenetica e Neurofarmacologia (INN), Consiglio Nazionale delle Ricerche, c/o Cittadella Universitaria di Monserrato, Monserrato, 09042 Cagliari, Italy;
- ‡‡Gerontology Research Center, National Institute on Aging, 5600 Nathan Shock Drive, Baltimore, MD 21224; and
- §§Center of Hemotherapy and Hematology, State University of Campinas, 13083-970 Campinas, Sau Paulo, Brazil
-
Contributed by Stuart H. Orkin, May 19, 2008
-
↵‡G.L. and V.G.S. contributed equally to this work. (received for review April 14, 2008)
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 Gγ-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 × 10−42). Together, common SNPs at the BCL11A, HBS1L-MYB, and β-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.
Footnotes
- §To whom correspondence may be addressed. E-mail: lettre{at}broad.mit.edu, joelh{at}broad.mit.edu, or stuart_orkin{at}dfci.harvard.edu
-
Author contributions: G.L., V.G.S., J.N.H., and S.H.O. designed research; G.L. and V.G.S. performed research; M.A.C.B., A.S.A., M.U., S.S., A.C., D.S., and F.F.C. contributed new reagents/analytic tools; G.L., V.G.S., J.N.H., and S.H.O. analyzed data; and G.L., V.G.S., J.N.H., and S.H.O. wrote the paper.
-
The authors declare no conflict of interest.
-
See Commentary on page 11595.
-
This article contains supporting information online at www.pnas.org/cgi/content/full/0804799105/DCSupplemental.
-
Freely available online through the PNAS open access option.
- © 2008 by The National Academy of Sciences of the USA
