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.
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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)
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Chemical References |
- BCL11A protein, human
- Carrier Proteins
- Nuclear Proteins
- Repressor Proteins
- Globins
- Fetal Hemoglobin
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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
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