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PMID: 15778708 Published · ppublish English Journal Article Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

Genetic dissection and prognostic modeling of overt stroke in sickle cell anemia.

Nature genetics ·Vol. 37 ·No. 4 ·2005-04-00 ·Pages 435-40

Sebastiani P, Ramoni MF, Nolan V, Baldwin CT, Steinberg MH

Abstract

Sickle cell anemia (SCA) is a paradigmatic single gene disorder caused by homozygosity with respect to a unique mutation at the beta-globin locus. SCA is phenotypically complex, with different clinical courses ranging from early childhood mortality to a virtually unrecognized condition. Overt stroke is a severe complication affecting 6-8% of individuals with SCA. Modifier genes might interact to determine the susceptibility to stroke, but such genes have not yet been identified. Using Bayesian networks, we analyzed 108 SNPs in 39 candidate genes in 1,398 individuals with SCA. We found that 31 SNPs in 12 genes interact with fetal hemoglobin to modulate the risk of stroke. This network of interactions includes three genes in the TGF-beta pathway and SELP, which is associated with stroke in the general population. We validated this model in a different population by predicting the occurrence of stroke in 114 individuals with 98.2% accuracy.

MeSH Terms
Anemia, Sickle Cell/genetics Fetal Hemoglobin/genetics,metabolism Genetic Markers Genetic Predisposition to Disease Genotype Hemoglobin, Sickle/genetics Humans Magnetic Resonance Imaging Models, Genetic Polymorphism, Single Nucleotide Prognosis Risk Factors Signal Transduction Stroke/genetics
Chemicals
Genetic Markers Hemoglobin, Sickle Fetal Hemoglobin
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Sebastiani Paola
Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA.
Ramoni Marco F
Nolan Vikki
Baldwin Clinton T
Steinberg Martin H
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Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1061-4036
DOI
10.1038/ng1533
Published
2005-04-00
Epub
2005-00-20
Pages
435-40
Language
English
Region
United States
NLM ID
9216904
PMCID
PMC2896308
Subset
IM
Grants
NHLBI NIH HHS · R21 HL080463 · United States
NHLBI NIH HHS · R21 HL080463-01 · United States
Corrections
CommentIn
PMID: 15800645
External Links
PubMed source DOI: 10.1038/ng1533 PMC Full Text View journal details
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