Genetic dissection and prognostic modeling of overt stroke in sickle cell anemia.
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.
Sebastiani
Paola
P
Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA.
Ramoni
Marco F
MF
Nolan
Vikki
V
Baldwin
Clinton T
CT
Steinberg
Martin H
MH
D000755:Anemia, Sickle Cell / Q000235:genetics*; D005319:Fetal Hemoglobin / Q000235:genetics / Q000378:metabolism*; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006451:Hemoglobin, Sickle / Q000235:genetics*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D012307:Risk Factors; D015398:Signal Transduction; D020521:Stroke / Q000235:genetics*
D005819:Genetic Markers; D006451:Hemoglobin, Sickle; D005319:Fetal Hemoglobin