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

• Published in: Nature genetics Vol. 37; no. 4; pp. 435 - 440
• Main Authors: Ramoni, Marco F, Sebastiani, Paola, Nolan, Vikki, Baldwin, Clinton T, Steinberg, Martin H
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 01.04.2005
• Subjects: Anemia, Sickle Cell - genetics; Anemias. Hemoglobinopathies; Biological and medical sciences; Complications and side effects; Diagnosis; Diseases of red blood cells; Fetal Hemoglobin - genetics; Fetal Hemoglobin - metabolism; Fundamental and applied biological sciences. Psychology; Gene mutations; Genetic aspects; Genetic Markers; Genetic Predisposition to Disease; Genetics of eukaryotes. Biological and molecular evolution; Genotype; Health risks; Hematologic and hematopoietic diseases; Hemoglobin, Sickle - genetics; Homozygosity; Humans; Magnetic Resonance Imaging; Medical sciences; Models, Genetic; Mortality; Mutation; Neurology; Polymorphism, Single Nucleotide; Prognosis; Risk Factors; Sickle cell anemia; Signal Transduction; Stroke (Disease); Stroke - genetics; Vascular diseases and vascular malformations of the nervous system; United States; Hemoglobinopathy; Nervous system diseases; Stroke; Sickle cell anemia; Prognosis; Mortality; Cardiovascular disease; Hemopathy; Modifier gene; Homozygosity; Cerebral disorder; Genetic disease; Vascular disease; Globin; Hemolytic anemia; Central nervous system disease; Genetics; Early; Mutation; Locus; Cerebrovascular disease
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng1533

Sickle cell anemia (SCA) is a paradigmatic single gene disorder caused by homozygosity with respect to a unique mutation at the β-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-β 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.