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Volume 9 (2009), Pages 46-67
Review Article

Genetic Etiologies for Phenotypic Diversity in Sickle Cell Anemia

Laboratory Medicine, Boston University School of Medicine, 72 E. Concord Street, Boston, MA 02118, USA

Received 7 August 2008; Revised 19 December 2008; Accepted 6 January 2009

Academic Editor: Susan Perrine

Copyright © 2009 Martin H. Steinberg.


The clinical course of patients with sickle cell anemia, a Mendelian trait, is characteristically highly variable. HbF concentration and the presence of a thalassemia are established modulators of the disease, but cannot account for all of its clinical heterogeneity. To find additional genetic modulators of disease, genotype-phenotype association studies, where single nucleotide polymorphisms (SNPs) in candidate genes are linked with a particular phenotype, have been informative. SNPs in several genes of the TGF-ß/MP superfamily, and some other genes linked to the endothelial function, and nitric oxide biology are associated with the subphenotypes of stroke, osteonecrosis, priapism, leg ulcers, pulmonary hypertension, and a more general measure of overall disease severity. Genome-wide association studies should help to confirm these observations and also to find hitherto unsuspected genetic modulators. Genetic association studies can have immediate prognostic value; they might also help to identify new pathophysiological pathways that could be susceptible to modulation.