Martin H. Steinberg, MD
Research Summary: The ability to genotype millions of polymorphisms in thousands of individuals, and to resequence megabases of DNA afford the opportunity to understand how human diversity is associated with many diseases and longevity. This knowledge will then allow the development of predictive networks that can be used prognostically and point to functional studies of interesting variants and novel pathways that might can lead to new treatment options. We are taking this approach to the study of hemoglobin disorders.
Fetal hemoglobin (HbF): The capability to produce HbF varies, and this variation is likely to be a multigenic trait explained by genetic heterogeneity in:cis-acting elements and trans-acting factors modulating gamma-globin gene expression; genes or loci controlling erythroid cell differentiation and proliferation; genes or loci that directly or indirectly modulate HbF concentration. We are identifying informative SNPs and haplotype structures in candidate genes, using family triads where parents are beta-thalassemia carriers, discovering SNPs, haplotypes and genes that are associated with HbF/F-cells levels.
HbF inhibits the polymerization of HbS and is therefore a key modulator of the phenotype of sickle cell anemia. Hydroxyurea can prevent some of the vasoocclusive complications of this disease. Patients who take hydroxyurea to increase HbF levels have an unpredictable response. We are discovering SNPs and haplotypes that predict the HbF level in sickle cell anemia patients taking hydroxyurea and SNPs associated with baseline HbF level.
Genetic modulation of sickle cell disease:. This work, now focused on genome-wide association studies, examines the hypothesis that while the HbS mutation causes a Mendelian, monogenic disease, the clinical expression of sickle cell anemia behaves like a complex genetic trait. The erythrocytic, vascular and inflammatory components of sickle cell anemia provide many sites for its genetic modulation and candidate gene association studies have discovered modifying genes that potentially affect the pathogenesis and modulate the phenotype of disease.
Modeling of interactions among genes and phenotypes: The genetic dissection of a complex trait requires the ability to disentangle the web of interactions among genes, environment and phenotype. To model these relationships, we are developing multivariate analysis using Bayesian networks. Their modular nature makes these networks ideal tools for the analysis of large association studies like the work on genotype-phenotype associations in sickle cell disease. A network capturing the relationship between genotypes and phenotype can be used to compute the probability that a new individual with particular genotype will manifest the phenotype.
Sebastiani, P., Wang, L., Nolan, V.G., Baldwin, C.T., Ma, Q., Steinberg, M.H. Fetal hemoglobin in sickle cell anemia: Bayesian modeling of genetic associations. Am. J. Hematol. 83: 189, 2008.
Morris, C.R., Suh, J.H., Larkin, S., Bland, D.A., Steinberg, M.H.,Vichinsky, E.P., Shigenaga, M., Ames, B., Kuypers, F.A., Klings, E.S. Erythrocyte glutamine depletion, altered redox environment, and pulmonary hypertension in sickle cell disease. Blood 111: 402, 2008.
Sebastiani, P., Zhao, Z., Abad-Grau, M, Riva, A., Hartley, S., Sedgewick, A., Doria, A., Montano, M., Melista, E., Terry, D., Perls, T.T., Steinberg, M.H., Baldwin, C.T. A hierarchical and modular approach to the discovery of robust associations in genome-wide association studies from pooled DNA samples. BMC Genet.ePub Jan 14, 2008.
Klings, E.S., Bland, A., Rosenman, D., Princeton, S., Odhiambo, A., Li, G., Bernard, S.A., Steinberg, M.H., Farber, H.W. Pulmonary arterial hypertension and left-sided heart disease in sickle cell disease: clinical characteristics and association with soluble adhesion molecule expression Am. J.Hematol. 83: 547, 2008.
Taylor, J.G., IV, Nolan, V.G., Mendelsohn, L., Kato, G J., Gladwin, M.T., Steinberg, M.H. Chronic hyper-hemolysis in sickle cell anemia: association of vascular complications and mortality with less frequent vasoocclusive pain. PLoS One May 7;3(5):e2095, 2008.
Gibney, G.T., Panhuysen, C.I.M., So, J.C.C., Ma, E.S.K., Ha, S.Y., Li, C.K., Lee, A.C.W., Li, C.K., Yuen, H.L., Lau, Y.L., Johnson, D., Farrell, J.J., Bisbee, A., Farrer, J.J., Steinberg, M.H., Chan, L.C., Chui, D.H.K. Variation and heritability of Hb F and F-cells among β-thalassemia heterozygotes in Hong Kong. Am. J. Hematol. 83: 458, 2008.
Chen,Z., Hong-yuan, L,. Basran, R.K., Rosenfield, C.G., Patrinos, G.P., Hardison, R.C., Steinberg, M.H., Chui, D.H.K. A T-to-G transversion at nucleotide -567 upstream of HBG2 in a GATA-1 binding motif is associated with elevated hemoglobin F. Mol. Cell. Biol. 28: 4386, 2008.
Sedgewick, A.E., Timofeev, N., Sebastiani, P., So, J.C.C., Ma, E.S.K., Chan, L.C., Fucharoen, G., Fucharoen, S., Barbosa, C.G., Vardarajan, B., Farrer, L.A., Baldwin, C.T., Steinberg, M.H., Chui, D.H.K. BCL11A is a major HbF quantitative trait locus in three different populations with β-hemoglobinopathies. Blood Cells, Mol. and Dis. 41: 255, 2008. http://dx.doi.org/10.1016/j.bcmd.2008.06.007
Nolan, V.G., Zhang, Y., Lash, T., Sebastiani, P., Steinberg, M.H. Association of wind speed and the occurrence of sickle cell acute painful episodes: Results of a case-crossover study. Br. J. Haematol. 143: 433, 2008.
Zhao, Z., Timofeev, N., Hartley, S., Chui, D.H.K., Fuchareon, Perls, T.T, Steinberg, M.H. Baldwin, C.T., Sebastiani, P. Imputation of missing genotypes: an empirical evaluation of IMPUTE. BMC Genetics (in press).