ß-Globin Gene Cluster Haplotypes and Clinical Severity in Sickle Cell Anemia Patients in Southern Brazil


Hematopoietic stem cell transplantation(HSCT)has emerged as a curative strategy for sickle cell anemia(SCA); it is necessary to find markers of SCA clinical severity to spare those SCA patients whose clinical course is mild from the morbidity and mortality associated with HSCT. Haplotypes have been correlated with the severity of clinical manifestations in SCA patients, and fetal hemoglobin(HbF)and socioeconomic status(SeS)have also been described as negative factors. We studied these factors and their impact on clinical manifestations in a population of Southern Brazilian patients attending the Center for Sickle Cell Anemia at Hospital de Clínicas de Porto Alegre/RS, Brazil. Clinical severity was defined as two or more veno-occlusive episodes per year. The βS haplotypes were determined by PCR in 75 SCA patients. Among the 150 βS chromosomes analyzed, 99(66%)were identified as Bantu(Ban), 41(27%)asBenin(Ben), and 10(7%)as other haplotypes. Most patients in our sample(62.7%)belonged to lower SeS groups, precluding meaningful statistical analysis of SeS impact on clinical severity. There was no correlation between haplotypes or HbF level and SCA clinical severity. Gene polymorphisms and environmental issues have to be taken into consideration.

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A. L. da Silva, M. , R. Friedrisch, J. , M. Bittar, C. , Urnau, M. , Merzoni, J. , S. Valim, V. , Amorin, B. , Pezzi, A. , Artur B. Chies, J. and M. da Rocha Silla, L. (2014) ß-Globin Gene Cluster Haplotypes and Clinical Severity in Sickle Cell Anemia Patients in Southern Brazil. Open Journal of Blood Diseases, 4, 16-23. doi: 10.4236/ojbd.2014.42003.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Steinberg, M.H. and Rodgers, G.P. (2001) Pathophysiology of Sickle Cell Disease: Role of Cellular and Genetic Modifiers. Seminars in Hematology, 38, 299-306.
[2] Hanchard, N., Elzein, A., Trafford, C., Rockett, K., Pinder, M., Jallow, M., Harding, R., Kwiatkowski, D. and McKenzie, C. (2007) Classical Sickle Beta-Globin Haplotypes Exhibit a High Degree of Long-Range Haplotype Similarity in African and Afro-Caribbean Populations. BMC Genetics, 8, 52.
[3] Inati, A., Taher, A., Bou Alawi, W., Koussa, S., Kaspar, H., Shbaklo, H. and Zalloua, P.A. (2003) Beta-Globin Gene Cluster Haplotypes and Hbf Levels Are Not the Only Modulators of Sickle Cell Disease in Lebanon. European Journal of Haematology, 70, 79-83.
[4] Kato, G.J., Gladwin, M.T. and Steinberg, M.H. (2007) Deconstructing Sickle Cell Disease: Reappraisal of the Role of Hemolysis in the Development of Clinical Subphenotypes. Blood Reviews, 21, 37-47.
[5] Rosse, W.F., Narla, M., Petz, L.D. and Steinberg, M.H. (2000) New Views of Sickle Cell Disease Pathophysiology and Treatment. Hematology/The Education Program of the American Society of Hematology, 2-17.
[6] Chies, J.A. and Nardi, N.B. (2001) Sickle Cell Disease: A Chronic Inflammatory Condition. Medical Hypotheses, 57, 46-50.
[7] Platt, O.S. (2000) Sickle Cell Anemia as an Inflammatory Disease. Journal of Clinical Investigation, 106, 337-338.
[8] Hebbel, R.P., Osarogiagbon, R. and Kaul, D. (2004) The Endothelial Biology of Sickle Cell Disease: Inflammation and a Chronic Vasculopathy. Microcirculation, 11, 129-151.
[9] Ballas, S.K. (1991) Sickle Cell Anemia with Few Painful Crises Is Characterized by Decreased Red Cell Deformability and Increased Number of Dense Cells. American Journal of Hematology, 36, 122-130.
[10] Steinberg, M.H. (2005) Predicting Clinical Severity in Sickle Cell Anaemia. British Journal of Haematology, 129, 465-481.
[11] Adekile, A.D. (2005) Mild-Phenotype Sickle Cell Disease: Molecular Basis, Clinical Presentation and Management Recommendations. Current Paediatrics, 15, 57-61.
[12] Zago, M.A. Figueiredo, M.S. and Ogo, S.H. (1992) Bantu βS Cluster Haplotype Predominates among Brazilian Blacks. American Journal of Physical Anthropology, 88, 295-298.
[13] Steinberg, M.H., Nagel, R.L., Lawrence, C., Swaminathan, V., Lu, Z.H., Plonczynski, M. and Harrell, A. (1996) Beta-Globin Gene Haplotype in Hb SC Disease. American Journal of Hematology, 52, 189-191
[14] Rusanova, I., Escames, G., Cossio, G., de Borace, R.G., Moreno, B., Chahboune, M., Lopez, L.C., Diez, T. and Acuna-Castroviejo, D. (2010) Oxidative Stress Status, Clinical Outcome, and Beta-Globin Gene Cluster Haplotypes in Pediatric Patients with Sickle Cell Disease. European Journal of Haematology, 85, 529-537.
[15] Figueiredo, M.S., Kerbauy, J., Goncalves, M.S., Arruda, V.R., Saad, S.T., Sonati, M.F., Stoming, T. and Costa, F.F. (1996) Effect of Alpha-Thalassemia and Beta-Globin Gene Cluster Haplotypes on the Hematological and Clinical Features of Sickle-Cell Anemia in Brazil. American Journal of Hematology, 53, 72-76.
[16] Pagnier, J., Mears, J.G., Dunda-Belkhodja, O., Schaefer-Rego, K.E., Beldjord, C., Nagel, R.L. and Labie, D. (1984) Evidence for the Multicentric Origin of the Sickle Cell Hemoglobin Gene in Africa. Proceedings of the National Academy of Sciences of the United States of America, 81, 1771-1773.
[17] Magana, M.T., Ongay, Z., Tagle, J., Bentura, G., Cobian, J.G., Perea, F.J., Casas-Castaneda, M., Sanchez-Lopez, Y.J. and Ibarra, B. (2002) Analysis of βS and βA Genes in a Mexican Population with African Roots. Blood Cells, Molecules, and Diseases, 28, 121-126.
[18] Nagel, R.L. and Steinberg, M.H. (2001) Role of Epistatic (Modifier) Genes in the Modulation of the Phenotypic Diversity of Sickle Cell Anemia. Fetal and Pediatric Pathology, 20, 123-136.
[19] Powars, D., Chan, L.S. and Schroeder, W.A. (1990) The Variable Expression of Sickle Cell Disease Is Genetically Determined. Seminars in Hematology, 27, 360-376.
[20] Okany, C.C. and Akinyanju, O.O. (1993) The Influence of Socio-Economic Status on the Severity of Sickle Cell Disease. African Journal of Medicine and Medical Sciences, 22, 57-60.
[21] Animasahun, B.A., Temiye, E.O., Ogunkunle, O.O., Izuora, A.N. and Njokanma, O.F. (2011) The Influence of Socioeconomic Status on the Hemoglobin Level and Anthropometry of Sickle Cell Anemia Patients in Steady State at the Lagos University Teaching Hospital. Nigerian Journal of Clinical Practice, 14, 422-427.
[22] Ellison, A.M. and Bauchner, H. (2007) Socioeconomic Status and Length of Hospital Stay in Children with Vaso-Occlusive Crises of Sickle Cell Disease. Journal of the National Medical Association, 99, 192-196.
[23] Ware, R.E., Eggleston, B., Redding-Lallinger, R., Wang, W.C., Smith-Whitley, K., Daeschner, C., Gee, B., Styles, L.A., Helms, R.W., Kinney, T.R. and Ohene-Frempong, K. (2002) Predictors of Fetal Hemoglobin Response in Children with Sickle Cell Anemia Receiving Hydroxyurea Therapy. Blood, 99, 10-14.
[24] Charache, S., Terrin, M.L., Moore, R.D., Dover, G.J., Barton, F.B., Eckert, S.V., McMahon, R.P. and Bonds, D.R. (1995) Effect of Hydroxyurea on the Frequency of Painful Crises in Sickle Cell Anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. New England Journal of Medicine, 332, 1317-1322.
[25] Kinney, T.R., Helms, R.W., O’Branski, E.E., Ohene-Frempong, K., Wang, W., Daeschner, C., Vichinsky, E., Redding-Lallinger, R., Gee, B., Platt, O.S. and Ware, R.E. (1999) Safety of Hydroxyurea in Children with Sickle Cell Anemia: Results of the HUG-KIDS Study, a Phase I/II Trial. Pediatric Hydroxyurea Group. Blood, 94, 1550-1554.
[26] (2012) CEB—Critério de Classificacao Economica Brasil.
[27] Lahiri, D.K. and Nurnberger Jr., J.I. (1991) A Rapid Non-Enzymatic Method for the Preparation of HMW DNA from Blood for RFLP Studies. Nucleic Acids Research, 19, 5444.
[28] Sutton, M., Bouhassira, E.E. and Nagel, R.L. (1989) Polymerase Chain Reaction Amplification Applied to the Determination of β-Like Globin Gene Cluster Haplotypes. American Journal of Hematology, 32, 66-69.
[29] Wagner, S.C., Friedrisch, J.R., Job, F. and Hutz, M.H. (1996) Caracterizacao molecular da anemia falciforme em pacientes de Porto Alegre. Revista Brasileira de Genetica, 19, 244.
[30] Lemos Cardoso, G. and Farias Guerreiro, J. (2006) African Gene Flow to North Brazil as Revealed by HBB*S Gene Haplotype Analysis. American Journal of Human Biology, 18, 93-98.
[31] Goncalves, M.S., Bomfim, G.C., Maciel, E., Cerqueira, I., Lyra, I., Zanette, A., Bomfim, G., Adorno, E.V., Albuquerque, A.L., Pontes, A., Dupuit, M.F., Fernandes, G.B. and dos Reis, M.G. (2003) βS-Haplotypes in Sickle Cell Anemia Patients from Salvador, Bahia, Northeastern Brazil. Brazilian Journal of Medical and Biological Research, 36, 1283-1288.
[32] Curtain, P.D. (1972) The Atlantic Slave Trade: A Census. University of Wisconsin Press, Wisconsin.
[33] Zago, M.A., Silva Jr., W.A., Dalle, B., Gualandro, S., Hutz, M.H., Lapoumeroulie, C., Tavella, M.H., Araujo, A.G., Krieger, J.E., Elion, J. and Krishnamoorthy, R. (2000) Atypical βS Haplotypes Are Generated by Diverse Genetic Mechanisms. American Journal of Hematology, 63, 79-84.
[34] Bank, A. (2006) Regulation of Human Fetal Hemoglobin: New Players, New Complexities. Blood, 107, 435-443.
[35] Powars, D.R. (1991) βS-Gene-Cluster Haplotypes in Sickle Cell Anemia. Clinical and Hematologic Features. Hematology/Oncology Clinics of North America, 5, 475-493.
[36] Green, N.S. and Barral, S. (2011) Genetic Modifiers of HbF and Response to Hydroxyurea in Sickle Cell Disease. Pediatric Blood & Cancer, 56, 177-181.
[37] Bauer, D.E. and Orkin, S.H. (2011) Update on Fetal Hemoglobin Gene Regulation in Hemoglobinopathies. Current Opinion in Pediatrics, 23, 1-8.
[38] Chies, J.A., Dresch, C., Cruz, M.S., da Silva, G., Barros, E., Bittar, C., Friedrisch, J. and Silla, L.M. (2005) Immunosuppressive Therapy for Kidney Transplant Prevents Vaso-Occlusive Crisis in a Haemoglobin SC Disease Patient. Medical Hypotheses, 64, 174-176.

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