Sickle cell anemia: clinical diversity and beta S-globin
               haplotypes

Loggetto, Sandra Regina

doi:10.5581/1516-8484.20130048

In sickle cell anemia (SCA), beta S-globin haplotypes represent the ethnic group or geographic region from which patients originated. The haplotypes include Senegal (SEN), Benin (BEN), Bantu or Central African Republic (CAR), Cameroon (CAM) and Arab-Indian (ARAB)⁽ ¹ ^, ² ⁾. Later, atypical haplotypes were described⁽ ³ ^- ⁵ ⁾.

African-American patients with SCA mainly have the BEN haplotype⁽ ⁶ ⁾. In Brazil the main beta S-globin haplotype is CAR followed by BEN. In agreement with the historical origin of the afro-descendant population, the CAR haplotype is more common in the states of São Paulo⁽ ⁴ ^, ⁷ ^- ¹¹ ⁾, Rio de Janeiro⁽ ¹² ^- ¹⁴ ⁾, Minas Gerais⁽ ¹⁵ ⁾, Pernambuco⁽ ¹⁶ ⁾, Rio Grande doNorte⁽ ¹⁷ ⁾, Ceará⁽ ¹⁸ ^, ¹⁹ ⁾ and Pará⁽ ²⁰ ^, ²¹ ⁾. The BEN haplotype is more frequent than CAR in Bahia in general⁽ ²² ^, ²³ ⁾, however, in Salvador (the capital city of Bahia), this frequency is different with similar frequencies for the CAR and BEN haplotypes⁽ ⁹ ^, ²⁴ ^, ²⁵ ⁾ probably as a consequence of the domestic slave trade and subsequent internal migrations from other regions of Brazil.

Fetal hemoglobin (Hb F) is related to the haplotype and correlates with the clinical course of SCA. SEN and ARAB haplotypes produce the highest levels of Hb F and are associated with fewer clinical manifestations of SCA and with a lower occurrence of organ damage. BEN and CAM haplotypes exhibit intermediate levels of Hb F and clinical severity. However, the CAR haplotype is associated with lowest levels of Hb F and consequently with the worst clinical severity including a three-fold risk to develop stroke, renal failure, chronic lung disease with cor pulmonale, leg ulcers, and young adult death. The risk of acute chest syndrome (ACS), pain crises and infections is similar in individuals with the BEN or CAR haplotypes. In the USA, it has been reported that co-inheritance with the alpha-thalassemia gene has little influence in acute events during childhood⁽ ²⁶ ^- ²⁸ ⁾.

Brazilian studies also found a correlation between SCA clinical manifestations, Hb Fand the beta S-globin haplotype⁽ ⁸ ^, ⁹ ^, ¹³ ^, ¹⁹ ^, ²⁵ ^, ²⁹ ^, ³⁰ ⁾, including more vaso-occlusive crises⁽ ⁹ ^, ²⁹ ⁾, more infections⁽ ⁹ ⁾ and slower growth⁽ ²⁹ ⁾ in the CAR haplotype, high levels of Hb F⁽ ¹³ ^, ¹⁹ ^, ²⁵ ⁾ and nitrites in the BEN haplotype⁽ ¹⁹ ⁾, and increased risk of cerebro vascular disease (CVD) in children with the Bantu/atypical haplotype compared to other beta S-globin haplotypes⁽ ³⁰ ⁾. Patients with the CAR/BEN haplotype had less painful crises compared to the other haplotypes⁽ ²² ⁾. Trials have shown no correlations between co-inheritance with alpha-thalassemia and clinical symptoms⁽ ⁸ ^, ⁹ ^, ²² ⁾, however it may be associated with less infections⁽ ¹³ ⁾ or with repeated acute pain crises⁽ ²⁹ ⁾.

Moreover, recent Brazilian publications have described that there are no correlations between beta S-globin haplotypes and the clinical course of SCA. Risk factors for conjunctival vessel alterations were lower hemoglobin and hematocrit levels and the SS phenotype and forretinal vessel alterations, risk was related to age over 17 years, however no correlation was found with Hb F, the beta-globin gene haplotype or alpha-thalassemia⁽ ¹⁰ ⁾. In a retrospective study in pediatrics, the mean Hb F level measured in over 2-year olds was lower in individuals with the CAR haplotype, but not statistically lower when compared to the BEN haplotype. One possible reason for this finding is that the Hb F may not have reached stable levels in these young children. Blood transfusions, ACT, acute spleen sequestration (ASS) and CVD were not significantly different between the different haplotypes⁽ ¹⁵ ⁾. Painful crises, ASS, hemolytic crises, hand-foot syndromes, ACS and infections were not related to the beta S-globin haplotype in another retrospective study of under 6-year-old children. Nevertheless, this lack of correlation could be due to the sample size, the number of heterozygous individuals, the miscegenation of the Brazilian population, and the multiplicity of the clinical expression in SCA⁽ ¹³ ⁾. It was not reported in these papers whether the patients (or how many patients) were receiving hydroxyurea (HU).If HU was being administered to SCA patients with the worst clinical symptoms, presumably those with the CAR haplotype, would this not explain the lack of clinical correlations between different beta S-globin haplotypes? A better response to HU was described in CAR haplotypepatients in respect to increases in Hb F⁽ ³¹ ⁾, but other trials did not support these results⁽ ³² ^, ³³ ⁾.

Chronic anemia and microcirculation disease of the renal medullary capillaries as a consequence of the physiopathology of SCA make renal damage a common complication. The incidence of renal disease is increasing as patient survival is improving. Children with SCA often develop hyposthenuria and increased glomerular filtration rates (GFR) at an early age, possibly contributing to the glomerular injury and renal insufficiency commonly seen later in life. Anemia, glomerular hyperfiltration, hypertension, microalbuminuria, proteinuria, nephrotic syndrome and microscopic hematuria are strong predictors of subsequent renal failure. Regarding haplotypes, the risk of renal failure inSCA is increased in patients who have the CAR beta S-globin haplotype⁽ ³⁴ ⁾. The co-inheritance of alpha-thalassemia was associated with a lower prevalence of macroalbuminuria in SCA patients suggesting renal protection⁽ ³⁵ ^, ³⁶ ⁾. No association was found between albuminuria and beta S-globin haplotypes (CAR versus non-CAR haplotypes)⁽ ³⁵ ^, ³⁶ ⁾. An evaluation of the association between kidney dysfunction and haplotypes in 84 Brazilian sickle cell disease patients is published in this issue of the Revista Brasileira de Hematologia e Hemoterapia (RBHH)⁽ ³⁷ ⁾. GFR, urinary concentrating capacity and urinary acidification were determined and there was no significant difference when comparing patients with the CAR/CAR and BEN/BEN haplotypes. However, there was a higher frequency of GFR between 60 and 120 mL/min among CAR patients. Despite initial data linking the CAR haplotype with renal failure, this data has not been confirmed over the years.

Survival in 102 over 60-year-old SCA patients from Jamaica was associated with female gender and higher Hb F but not with alpha-thalassemia or the beta-globin haplotype. The lack of effect of beta S-globin haplotype on survival may be explained by the high prevalence of the BEN haplotype in Jamaica. None received HU. Age-related changes were improvement of bone pain, increased serum creatinine and decreased hemoglobin levels. Renal failure affected 24% of SCA patients and was a major problem in this population⁽ ³⁸ ⁾. In the USA, mortality in patients between 16 and 68 years while on HU therapy was shown to be mainly due to ACS (35%), but also due to multiple organ failure, stroke, end-stage renal disease, sepsis, cardiac arrhythmia, and pulmonary embolism. In this trial, homozygous BEN or heterozygous CAM haplotypes, possibly with more severe disease and organ damage, were significantly associated to death⁽ ³⁹ ⁾.

Although Hb F and beta S-globin haplotypes are widely studied as a genetic modulator for SCA, the diversity of the disease is not entirely explained. So, genetic polymorphisms that might explain the clinical diversity in SCA related to inflammation, vaso-regulation, blood coagulation, hemostasis, growth factors, cytokines and cytokine receptors, and transcriptional factors have been studied. Examples of polymorphism studies include the genes of the TGF-beta/BMP pathway suggesting that haplotypes in BMPR1B [a bone morphogenetic protein (BMP) receptor gene] are associated with higher GFRs in SCA⁽ ⁴⁰ ⁾, and the association of 844ins68, a genetic polymorphism of the cystathionine betasynthase enzyme gene (CBS) and C677T MTHFR, a genetic polymorphism of the methylenetetrahydrofolate reductase enzyme gene (MTHFR) is a risk factor for vaso-occlusive episodes in SCD patients⁽ ⁴¹ ⁾.

More studies on genetic polymorphisms are necessary to better understand SCA and if possible, to find genetic modulators of disease severity that could guide prognosis to determine preventive measures and the best treatment for acute and chronic organ damage.

References

¹ Pagnier J, Mears JG, Dunda-Belkhodja O, Schaefer-Rego KE, Beldjord C, Nagel RL, et al. Evidence for the multicentric origin of the sickle cellhemoglobin gene in Africa. Proc Natl Acad Sci U S A. 1984;81(6):1771-3.
² Lapouméroulie C, Dunda O, Ducrocq R, Trabuchet G, Mony-Lobé M, Bodo M, et al. A novel sickle cell mutation of yet another origin in Africa: the Cameroon type. Hum Genet. 1992;89(3):333-7.
³ Srinivas R, Dunda O, Krishnamoorthy R, Fabry ME, Georges A, Labie D, et al. Atypical haplotypes linked to the beta-S gene in Africa are likely to be the product of recombination. Am J Hematol.1988;29(1):60-2.
⁴ Zago MA, Figueiredo MS, Ogo SH. Bantu beta-S cluster haplotype predominates among Brazilian blacks. Am J Phys Anthropol. 1992;88(3):295-8.
⁵ Zago MA, Silva-Júnior WA, Dalle B, Gualandro S, Hutz MH, Lapoumeroulie C, et al. Atypical beta-S haplotypes are generated by diverse genetic mechanisms. Am J Hematol. 2000;63(2):79-84.
⁶ Hattori Y, Kutlar F, Kutlar A, McKie VC, Huisman TH. Haplotypes of beta S chromosomes among patients with sickle cell anemia from Georgia. Hemoglobin. 1986;10(6):623-42.
⁷ Gonçalves MS, Nechtman JF, Figueiredo MS, Kerbauy J, Arruda VR, Sonati MF, et al. Sickle cell disease in a Brazilian population from São Paulo: A study of the beta-S haplotypes. Hum Hered. 1994;44(6):322-7.
⁸ Figueiredo MS, Kerbauy J, Gonçalves MS, Arruda VR, Saad ST, Sonati MF, et al. Effect of alpha-thalassemia and beta-globin gene cluster haplotypes on the hematological and clinical features of sickle-cell anemia in Brazil. Am J Hematol. 1996;53(2):72-6.
⁹ Lyra IM, Gonçalves MS, Braga JA, Gesteira MF, Carvalho MH, Saad ST, et al. Clinical, hematological, and molecular characterization of sickle cell anemia pediatric patients from two different cities in Brazil. Cad Saúde Pública. 2005;21(4):1287-90.
¹⁰ Lima CS, Rocha EM, Silva NM, Sonatti MF, Costa FF, Saad ST. Risk factors for conjunctival and retinal vessel alterations in sickle cell disease. Acta Ophthalmol. Scand. 2006;84(2):234-41.
¹¹ Auricchio MT, Vicente JP, Meyer D, Mingroni-Netto RC. Frequency and origins of hemoglobin S mutation in African-derived Brazilian populations. Hum Biol. 2007;79(6):667-77.
¹² Fleury MK. Haplótipos do cluster da globina beta em pacientes com anemia falciforme no Rio de Janeiro: aspectos clínicos e laboratoriais. Rev Bras Anal Clín. 2007;39(2):89-93.
¹³ Silva Filho IL, Ribeiro GS, Moura PG, Vechi ML, Cavalcante AC, Andrada-Serpa MJ. Sickle cell disease: acute clinical manifestations in early childhood and molecular characteristics in a group of children in Rio de Janeiro. Rev Bras Hematol Hemoter. 2012;34(3):196-201.
¹⁴ Okumura JV, Lobo CL, Bonini-Domingos CR. Beta-S globin haplotypes in patients with sickle cell anemia: one approach to understand the diversity in Brazil. Rev Bras Hematol Hemoter. 2013;35(1):71-2.
¹⁵ Belisário AR, Martins ML, Brito AM, Rodrigues CV, Silva CM, Viana MB. B-Globin gene cluster haplotypes in a cohort of 221 children with sickle cell anemia or S beta0-thalassemia and their association with clinical and hematological features. Acta Haematol. 2010;124(3):162-70. Erratum in: Acta Haematol. 2011;125(3):120.
¹⁶ Bezerra MA, Santos MN, Araújo AS, Gomes YM, Abath FG, Bandeira MG. Molecular variations linked to the grouping of beta- and alphaglobin genes in neonatal patients with sickle cell disease in the state of Pernambuco, Brazil. Hemoglobin. 2007;31(1):83-8.
¹⁷ Cabral CH, Serafim ES, Medeiros WR, de Medeiros Fernandes TA, Kimura EM, Costa FF, et al. Determination of beta-S haplotypes in patients with sickle-cell anemia in the state of Rio Grande do Norte, Brazil. Genet Mol Biol. 2011;34(3):421-4.
¹⁸ Silva LB, Gonçalves RP, Rabenhorst SHB. Analysis of sickle cell anemia haplotypes in Fortaleza reveals the ethnic origins of Ceará state population. J Bras Patol Med Lab. 2009;45(2):115-118.
¹⁹ Carvalho-dos Santos BS, Dias-Elias DB, da Silva-Rocha LB, Cavalcante-Barbosa M, Pinheiro-Gonçalves R. Impact of βS-globin haplotypes on oxidative stress in patients with sickle cell anemia in steady state. Arch Med Res. 2012;43(7):536-40.
²⁰ Pante de Sousa G, Mousinho-Ribeiro RC, Santos EJM, Zago MA, Guerreiro JF. Origin of the hemoglobin S gene in a northern Brazilian population: The combined effects of slave trade and internal migrations. Genet Mol Biol. 1998;21(4):427-30.
²¹ Lemos Cardoso G, Farias Guerreiro J. African gene flow to North Brazil as revealed by HBB*S gene haplotype analysis. Am J Hum Biol. 2006;18(1):93-8.
²² Adorno EV, Zanette A, Lyra I, Seixas MO, Reis MG, Gonçalves MS. Clinical and molecular characteristics of sickle cell anemia in northeast of Brazil. Genet Mol Biol 2008;31(3):621-5.
²³ Silva WS, Klautau-Guimarães MN, Grisolia CK. Beta-globin haplotypes in normal and hemoglobinopathic individuals from Reconcavo Baiano, State of Bahia, Brazil. Genet Mol Biol. 2010;33(3):411-7.
²⁴ Gonçalves MS, Bomfim GC, Maciel E, Cerqueira I, Lyra I, Zanette A, et al. Beta S-haplotypes in sickle cell anemia patients from Salvador, Bahia, Northeastern Brazil. Braz J Med Biol Res. 2003;36(10):1283-8.
²⁵ Adorno EV, Zanette A, Lyra I, Souza CC, Santos LF, Menezes JF, et al. The beta-globin gene cluster haplotypes in sickle cell anemia patients from northeast Brazil: A clinical and molecular view. Hemoglobin. 2004;28(3):267-71.
²⁶ Kulozik AE, Kar BC, Satapathy RK, Serjeant BE, Serjeant GR, Weatherall DJ. Fetal hemoglobin levels and βS globin haplotype in an Indian population with sickle cell disease. Blood. 1987;69(6):1742-6.
²⁷ Powars DR, Chan L, Schroeder WA. Beta-S-gene-cluster haplotypes in sickle cell anemia: clinical implications. Am J Pediatr Hematol Oncol. 1990;12(3):367-74.
²⁸ Month SR, Wood RW, Trifillis PT, Orchowski PJ, Sharon B, Ballas SK, et al. Analysis of the 5' flanking regions of the gamma globin genes from major African haplotype backgrounds associated with sickle cell disease. J Clin Invest. 1990;85(2):364-70.
²⁹ Luporini SM, Bendit I, Manhani R, Bracco OL, Manzella L, Giannella-Neto D. Growth hormone and insulin-like growth factor I axis and growth of children with different sickle cell anemia haplotypes. J Pediatr Hematol Oncol. 2001;23(6):357-63.
³⁰ Silva Filho IL, Leite AC, Moura PG, Ribeiro GS, Cavalcante AC, Azevedo FC, et al. Genetic polymorphisms and cerebrovascular disease in children with sickle cell anemia from Rio de Janeiro. Brazil. Arq Neuropsiquiatr. 2011;69(3):431-5.
³¹ Vicari P, Barretto de Mello A, Figueiredo MS. Effects of hydroxyurea in a population of Brazilian patients with sickle cell anemia. Am J Hematol. 2005;78(3):243-4.
³² Charache S, Dover GJ, Moore RD, Eckert S, Ballas SK, Koshy M, et al. Hydroxyurea: effects on hemoglobin F production in patients with sickle cell anemia. Blood. 1992;79(10):2555-65.
³³ Steinberg MH, Lu ZH, Barton FB, Terrin ML, Charache S, Dover GJ. Fetal hemoglobin in sickle cell anemia: determinants of response to hydroxyurea. Multicenter Study of Hydroxyurea. Blood. 1997;89(3):1078-88.
³⁴ Powars DR, Elliott-Mills DD, Chan L, Niland J, Hiti AL, Opas LM, et al. Chronic renal failure in sickle cell disease: risk factors, clinical course, and mortality. Ann Intern Med. 1991;115(8):614-20.
³⁵ Guasch A, Zayas CF, Eckman JR, Muralidharan K, Zhang W, Elsas LJ. Evidence that microdeletions in the alpha globin gene protect against the development of sickle cell glomerulopathy in humans. J Am Soc Nephrol. 1999;10(5):1014-9.
³⁶ Nebor D, Broquere C, Brudey K, Mougenel D, Tarer V, Connes P, et al. Alpha-thalassemia is associated with a decreased occurrence and a delayed age-at-onset of albuminuria in sickle cell anemia patients. Blood Cells Mol Dis. 2010;45(2):154-8.
³⁷ Rocha LB, Silva Junior GB, Daher EF, Rocha HA, Elias DB, Gonçalves RP. Kidney dysfunction and beta S-haplotypes in patients with sickle cell disease. Rev Bras Hematol Hemoter. 2013;35(3):171-3.
³⁸ Serjeant GR, Serjeant BE, Mason KP, Hambleton IR, Fisher C, Higgs DR. The changing face of homozygous sickle cell disease: 102 patients over 60 years. Int J Lab Hematol. 2009;31(6):585-96.
³⁹ Bakanay SM, Dainer E, Clair B, Adekile A, Daitch L, Wells L, et al. Mortality in sickle cell patients on hydroxyurea therapy. Blood. 2005;105(2):545-7.
⁴⁰ Nolan VG, Ma Q, Cohen HT, Adewoye A, Rybicki AC, Baldwin C, et al. Estimated glomerular filtration rate in sickle cell anemia is associated with polymorphisms of bone morphogenetic protein receptor 1B. Am J Hematol. 2007;82(3):179-84.
⁴¹ Alves Jacob M, da Cunha Bastos C, Regina Bonini-Domingos C.The 844ins68 cystathionine beta-synthase and C677T MTHFR gene polymorphism and the vaso-occlusive event risk in sickle cell disease. Arch Med Sci. 2011;7(1):97-101.

Publication Dates

Publication in this collection
June 2013

History

Received
11 Apr 2013
Accepted
17 Apr 2013

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

[1] ¹ Pagnier J, Mears JG, Dunda-Belkhodja O, Schaefer-Rego KE, Beldjord C, Nagel RL, et al. Evidence for the multicentric origin of the sickle cellhemoglobin gene in Africa. Proc Natl Acad Sci U S A. 1984;81(6):1771-3.

[2] ² Lapouméroulie C, Dunda O, Ducrocq R, Trabuchet G, Mony-Lobé M, Bodo M, et al. A novel sickle cell mutation of yet another origin in Africa: the Cameroon type. Hum Genet. 1992;89(3):333-7.

[3] ³ Srinivas R, Dunda O, Krishnamoorthy R, Fabry ME, Georges A, Labie D, et al. Atypical haplotypes linked to the beta-S gene in Africa are likely to be the product of recombination. Am J Hematol.1988;29(1):60-2.

[4] ⁴ Zago MA, Figueiredo MS, Ogo SH. Bantu beta-S cluster haplotype predominates among Brazilian blacks. Am J Phys Anthropol. 1992;88(3):295-8.

[5] ⁵ Zago MA, Silva-Júnior WA, Dalle B, Gualandro S, Hutz MH, Lapoumeroulie C, et al. Atypical beta-S haplotypes are generated by diverse genetic mechanisms. Am J Hematol. 2000;63(2):79-84.

[6] ⁶ Hattori Y, Kutlar F, Kutlar A, McKie VC, Huisman TH. Haplotypes of beta S chromosomes among patients with sickle cell anemia from Georgia. Hemoglobin. 1986;10(6):623-42.

[7] ⁷ Gonçalves MS, Nechtman JF, Figueiredo MS, Kerbauy J, Arruda VR, Sonati MF, et al. Sickle cell disease in a Brazilian population from São Paulo: A study of the beta-S haplotypes. Hum Hered. 1994;44(6):322-7.

[8] ⁸ Figueiredo MS, Kerbauy J, Gonçalves MS, Arruda VR, Saad ST, Sonati MF, et al. Effect of alpha-thalassemia and beta-globin gene cluster haplotypes on the hematological and clinical features of sickle-cell anemia in Brazil. Am J Hematol. 1996;53(2):72-6.

[9] ⁹ Lyra IM, Gonçalves MS, Braga JA, Gesteira MF, Carvalho MH, Saad ST, et al. Clinical, hematological, and molecular characterization of sickle cell anemia pediatric patients from two different cities in Brazil. Cad Saúde Pública. 2005;21(4):1287-90.

[10] ¹⁰ Lima CS, Rocha EM, Silva NM, Sonatti MF, Costa FF, Saad ST. Risk factors for conjunctival and retinal vessel alterations in sickle cell disease. Acta Ophthalmol. Scand. 2006;84(2):234-41.

[11] ¹¹ Auricchio MT, Vicente JP, Meyer D, Mingroni-Netto RC. Frequency and origins of hemoglobin S mutation in African-derived Brazilian populations. Hum Biol. 2007;79(6):667-77.

[12] ¹² Fleury MK. Haplótipos do cluster da globina beta em pacientes com anemia falciforme no Rio de Janeiro: aspectos clínicos e laboratoriais. Rev Bras Anal Clín. 2007;39(2):89-93.

[13] ¹³ Silva Filho IL, Ribeiro GS, Moura PG, Vechi ML, Cavalcante AC, Andrada-Serpa MJ. Sickle cell disease: acute clinical manifestations in early childhood and molecular characteristics in a group of children in Rio de Janeiro. Rev Bras Hematol Hemoter. 2012;34(3):196-201.

[14] ¹⁴ Okumura JV, Lobo CL, Bonini-Domingos CR. Beta-S globin haplotypes in patients with sickle cell anemia: one approach to understand the diversity in Brazil. Rev Bras Hematol Hemoter. 2013;35(1):71-2.

[15] ¹⁵ Belisário AR, Martins ML, Brito AM, Rodrigues CV, Silva CM, Viana MB. B-Globin gene cluster haplotypes in a cohort of 221 children with sickle cell anemia or S beta0-thalassemia and their association with clinical and hematological features. Acta Haematol. 2010;124(3):162-70. Erratum in: Acta Haematol. 2011;125(3):120.

[16] ¹⁶ Bezerra MA, Santos MN, Araújo AS, Gomes YM, Abath FG, Bandeira MG. Molecular variations linked to the grouping of beta- and alphaglobin genes in neonatal patients with sickle cell disease in the state of Pernambuco, Brazil. Hemoglobin. 2007;31(1):83-8.

[17] ¹⁷ Cabral CH, Serafim ES, Medeiros WR, de Medeiros Fernandes TA, Kimura EM, Costa FF, et al. Determination of beta-S haplotypes in patients with sickle-cell anemia in the state of Rio Grande do Norte, Brazil. Genet Mol Biol. 2011;34(3):421-4.

[18] ¹⁸ Silva LB, Gonçalves RP, Rabenhorst SHB. Analysis of sickle cell anemia haplotypes in Fortaleza reveals the ethnic origins of Ceará state population. J Bras Patol Med Lab. 2009;45(2):115-118.

[19] ¹⁹ Carvalho-dos Santos BS, Dias-Elias DB, da Silva-Rocha LB, Cavalcante-Barbosa M, Pinheiro-Gonçalves R. Impact of βS-globin haplotypes on oxidative stress in patients with sickle cell anemia in steady state. Arch Med Res. 2012;43(7):536-40.

[20] ²⁰ Pante de Sousa G, Mousinho-Ribeiro RC, Santos EJM, Zago MA, Guerreiro JF. Origin of the hemoglobin S gene in a northern Brazilian population: The combined effects of slave trade and internal migrations. Genet Mol Biol. 1998;21(4):427-30.

[21] ²¹ Lemos Cardoso G, Farias Guerreiro J. African gene flow to North Brazil as revealed by HBB*S gene haplotype analysis. Am J Hum Biol. 2006;18(1):93-8.

[22] ²² Adorno EV, Zanette A, Lyra I, Seixas MO, Reis MG, Gonçalves MS. Clinical and molecular characteristics of sickle cell anemia in northeast of Brazil. Genet Mol Biol 2008;31(3):621-5.

[23] ²³ Silva WS, Klautau-Guimarães MN, Grisolia CK. Beta-globin haplotypes in normal and hemoglobinopathic individuals from Reconcavo Baiano, State of Bahia, Brazil. Genet Mol Biol. 2010;33(3):411-7.

[24] ²⁴ Gonçalves MS, Bomfim GC, Maciel E, Cerqueira I, Lyra I, Zanette A, et al. Beta S-haplotypes in sickle cell anemia patients from Salvador, Bahia, Northeastern Brazil. Braz J Med Biol Res. 2003;36(10):1283-8.

[25] ²⁵ Adorno EV, Zanette A, Lyra I, Souza CC, Santos LF, Menezes JF, et al. The beta-globin gene cluster haplotypes in sickle cell anemia patients from northeast Brazil: A clinical and molecular view. Hemoglobin. 2004;28(3):267-71.

[26] ²⁶ Kulozik AE, Kar BC, Satapathy RK, Serjeant BE, Serjeant GR, Weatherall DJ. Fetal hemoglobin levels and βS globin haplotype in an Indian population with sickle cell disease. Blood. 1987;69(6):1742-6.

[27] ²⁷ Powars DR, Chan L, Schroeder WA. Beta-S-gene-cluster haplotypes in sickle cell anemia: clinical implications. Am J Pediatr Hematol Oncol. 1990;12(3):367-74.

[28] ²⁸ Month SR, Wood RW, Trifillis PT, Orchowski PJ, Sharon B, Ballas SK, et al. Analysis of the 5' flanking regions of the gamma globin genes from major African haplotype backgrounds associated with sickle cell disease. J Clin Invest. 1990;85(2):364-70.

[29] ²⁹ Luporini SM, Bendit I, Manhani R, Bracco OL, Manzella L, Giannella-Neto D. Growth hormone and insulin-like growth factor I axis and growth of children with different sickle cell anemia haplotypes. J Pediatr Hematol Oncol. 2001;23(6):357-63.

[30] ³⁰ Silva Filho IL, Leite AC, Moura PG, Ribeiro GS, Cavalcante AC, Azevedo FC, et al. Genetic polymorphisms and cerebrovascular disease in children with sickle cell anemia from Rio de Janeiro. Brazil. Arq Neuropsiquiatr. 2011;69(3):431-5.

[31] ³¹ Vicari P, Barretto de Mello A, Figueiredo MS. Effects of hydroxyurea in a population of Brazilian patients with sickle cell anemia. Am J Hematol. 2005;78(3):243-4.

[32] ³² Charache S, Dover GJ, Moore RD, Eckert S, Ballas SK, Koshy M, et al. Hydroxyurea: effects on hemoglobin F production in patients with sickle cell anemia. Blood. 1992;79(10):2555-65.

[33] ³³ Steinberg MH, Lu ZH, Barton FB, Terrin ML, Charache S, Dover GJ. Fetal hemoglobin in sickle cell anemia: determinants of response to hydroxyurea. Multicenter Study of Hydroxyurea. Blood. 1997;89(3):1078-88.

[34] ³⁴ Powars DR, Elliott-Mills DD, Chan L, Niland J, Hiti AL, Opas LM, et al. Chronic renal failure in sickle cell disease: risk factors, clinical course, and mortality. Ann Intern Med. 1991;115(8):614-20.

[35] ³⁵ Guasch A, Zayas CF, Eckman JR, Muralidharan K, Zhang W, Elsas LJ. Evidence that microdeletions in the alpha globin gene protect against the development of sickle cell glomerulopathy in humans. J Am Soc Nephrol. 1999;10(5):1014-9.

[36] ³⁶ Nebor D, Broquere C, Brudey K, Mougenel D, Tarer V, Connes P, et al. Alpha-thalassemia is associated with a decreased occurrence and a delayed age-at-onset of albuminuria in sickle cell anemia patients. Blood Cells Mol Dis. 2010;45(2):154-8.

[37] ³⁷ Rocha LB, Silva Junior GB, Daher EF, Rocha HA, Elias DB, Gonçalves RP. Kidney dysfunction and beta S-haplotypes in patients with sickle cell disease. Rev Bras Hematol Hemoter. 2013;35(3):171-3.

[38] ³⁸ Serjeant GR, Serjeant BE, Mason KP, Hambleton IR, Fisher C, Higgs DR. The changing face of homozygous sickle cell disease: 102 patients over 60 years. Int J Lab Hematol. 2009;31(6):585-96.

[39] ³⁹ Bakanay SM, Dainer E, Clair B, Adekile A, Daitch L, Wells L, et al. Mortality in sickle cell patients on hydroxyurea therapy. Blood. 2005;105(2):545-7.

[40] ⁴⁰ Nolan VG, Ma Q, Cohen HT, Adewoye A, Rybicki AC, Baldwin C, et al. Estimated glomerular filtration rate in sickle cell anemia is associated with polymorphisms of bone morphogenetic protein receptor 1B. Am J Hematol. 2007;82(3):179-84.

[41] ⁴¹ Alves Jacob M, da Cunha Bastos C, Regina Bonini-Domingos C.The 844ins68 cystathionine beta-synthase and C677T MTHFR gene polymorphism and the vaso-occlusive event risk in sickle cell disease. Arch Med Sci. 2011;7(1):97-101.

Sickle cell anemia: clinical diversity and beta S-globin haplotypes

References

Publication Dates

History