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Alpha thalassemia, but not βS-globin haplotypes, influence sickle cell anemia clinical outcome in a large, single-center Brazilian cohort

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Abstract

Alpha thalassemia and beta-globin haplotype are considered classical genetic disease modifiers in sickle cell anemia (SCA) causing clinical heterogeneity. Nevertheless, their functional impact on SCA disease emergence and progression remains elusive. To better understand the role of alpha thalassemia and beta-globin haplotype in SCA, we performed a retrospective study evaluating the clinical manifestations of 614 patients. The univariate analysis showed that the presence of alpha-thalassemia −3.7-kb mutation (αα/-α and -α/-α) decreased the risk of stroke development (p = 0.046), priapism (p = 0.033), and cholelithiasis (p = 0.021). Furthermore, the cumulative incidence of stroke (p = 0.023) and cholelithiasis (p = 0.006) was also significantly lower for patients carrying the alpha thalassemia −3.7-kb mutation. No clinical effects were associated with the beta-globin haplotype analysis, which could be explained by the relatively homogeneous haplotype composition in our cohort. Our results reinforce that alpha thalassemia can provide protective functions against hemolysis-related symptoms in SCA. Although, several genetic modifiers can impact the inflammatory state of SCA patients, the alpha thalassemia mutation remains one of the most recurrent genetic aberration and should therefore always be considered first.

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References

  1. Ballas SK, Kesen MR, Goldberg MF, Lutty GA, Dampier C, Osunkwo I, Wang WC, Hoppe C, Hagar W, Darbari DS, Malik P (2012) Beyond the definitions of the phenotypic complications of sickle cell disease: an update on management. Sci World J 2012:1–55. https://doi.org/10.1100/2012/949535

    Article  Google Scholar 

  2. Driss A, Asare K, Hibbert J et al (2009) Sickle cell disease in the post genomic era: a monogenic disease with a polygenic phenotype. Genomics Insights 2009:23–48

    CAS  PubMed  Google Scholar 

  3. Serjeant GR (2013) The natural history of sickle cell disease. Cold Spring Harb Perspect Med 3:1–11. https://doi.org/10.1101/cshperspect.a011783

    Article  CAS  Google Scholar 

  4. Kutlar A (2007) Sickle cell disease: a multigenic perspective of a single gene disorder. Hemoglobin 31:209–224. https://doi.org/10.1080/03630260701290233

    Article  CAS  PubMed  Google Scholar 

  5. Steinberg MH, Embury SH (1986) Alpha-thalassemia in blacks: genetic and clinical aspects and interactions with the sickle hemoglobin gene. Blood 68:985–990

    Article  CAS  Google Scholar 

  6. Powars DR (1991) Beta s-gene-cluster haplotypes in sickle cell anemia. Clinical and hematologic features. Hematol Oncol Clin North Am 5:475–493

    Article  CAS  Google Scholar 

  7. Zago MA, Pinto ACS (2007) Fisiopatologia das doenças falciformes: da mutação genética à insuficiência de múltiplos órgãos. Rev Bras Hematol Hemoter 29:207–214. https://doi.org/10.1590/S1516-84842007000300003

    Article  Google Scholar 

  8. Silva Lilianne B, Gonçalves Romélia P (2010) Características fenotípicas dos pacientes com anemia falciforme de acordo com os haplótipos do gene da βS-globina em Fortaleza, Ceará. Rev Bras Hematol Hemoter 32(1):40–44. https://doi.org/10.1590/S1516-84842010005000005

    Article  Google Scholar 

  9. Shimauti ELT, Humberto Silva DG, Menezes de Souza E et al (2015) Prevalence of b -globin gene haplotypes , a -thalassemia ( 3 . 7 kb deletion ) and redox status in patients with sickle cell anemia in the state of Paraná , Brazil. Genet Mol Biol 323:316–323. https://doi.org/10.1590/S1415-475738320140231

    Article  Google Scholar 

  10. Serjeant GR, Vichinsky E, Herrick J, Mason V (2017) Variability of homozygous sickle cell disease: the role of alpha and beta globin chain variation and other factors. Blood Cells Mol Dis 70:0–1. https://doi.org/10.1016/j.bcmd.2017.06.004

  11. Steinberg MH (2005) Predicting clinical severity in sickle cell anaemia. Br J Haematol 129:465–481. https://doi.org/10.1111/j.1365-2141.2005.05411.x

    Article  CAS  PubMed  Google Scholar 

  12. Kato GJ, Gladwin MT, Steinberg MH (2007) Deconstructing sickle cell disease: reappraisal of the role of hemolysis in the development of clinical subphenotypes. Blood Rev 21:37–47. https://doi.org/10.1016/j.blre.2006.07.001

    Article  PubMed  Google Scholar 

  13. Nolan VG, Wyszynski DF, Farrer LA, Steinberg MH (2005) Hemolysis-associated priapism in sickle cell disease. Blood 106:3264–3267. https://doi.org/10.1182/blood-2005-04-1594

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Vasavda N, Menzel S, Kondaveeti S, Maytham E, Awogbade M, Bannister S, Cunningham J, Eichholz A, Daniel Y, Okpala I, Fulford T, Thein SL (2007) The linear effects of a-thalassaemia, the UGT1A1 and HMOX1 polymorphisms on cholelithiasis in sickle cell disease. Br J Haematol 138:263–270. https://doi.org/10.1111/j.1365-2141.2007.06643.x

    Article  CAS  PubMed  Google Scholar 

  15. Fertrin KY, Costa FF (2010) Genomic polymorphisms in sickle cell disease: implications for clinical diversity and treatment. Expert Rev Hematol 3:443–458. https://doi.org/10.1586/ehm.10.44

    Article  CAS  PubMed  Google Scholar 

  16. Darbari DS, Onyekwere O, Nouraie M, Minniti CP, Luchtman-Jones L, Rana S, Sable C, Ensing G, Dham N, Campbell A, Arteta M, Gladwin MT, Castro O, Taylor JG VI, Kato GJ, Gordeuk V (2012) Markers of severe vaso-occlusive painful episode frequency in children and adolescents with sickle cell anemia. J Pediatr 160:286–290. https://doi.org/10.1016/j.jpeds.2011.07.018

    Article  PubMed  Google Scholar 

  17. Alkindi SY, Pathare A, Al Zadjali S, Panjwani V, Wasim F, Khan H, Chopra P, Krishnamoorthy R, Alkindi S (2015) Serum Total Bilirubin, not Cholelithiasis, is Influenced by UGT1A1 Polymorphism, Alpha Thalassemia and β(s) Haplotype: First Report on Comparison between Arab-Indian and African β(s) Genes. Mediterr J Hematol Infect Dis 7(1):e2015060. https://doi.org/10.4084/mjhid.2015.060

    Article  PubMed  PubMed Central  Google Scholar 

  18. Balkaran B, Char G, Morris JS, Thomas PW, Serjeant BE, Serjeant GR (1992) Stroke in a cohort of patients with homozygous sickle cell disease. J Pediatr 120:360–366. https://doi.org/10.1016/S0022-3476(05)80897-2

    Article  CAS  PubMed  Google Scholar 

  19. Ballas SK, Talacki CA, Rao VM, Steiner RM (1989) The prevalence of avascular necrosis in sickle cell anemia: correlation with αthalassemia. Hemoglobin 13:649–655. https://doi.org/10.3109/03630268908998842

    Article  CAS  PubMed  Google Scholar 

  20. Steinberg MH (2009) Genetic etiologies for phenotypic diversity in sickle cell anemia. ScientificWorldJournal 9:46–67. https://doi.org/10.1100/tsw.2009.10

    Article  PubMed  PubMed Central  Google Scholar 

  21. Joly P, Pondarré C, Bardel C, Francina A, Martin C (2012) The alpha-globin genotype does not influence sickle cell disease severity in a retrospective cross-validation study of the pediatric severity score. Eur J Haematol 88:61–67. https://doi.org/10.1111/j.1600-0609.2011.01705.x

    Article  PubMed  Google Scholar 

  22. Kato GJ, Steinberg MH, Gladwin MT (2017) Intravascular hemolysis and the pathophysiology of sickle cell disease. J Clin Invest 127:750–760. https://doi.org/10.1172/JCI89741

    Article  PubMed  PubMed Central  Google Scholar 

  23. Akinsheye I, Alsultan A, Solovieff N, Ngo D, Baldwin CT, Sebastiani P, Chui DHK, Steinberg MH (2011) Fetal hemoglobin in sickle cell anemia. Blood 118:19–27. https://doi.org/10.1182/blood-2011-03-325258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. McGann PT, Ware RE (2015) Hydroxyurea therapy for sickle cell anemia. Expert Opin Drug Saf 42:407–420. https://doi.org/10.1002/jmri.24785.Free-Breathing

    Article  Google Scholar 

  25. Nagel RL, Fabry ME, Pagnier J, Zohoun I, Wajcman H, Baudin V, Labie D (1985) Hematologically and genetically distinct forms of sickle cell anemia in Africa. N Engl J Med 312:880–884. https://doi.org/10.1056/NEJM198504043121403

    Article  CAS  PubMed  Google Scholar 

  26. Rusanova I, Escames G, Cossio G, de Borace RG, Moreno B, Chahboune M, López LC, Díez T, Acuña-Castroviejo D (2010) Oxidative stress status, clinical outcome, and β-globin gene cluster haplotypes in pediatric patients with sickle cell disease. Eur J Haematol 85:529–537. https://doi.org/10.1111/j.1600-0609.2010.01528.x

    Article  CAS  PubMed  Google Scholar 

  27. Pagnier J, Mears JG, Dunda-Belkhodja O, Schaefer-Rego KE, Beldjord C, Nagel RL, Labie D (1984) Evidence for the multicentric origin of the sickle cell hemoglobin gene in Africa. Proc Natl Acad Sci U S A 81:1771–1773. https://doi.org/10.1073/pnas.81.6.1771

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Rahgozar S, Poorfathollah AA, Moafi AR, Old JM (2000) BS gene in Central Iran is in linkage disequilibrium with the Indian – Arab haplotype. Am J Hematol 195:192–195

    Article  Google Scholar 

  29. Piel FB, Steinberg MH, Rees DC (2017) Sickle cell disease. N Engl J Med 376:1561–1573. https://doi.org/10.1056/NEJMra1510865

    Article  CAS  PubMed  Google Scholar 

  30. Steinberg MH, Sebastiani P (2012) Genetic modifiers of sickle cell disease. Am J Hematol 87:795–803. https://doi.org/10.1002/ajh.23232

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Powars D, Chan L, Schroed WA (1990) βS-gene-cluster haplotypes in sickle cell anemia: clinical implications. Am J Pediatr Hematol Oncol 12:367–374

    Article  CAS  Google Scholar 

  32. Adekile AD (2005) Mild-phenotype sickle cell disease: molecular basis, clinical presentation and management recommendations. Curr Paediatr 15:57–61. https://doi.org/10.1016/j.cupe.2004.10.009

    Article  Google Scholar 

  33. Cabral CHK, Serafim ÉSS, de Medeiros WRDB et al (2011) Determination of βS haplotypes in patients with sickle-cell anemia in the state of Rio Grande do Norte, Brazil. Genet Mol Biol 34:421–424. https://doi.org/10.1590/S1415-47572011005000027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Loggetto SR (2013) Sickle cell anemia: clinical diversity and beta S-globin haplotypes. Rev Bras Hematol Hemoter 35:155–157. https://doi.org/10.5581/1516-8484.20130048

    Article  PubMed  PubMed Central  Google Scholar 

  35. Thein SL, Menzel S, Peng X, Best S, Jiang J, Close J, Silver N, Gerovasilli A, Ping C, Yamaguchi M, Wahlberg K, Ulug P, Spector TD, Garner C, Matsuda F, Farrall M, Lathrop M (2007) Intergenic variants of HBS1L-MYB are responsible for a major quantitative trait locus on chromosome 6q23 influencing fetal hemoglobin levels in adults. Proc Natl Acad Sci U S A 104:11346–11351. https://doi.org/10.1073/pnas.0611393104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Uda M, Galanello R, Sanna S, Lettre G, Sankaran VG, Chen W, Usala G, Busonero F, Maschio A, Albai G, Piras MG, Sestu N, Lai S, Dei M, Mulas A, Crisponi L, Naitza S, Asunis I, Deiana M, Nagaraja R, Perseu L, Satta S, Cipollina MD, Sollaino C, Moi P, Hirschhorn JN, Orkin SH, Abecasis GR, Schlessinger D, Cao A (2008) Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of -thalassemia. Proc Natl Acad Sci 105:1620–1625. https://doi.org/10.1073/pnas.0711566105

    Article  PubMed  Google Scholar 

  37. Liu L, Pertsemlidis A, Ding L-H, Story MD, Steinberg MH, Sebastiani P, Hoppe C, Ballas SK, Pace BS (2016) Original research: a case-control genome-wide association study identifies genetic modifiers of fetal hemoglobin in sickle cell disease. Exp Biol Med 241:706–718. https://doi.org/10.1177/1535370216642047

    Article  CAS  Google Scholar 

  38. Menzel S, Thein SL (2019) Genetic modifiers of fetal haemoglobin in sickle cell disease. Mol Diagnosis Ther 23:235–244. https://doi.org/10.1007/s40291-018-0370-8

    Article  CAS  Google Scholar 

  39. Chang Y, Smith K, Moore R, Serjeant GR, Dover GJ (1995) An analysis of fetal hemoglobin variation in sickle cell disease: the relative contributions of the X-linked factor, beta-globin haplotypes, alpha-globin gene number, gender, and age. Blood 85:1111–1117

    Article  CAS  Google Scholar 

  40. Belisario AR, Martins ML, Brito AMS et al (2010) b-Globin gene cluster haplotypes in a cohort of 221 children with sickle cell anemia or Sb-thalassemia and their association with clinical and hematological features. Acta Haematol 124:162–170. https://doi.org/10.1159/000320271

    Article  CAS  PubMed  Google Scholar 

  41. Gaston MH, Verter JI, Woods G, Pegelow C, Kelleher J, Presbury G, Zarkowsky H, Vichinsky E, Iyer R, Lobel JS, Diamond S, Holbrook CT, Gill FM, Ritchey K, Falletta JM, For the Prophylactic Penicillin Study Group (1986) Prophylaxis with oral penicillin in children with sickle cell anemia. N Engl J Med 314:1593–1599. https://doi.org/10.1056/NEJM198606193142501

    Article  CAS  PubMed  Google Scholar 

  42. Silveira, E. L., da Rocha Silla, L. M., Krug, B. C., & Amaral, K. M. (2010). Doença Falciforme. Protocolo Clínico e Diretrizes Terapeuticas.

  43. Charache S, Terrin ML, Moore RD, Dover GJ, Barton FB, Eckert SV, McMahon RP, Bonds DR (1995) Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. N Engl J Med 332:1317–1322. https://doi.org/10.1056/nejm199505183322001

    Article  CAS  PubMed  Google Scholar 

  44. Baldwin C, Nolan VG, Wyszynski DF, Ma QL, Sebastiani P, Embury SH, Bisbee A, Farrell J, Farrer L, Steinberg MH (2005) Association of klotho, bone morphogenic protein 6, and annexin A2 polymorphisms with sickle cell osteonecrosis. Blood 106:372–375. https://doi.org/10.1182/blood-2005-02-0548

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Nolan VG, Baldwin C, Ma Q, Wyszynski DF, Amirault Y, Farrell JJ, Bisbee A, Embury SH, Farrer LA, Steinberg MH (2005) Association of single nucleotide polymorphisms in klotho with priapism in sickle cell anaemia. Br J Haematol 128:266–272. https://doi.org/10.1111/j.1365-2141.2004.05295.x

    Article  CAS  PubMed  Google Scholar 

  46. Nolan VG, Adewoye A, Baldwin C, Wang L, Ma Q, Wyszynski DF, Farrell JJ, Sebastiani P, Farrer LA, Steinberg MH (2006) Sickle cell leg ulcers: associations with haemolysis and SNPs in Klotho, TEK and genes of the TGF-β/BMP pathway. Br J Haematol 133:570–578

    Article  CAS  Google Scholar 

  47. Davis LG, Dibner MD, Battey JF (1986) Basic methods in molecular biology, 1st edn. Elsevier Science Publishing, New York, NY

    Google Scholar 

  48. Sutton M, Bouhassira EE, Nagel RL (1989) Polymerase chain reaction amplification applied to the determination of β-like globin gene cluster haplotypes. Am J Hematol 32:66–69. https://doi.org/10.1002/ajh.2830320113

    Article  CAS  PubMed  Google Scholar 

  49. Dodé C, Krishnamoorthy R, Lamb J, Rochette J (1993) Rapid analysis of -α 3.7 thalassaemia and ααα anti 3.7 triplication by enzymatic amplification analysis. Br J Haematol 83:105–111. https://doi.org/10.1111/j.1365-2141.1993.tb04639.x

    Article  PubMed  Google Scholar 

  50. Kato GJ, Piel FB, Reid CD, Gaston MH, Ohene-Frempong K, Krishnamurti L, Smith WR, Panepinto JA, Weatherall DJ, Costa FF, Vichinsky EP (2018) Sickle cell disease. Nat Rev Dis Prim 4. https://doi.org/10.1038/nrdp.2018.10

  51. Conran N, Belcher JD (2018) Inflammation in sickle cell disease. Clin Hemorheol Microcirc 68:263–299. https://doi.org/10.3233/CH-189012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Noubouossie D, Key NS, Ataga KI (2016) Coagulation abnormalities of sickle cell disease: relationship with clinical outcomes and the effect of disease modifying therapies. Blood Rev 30:245–256. https://doi.org/10.1016/j.blre.2015.12.003

    Article  CAS  PubMed  Google Scholar 

  53. Nasimuzzaman M, Malik P (2019) Role of the coagulation system in the pathogenesis of sickle cell disease. Blood Adv 3:3170–3180. https://doi.org/10.1182/bloodadvances.2019000193

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Kim-Shapiro DB, Gladwin MT (2018) Nitric oxide pathology and therapeutics in sickle cell disease. Clin Hemorheol Microcirc 68:223–237. https://doi.org/10.3233/CH-189009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Belisario AR, Rodrigues CV, Martins ML et al (2010) Coinheritance of α-thalassemia decreases the risk of cerebrovascular disease in a cohort of children with sickle cell anemia. Hemoglobin 34:516–529. https://doi.org/10.3109/03630269.2010.526003

    Article  CAS  PubMed  Google Scholar 

  56. Adorno EV, Zanette Â, Lyra I, Seixas MO, Reis MG, Gonçalves MS (2008) Clinical and molecular characteristics of sickle cell anemia in the northeast of Brazil. Genet Mol Biol 31:621–625. https://doi.org/10.1590/S1415-47572008000400003

    Article  CAS  Google Scholar 

  57. Neonato MG, Guilloud-Bataille M, Beauvais P, Bégué P, Belloy M, Benkerrou M, Ducrocq R, Maier-Redelsperger M, de Montalembert M, Quinet B, Elion J, Feingold J, Girot R, French Study Group on Sickle Cell Disease (2000) Acute clinical events in 299 homozygous sickle cell patients living in France. French Study Group on Sickle Cell Disease. Eur J Haematol 65:155–164. https://doi.org/10.1034/j.1600-0609.2000.90210.x

    Article  CAS  PubMed  Google Scholar 

  58. Castro O, Brambilla D, Thorington B, Reindorf CA, Scott RB, Gillette P, Vera JC, Levy PS (1994) The acute chest syndrome in sickle cell disease: incidence and risk factors. The Cooperative Study of Sickle Cell Disease. Blood 84:643–649

    Article  CAS  Google Scholar 

  59. Arends A, Alvarez M, Velázquez D, Bravo M, Salazar R, Guevara JM, Castillo O (2000) Determination of b-globin gene cluster haplotypes and prevalence of a-thalassemia in sickle cell anemia patients in Venezuela. Am J Hematol 64:87–90

    Article  CAS  Google Scholar 

  60. Koshy M, Entsuah R, Koranda A, Kraus AP, Johnson R, Bellvue R, Flournoy-Gill Z, Levy P (1989) Leg ulcers in patients with sickle cell disease. Blood 74:1403–1408

    Article  CAS  Google Scholar 

  61. Adams RJ, Kutlar A, McKie V, Carl E, Nichols FT, Liu JC, McKie K, Clary A (1994) Alpha thalassemia and stroke risk in sickle cell anemia. Am J Hematol 45:279–282. https://doi.org/10.1002/ajh.2830450402

    Article  CAS  PubMed  Google Scholar 

  62. Flanagan JM, Frohlich DM, Howard TA et al (2011) Genetic predictors for stroke in children with sickle cell anemia. Blood 117:6681–6684. https://doi.org/10.1182/blood-2011-01-332205

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Joly P, Garnier N, Kebaili K, Renoux C, Dony A, Cheikh N, Renard C, Ceraulo A, Cuzzubbo D, Pondarré C, Martin C, Pialoux V, Francina A, Bertrand Y, Connes P (2016) G6PD deficiency and absence of α-thalassemia increase the risk for cerebral vasculopathy in children with sickle cell anemia. Eur J Haematol 96:404–408. https://doi.org/10.1111/ejh.12607

    Article  CAS  PubMed  Google Scholar 

  64. Ohene-Frempong K, Weiner SJ, Sleeper LA et al (1998) Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood 91:288–294

    CAS  PubMed  Google Scholar 

  65. Adams GT, Snieder H, McKie VC et al (2003) Genetic risk factors for cerebrovascular disease in children with sickle cell disease: design of a case-control association study and genomewide screen. BMC Med Genet 4:6. https://doi.org/10.1186/1471-2350-4-6

    Article  PubMed  PubMed Central  Google Scholar 

  66. Steinberg MH, Rodgers GP (2001) Pathophysiology of sickle cell disease: role of cellular and genetic modifiers. Semin Hematol 38:299–306

    Article  CAS  Google Scholar 

  67. Chaar V, Diara JP, Clayton J (2005) Association of UGT1A1 polymorphism with prevalence and age at onset of cholelithiasis in sickle cell anemia. Haematologica 90:188–193

    CAS  PubMed  Google Scholar 

  68. Powars DR, Hiti A, Ramicone E, Johnson C, Chan L (2002) Outcome in hemoglobin SC disease: a four-decade observational study of clinical, hematologic, and genetic factors. Am J Hematol 70:206–215. https://doi.org/10.1002/ajh.10140

    Article  CAS  PubMed  Google Scholar 

  69. Curro G, Meo A, Ippolito D et al (2007) Asymptomatic cholelithiasis in children with sickle cell disease. Ann Surg 245:126–129. https://doi.org/10.1097/01.sla.0000242716.66878.23

    Article  PubMed  PubMed Central  Google Scholar 

  70. Haider MZ, Ashebu S, Aduh P, Adekile AD (1998) Influence of a-thalassemia on cholelithiasis in SS patients with elevated Hb F. Acta Haematol 100:147–150. https://doi.org/10.1159/000040890

    Article  CAS  PubMed  Google Scholar 

  71. Parody R, Rabella N, Martino R, Otegui M, del Cuerpo M, Coll P, Sierra J (2007) UGT1A1 Polymorphism outweighs the modest effect of deletional (–3.7 Kb) a-thalassemia on cholelithogenesis in sickle cell anemia vicky. Am J Hematol 82:807–811. https://doi.org/10.1002/ajh20574

    Article  CAS  PubMed  Google Scholar 

  72. Higgs DR, Aldridge BE, Lamb J, Clegg JB, Weatherall DJ, Hayes RJ, Grandison Y, Lowrie Y, Mason KP, Serjeant BE, Serjeant GR (1982) The interaction of alpha-thalassemia and homozygous sickle-cell disease. N Engl J Med 306:1441–1446. https://doi.org/10.1056/NEJM198206173062402

    Article  CAS  PubMed  Google Scholar 

  73. Pandey S, Pandey S, Mishra RM, Sharma M, Saxena R (2011) Genotypic influence of α-deletions on the phenotype of Indian sickle cell anemia patients. Korean J Hematol 46:192–195. https://doi.org/10.5045/kjh.2011.46.3.192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Minniti CP, Eckman J, Sebastiani P, Steinberg MH, Ballas SK (2010) Leg ulcers in sickle cell disease. Am J Hematol 85:831–833. https://doi.org/10.1002/ajh.21838

    Article  PubMed  PubMed Central  Google Scholar 

  75. Camilo-Araujo RF, Amancio OMS, Figueiredo MS et al (2014) Molecular analysis and association with clinical and laboratory manifestations in children with sickle cell anemia. Rev Bras Hematol Hemoter 36:334–339. https://doi.org/10.1016/j.bjhh.2014.06.002

    Article  PubMed  PubMed Central  Google Scholar 

  76. Olatunya OS, Albuquerque DM, Adekile A, Costa FF (2019) Influence of alpha thalassemia on clinical and laboratory parameters among nigerian children with sickle cell anemia. J Clin Lab Anal 33:10–12. https://doi.org/10.1002/jcla.22656

    Article  CAS  Google Scholar 

  77. Rumaney MB, Ngo Bitoungui VJ, Vorster AA, Ramesar R, Kengne AP, Ngogang J, Wonkam A (2014) The co-inheritance of alpha-thalassemia and sickle cell anemia is associated with better hematological indices and lower consultations rate in Cameroonian patients and could improve their survival. PLoS One 9:1–10. https://doi.org/10.1371/journal.pone.0100516

    Article  CAS  Google Scholar 

  78. Hoppe CC (2014) Inflammatory mediators of endothelial injury in sickle cell disease. Hematol Oncol Clin North Am 28:265–286. https://doi.org/10.1016/j.hoc.2013.11.006

    Article  PubMed  Google Scholar 

  79. Wonkam A, Rumaney MB, Ngo Bitoungui VJ, Vorster AA, Ramesar R, Ngogang J (2014) Coinheritance of sickle cell anemia and α-thalassemia delays disease onset and could improve survival in cameroonian’s patients (Sub-Saharan Africa). Am J Hematol 89:664–665. https://doi.org/10.1002/ajh.23711

    Article  PubMed  Google Scholar 

  80. Fabry ME, Mears GJ, Patel P et al (1984) Dense cells in sickle cell anemia: the effect of gene interaction. Blood 64:1042–1046

    Article  CAS  Google Scholar 

  81. Platt OS, Brambilla D, Rosse WF et al (1994) Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med 330:1639–1644

    Article  CAS  Google Scholar 

  82. Miller S, Sleeper L, Charles P et al (2000) Prediction of adverse outcomes in children with sickle cell disease. N Engl J Med 342:1612–1613. https://doi.org/10.1056/NEJM200005253422114

    Article  Google Scholar 

  83. Powars DR, Chan LS, Hiti A, Ramicone E, Johnson C (2005) Outcome of sickle cell anemia: a 4-decade observational study of 1056 patients. Medicine (Baltimore) 84:363–376. https://doi.org/10.1097/01.md.0000189089.45003.52

    Article  Google Scholar 

  84. Hanchard N, Elzein A, Trafford C, Rockett K, Pinder M, Jallow M, Harding R, Kwiatkowski D, McKenzie C (2007) Classical sickle beta-globin haplotypes exhibit a high degree of long-range haplotype similarity in African and Afro-Caribbean populations. BMC Genet 8:1–11. https://doi.org/10.1186/1471-2156-8-52

    Article  CAS  Google Scholar 

  85. Alves AC, da Silva VAL, Dos Santos A, Serra MB, Marques FA, Cruz SMP, Barroso WA, de Oliveira RAG (2020) Sickle cell anemia in the state of Maranhão: a haplotype study. Ann Hematol 99:1225–1230. https://doi.org/10.1007/s00277-020-04048-9

    Article  CAS  PubMed  Google Scholar 

  86. Zago MA, Figueiredo MS, Ogo SH (1992) Bantu BS cluster haplotype predominates among Brazilian Blacks. Am J Phys Anthropol 298:295–298

    Article  Google Scholar 

  87. Figueiredo MS, Kerbauy J, Gonçalves MS, Arruda VR, Saad STO, Sonati MF, Stoming T, Costa FF (1996) Effect of α-thalassemia and β-globin gene cluster haplotypes on the hematological and clinical features of sickle-cell anemia in Brazil. Am J Hematol 53:72–76. https://doi.org/10.1002/(SICI)1096-8652(199610)53:2<72::AID-AJH3>3.0.CO;2-0

    Article  CAS  PubMed  Google Scholar 

  88. Cardoso GL, Guerreiro JF (2010) Molecular characterization of sickle cell anemia in the Northern Brazilian state of Pará. Am J Hum Biol 22:573–577. https://doi.org/10.1002/ajhb.21047

    Article  Google Scholar 

  89. Filho ILS, Ribeiro GS, Pimenta-Bueno LM, Serpa MJA (2010) The frequency of β-globin gene haplotypes, α-thalassemia and genetic polymorphisms of methylenetetrahydrofolate reductase, factor V leiden and prothrombin genes in children with sickle cell disease in Rio de Janeiro, Brazil. Rev Bras Hematol Hemoter 32:76–78

    Article  Google Scholar 

  90. da Silva MAL, Friedrisch JR, Bittar CM et al (2014) B-Globin gene cluster haplotypes and clinical severity in sickle cell anemia patients in Southern Brazil. Open J Blood Dis 04:16–23. https://doi.org/10.4236/ojbd.2014.42003

    Article  CAS  Google Scholar 

  91. Leal Alexandra S, Martins Paulo Roberto, J., Balarin, Marly Aparecida S., Pereira, Gilberto A., & Resende, Gláucia Aparecida D. (2016) Haplotypes βs-globin and its clinical-haematological correlation in patients with sickle-cell anemia in Triângulo Mineiro, Minas Gerais, Brazil. J Bras Patol Med Lab 52(1):6–10. https://doi.org/10.5935/1676-2444.20160001

    Article  CAS  Google Scholar 

  92. Powars D, Hiti A (1993) Sickle cell anemia. BS gene cluster haplotypes as genetic markers for severe disease expression. Am J Dis Child 147:1197–1202. https://doi.org/10.1001/archpedi.1993.02160350071011

    Article  CAS  PubMed  Google Scholar 

  93. Rieder RF, Safaya S, Gillette P, Fryd S, Hsu H, Adams JG, Steinberg MH (1991) Effect of beta-globin gene cluster haplotype on the hematological and clinical features of sickle cell anemia. Am J Hematol 36:184–189

    Article  CAS  Google Scholar 

  94. Ngo D, Bae H, Steinberg MH, Sebastiani P, Solovieff N, Baldwin CT, Melista E, Safaya S, Farrer LA, al-Suliman AM, Albuali WH, al Bagshi MH, Naserullah Z, Akinsheye I, Gallagher P, Luo HY, Chui DHK, Farrell JJ, al-Ali AK, Alsultan A (2013) Fetal hemoglobin in sickle cell anemia: genetic studies of the Arab-Indian haplotype. Blood Cells Mol Dis 51:22–26. https://doi.org/10.1016/j.bcmd.2012.12.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Lettre G, Sankaran VG, Bezerra MAC, Araujo AS, Uda M, Sanna S, Cao A, Schlessinger D, Costa FF, Hirschhorn JN, Orkin SH (2008) DNA polymorphisms at the BCL11A, HBS1L-MYB, and -globin loci associate with fetal hemoglobin levels and pain crises in sickle cell disease. Proc Natl Acad Sci 105:11869–11874. https://doi.org/10.1073/pnas.0804799105

    Article  PubMed  Google Scholar 

  96. Bezerra MAC, Santos MNN, Araújo AS, Gomes YM, Abath FGC, Bandeira FMGC (2007) Molecular variations linked to the grouping of beta- and alpha-globin genes in neonatal patients with sickle cell disease in the State of Pernambuco, Brazil. Hemoglobin 31:83–88. https://doi.org/10.1080/03630260601057153

    Article  CAS  PubMed  Google Scholar 

  97. Gonçalves MS (2003) ß S -Haplotypes in sickle cell anemia patients from Salvador, Bahia , Northeastern Brazil. Braz J Med Biol Res 36:1283–1288

    Article  Google Scholar 

  98. Adorno EV, Zanette A, Lyra I, Souza CC, Santos LF, Menezes JF, Dupuit MF, Almeida MNT, Reis MG, Gonçalves MS (2004) The beta-globin gene cluster haplotypes in sickle cell anemia patients from Northeast Brazil: a clinical and molecular view. Hemoglobin 28:267–271. https://doi.org/10.1081/HEM-120040310

    Article  CAS  PubMed  Google Scholar 

  99. Rodrigues DOW, Ribeiro LC, Sudário LC, Teixeira MTB, Martins ML, Pittella AMOL, Junior IOF (2016) Genetic determinants and stroke in children with sickle cell disease. J Pediatr 92:1–7. https://doi.org/10.1016/j.jped.2016.01.010

    Article  Google Scholar 

  100. Bitoungui VJN, Pule GD, Hanchard N, Ngogang J, Wonkam A (2015) Beta-Globin gene haplotypes among Cameroonians and review of the global distribution: is there a case for a single sickle mutation origin in Africa? Omics 19:171–179. https://doi.org/10.1089/omi.2014.0134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Bernaudin F, Arnaud C, Kamdem A, Hau I, Lelong F, Epaud R, Pondarré C, Pissard S (2018) Biological impact of α genes, β haplotypes, and G6PD activity in sickle cell anemia at baseline and with hydroxyurea. Blood Adv 2:626–637. https://doi.org/10.1182/bloodadvances.2017014555

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors would like to thank the sickle cell anemia patients and their families who made this research possible.

Funding

This work was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Grant #483714/2013-5).

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Health Sciences Centre, Federal University of Pernambuco, Av. Prof. Arthur de Sá, s/n, Cidade Universitária, Recife, PE, 50740-521, Brazil

    Betânia Lucena Domingues Hatzlhofer

  2. Genetics Postgraduate Program, Centre of Biosciences, Federal University of Pernambuco, Recife, Brazil

    Betânia Lucena Domingues Hatzlhofer, Diego Antonio Pereira-Martins, Igor de Farias Domingos, Gabriela da Silva Arcanjo, Diego Arruda Falcão, Jéssica Vitória Gadelha de Freitas Batista, Luana Priscilla Laranjeira Prado, Jéssica Maria Florencio Oliveira, Thais Helena Chaves Batista, Marcondes José de Vasconcelos Costa Sobreira, Rodrigo Marcionilo de Santana, Amanda Bezerra de Sá Araújo, Manuela Albuquerque de Melo, Bruna Vasconcelos de Ancântara, Juan Luiz Coelho-Silva, Ana Beatriz Lucas de Moura Rafael, Danízia Menezes de Lima Silva, Flávia Peixoto Albuquerque, Antonio Roberto Lucena-Araújo & Marcos André Cavalcanti Bezerra

  3. Department of Internal Medicine, Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil

    Diego Antonio Pereira-Martins & Isabel Weinhäuser

  4. Department of Clinical and Toxicological Analysis, Federal University of Rio Grande do Norte, Natal, Brazil

    Igor de Farias Domingos

  5. Biological Science Institute and College of Medical Sciences, University of Pernambuco, Recife, Brazil

    Isabela Cristina Cordeiro Farias

  6. Department of Medical Images, Hematology and, Clinical Oncology of The University of São Paulo, Ribeirão Preto Medical School, Ribeirão Preto, Brazil

    Juan Luiz Coelho-Silva

  7. Hematology and Hemotherapy Centre, State University of Campinas, Campinas, São Paulo, Brazil

    Flávia Peixoto Albuquerque & Fernando Ferreira Costa

  8. Department of Clinical Pathology, School of Medical Sciences, State University of Campinas, Campinas, São Paulo, Brazil

    Magnun Nueldo Nunes Santos

  9. Department of Internal Medicine, Hematology and Hemotherapy Foundation of Pernambuco, Recife, Brazil

    Ana Cláudia dos Anjos & Aderson da Silva Araújo

Authors
  1. Betânia Lucena Domingues Hatzlhofer
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  2. Diego Antonio Pereira-Martins
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Contributions

BLDH performed experiments, analyzed and interpreted data, and drafted the manuscript; DAP-M. and IFD performed experiments, analyzed and interpreted data, performed statistical analyses, and reviewed the manuscript; MNNS performed experiments, analyzed and interpreted data, and reviewed the manuscript; DAF, LPLP, ASA, MAM, BVA, ABLMR, DMLS, FPA, performed experiments, recruited patients, and updated the clinical data; ICCF, JMFO, GSA, THCB, MJS, and RMS recruited patients, updated the clinical data, and reviewed the manuscript; JVGFB updated the clinical data, analyzed and interpreted data, performed statistical analyses, and reviewed the manuscript; ARL-A and JLCS analyzed and interpreted data, performed statistical analyses, and reviewed the manuscript; IW drafted and reviewed the manuscript. ACA, FFC, ASA, and MACB conceived and designed the study and reviewed the manuscript; MACB gave the final approval of the version to be submitted.

Corresponding author

Correspondence to Betânia Lucena Domingues Hatzlhofer.

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Informed consent was obtained from all patients for being included in the study.

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The authors declare no competing interests.

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Hatzlhofer, B.L.D., Pereira-Martins, D.A., de Farias Domingos, I. et al. Alpha thalassemia, but not βS-globin haplotypes, influence sickle cell anemia clinical outcome in a large, single-center Brazilian cohort. Ann Hematol 100, 921–931 (2021). https://doi.org/10.1007/s00277-021-04450-x

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