Genomic approaches to identifying targets for treating β hemoglobinopathies

BMC Medical Genomics

Volumn 8, Issue 1, 2015, Pages

  Ngo, Duyen A ^a   Steinberg, Martin H ^a  

^a BOSTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIBODY; COPOLYMER; HEMOGLOBIN F; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; JANUS KINASE 2 INHIBITOR; P SELECTIN ANTIBODY; PADGEM PROTEIN; SELECTIN ANTAGONIST; UNCLASSIFIED DRUG;

BETA HEMOGLOBINOPATHY; CANDIDATE GENE ASSOCIATION STUDY; DRUG EFFICACY; GENE; GENETIC ANALYSIS; GENETIC ASSOCIATION; GENETIC HETEROGENEITY; GENETIC VARIABILITY; GENOME ANALYSIS; GENOMICS; HBB GENE; HBG1 GENE; HBG2 GENE; HEMOGLOBIN SD DISEASE; HEMOGLOBINOPATHY; HUMAN; NEXT GENERATION SEQUENCING; NONHUMAN; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; QUANTITATIVE TRAIT LOCUS; REVIEW; SINGLE NUCLEOTIDE POLYMORPHISM; THALASSEMIA; BETA-THALASSEMIA; BIOSYNTHESIS; GENE EXPRESSION REGULATION; GENETICS; METABOLISM; PATHOLOGY;

BETA-THALASSEMIA; FETAL HEMOGLOBIN; GENE EXPRESSION REGULATION; GENOMICS; HUMANS; QUANTITATIVE TRAIT LOCI;

EID: 84938073672     PISSN: None     EISSN: 17558794     Source Type: Journal    
DOI: 10.1186/s12920-015-0120-2     Document Type: Review

References (148)

1. Giardine B, Borg J, Viennas E, Pavlidis C, Moradkhani K, Joly P, et al. Updates of the HbVar database of human hemoglobin variants and thalassemia mutations. Nucl Acids Res. 2014;42:D1063-1069.
2. Piel FB, Weatherall DJ. The alpha-thalassemias. N Engl J Med. 2014;371:1908-16.
3. Piel FB, Hay SI, Gupta S, Weatherall DJ, Williams TN. Global burden of sickle cell anaemia in children under five, 2010-2050: modelling based on demographics, excess mortality, and interventions. PLoS Med. 2013;10:e1001484.
4. Colah R, Gorakshakar A, Nadkarni A. Global burden, distribution and prevention of beta-thalassemias and hemoglobin E disorders. Expert Rev Hematol. 2010;3:103-17.
5. Organization WH. Management of Haemoglobin Disorders, Report of Joint WHO/TIF Meeting. Nicosia: Cyprus; 2007.
6. Yuan J, Bunyaratvej A, Fucharoen S, Fung C, Shinar E, Schrier SL. The instability of the membrane skeleton in thalassemic red blood cells. Blood. 1995;86:3945-50.
7. Steinberg MH, Embury SH. Alpha-thalassemia in blacks: genetic and clinical aspects and interactions with the sickle hemoglobin gene. Blood. 1986;68:985-90.
8. Steinberg MH, Sebastiani P. Genetic modifiers of sickle cell disease. Am J Hematol. 2012;87:824-6.
9. Taylor JG, Nolan VG, Mendelsohn L, Kato GJ, Gladwin MT, Steinberg MH. Chronic hyper-hemolysis in sickle cell anemia: association of vascular complications and mortality with less frequent vasoocclusive pain. PLoS One. 2008;3:e2095.
10. Kato GJ, Gladwin MT, Steinberg MH. Deconstructing sickle cell disease: reappraisal of the role of hemolysis in the development of clinical subphenotypes. Blood Rev. 2007;21:37-47.
11. Gallagher PG. Disorders of red cell volume regulation. Curr Opin Hematol. 2013;20:201-7.
12. Ataga KI, Reid M, Ballas SK, Yasin Z, Bigelow C, James LS, et al. Improvements in haemolysis and indicators of erythrocyte survival do not correlate with acute vaso-occlusive crises in patients with sickle cell disease: a phase III randomized, placebo-controlled, double-blind study of the Gardos channel blocker senicapoc (ICA-17043). Br J Haematol. 2011;153:92-104.
13. Cardon LR, Bell JI. Association study designs for complex diseases. Nat Rev Genet. 2001;2:91-9.
14. Lettre G. The search for genetic modifiers of disease severity in the beta-hemoglobinopathies. Cold Spring Harb Perspect Med. 2012; 2(10). doi10.1101/cshperspect.a015032.
15. Akhurst RJ, Hata A. Targeting the TGFbeta signalling pathway in disease. Nat Rev Drug Discov. 2012;11:790-811.
16. Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature. 2003;425:577-84.
17. Bertolino P, Deckers M, Lebrin F, ten Dijke P. Transforming growth factor-beta signal transduction in angiogenesis and vascular disorders. Chest. 2005;128:585S-90S.
18. Pober JS, Cotran RS. The role of endothelial cells in inflammation. Transplantation. 1990;50:537-44.
19. Solovey A, Lin Y, Browne P, Choong S, Wayner E, Hebbel RP. Circulating activated endothelial cells in sickle cell anemia. N Engl J Med. 1997;337:1584-90.
20. Suragani RN, Cawley SM, Li R, Wallner S, Alexander MJ, Mulivor AW, et al. Modified activin receptor IIB ligand trap mitigates ineffective erythropoiesis and disease complications in murine beta-thalassemia. Blood. 2014;123:3864-72.
21. Steinberg MH, Nagel RL. Genetic modulation of sickle cell disease and thalassemia. In: Steinberg MH, Forget BG, Higgs DR, Weatherall D, editors. Disorders of Hemoglobin: Genetics, Pathophysiology, and Clinical Management. 2nd ed. New York, NY: Cambridge University Press; 2009. p. 638-57.
22. Passon RG, Howard TA, Zimmerman SA, Schultz WH, Ware RE. Influence of bilirubin uridine diphosphate-glucuronosyltransferase 1A promoter polymorphisms on serum bilirubin levels and cholelithiasis in children with sickle cell anemia. J Pediatr Hematol Oncol. 2001;23:448-51.
23. Fertrin KY, Melo MB, Assis AM, Saad ST, Costa FF. UDP-glucuronosyltransferase 1 gene promoter polymorphism is associated with increased serum bilirubin levels and cholecystectomy in patients with sickle cell anemia. Clin Genet. 2003;64:160-2.
24. Milton JN, Sebastiani P, Solovieff N, Hartley SW, Bhatnagar P, Arking DE, et al. A genome-wide association study of total bilirubin and cholelithiasis risk in sickle cell anemia. PLoS One. 2012;7:e34741.
25. Milton JN, Rooks H, Drasar E, McCabe EL, Baldwin CT, Melista E, et al. Genetic determinants of haemolysis in sickle cell anaemia. Br J Haematol. 2013;161:270-8.
26. Griffin PJ, Sebastiani P, Edward H, Baldwin CT, Gladwin MT, Gordeuk VR, et al. The genetics of hemoglobin A2 regulation in sickle cell anemia. Am J Hematol. 2014;89:1019-23.
27. Desai AA, Zhou T, Ahmad H, Zhang W, Mu W, Trevino S, et al. A novel molecular signature for elevated tricuspid regurgitation velocity in sickle cell disease. Am J Respir Crit Care Med. 2012;186:359-68.
28. Flanagan JM, Sheehan V, Linder H, Howard TA, Wang YD, Hoppe CC, et al. Genetic mapping and exome sequencing identify 2 mutations associated with stroke protection in pediatric patients with sickle cell anemia. Blood. 2013;121:3237-45.
29. Bhatnagar P, Barron-Casella E, Bean CJ, Milton JN, Baldwin CT, Steinberg MH, et al. Genome-wide meta-analysis of systolic blood pressure in children with sickle cell disease. PLoS One. 2013;8:e74193.
30. Menzel S, Garner C, Rooks H, Spector TD, Thein SL. HbA2 levels in normal adults are influenced by two distinct genetic mechanisms. Br J Haematol. 2013;160:101-5.
31. Bhattacharyya T, Nicholls SJ, Topol EJ, Zhang R, Yang X, Schmitt D, et al. Relationship of paraoxonase 1 (PON1) gene polymorphisms and functional activity with systemic oxidative stress and cardiovascular risk. JAMA. 2008;299:1265-76.
32. Luu HN, Kingah PL, North K, Boerwinkle E, Volcik KA. Interaction of folate intake and the paraoxonase Q192R polymorphism with risk of incident coronary heart disease and ischemic stroke: the atherosclerosis risk in communities study. Ann Epidemiol. 2011;21:815-23.
33. Raghavachari N, Barb J, Yang Y, Liu P, Woodhouse K, Levy D, et al. A systematic comparison and evaluation of high density exon arrays and RNA-seq technology used to unravel the peripheral blood transcriptome of sickle cell disease. BMC Med Genomics. 2012;5:28.
34. Menzel S, Garner C, Gut I, Matsuda F, Yamaguchi M, Heath S, et al. A QTL influencing F cell production maps to a gene encoding a zinc-finger protein on chromosome 2p15. Nat Genet. 2007;39:1197-9.
35. Watson J. The significance of the paucity of sickle cells in newborn Negro infants. Am J Med Sci. 1948;215:419-23.
36. Ngo D, Bae H, Steinberg MH, Sebastiani P, Solovieff N, Baldwin CT, et al. Fetal hemoglobin in sickle cell anemia: genetic studies of the Arab-Indian haplotype. Blood Cells, Mol & Dis. 2013;51:22-6.
37. Forget BG. Molecular basis of hereditary persistence of fetal hemoglobin. Ann N Y Acad Sci. 1998;850:38-44.
38. Ngo DA, Aygun B, Akinsheye I, Hankins JS, Bhan I, Luo HY, et al. Fetal haemoglobin levels and haematological characteristics of compound heterozygotes for haemoglobin S and deletional hereditary persistence of fetal haemoglobin. Br J Haematol. 2012;156:259-64.
39. Weatherall DJ, Clegg JB. The Thalassaemia Syndromes. Oxford: Blackwell Science; 2001.
40. Thein SL, Menzel S, Lathrop M, Garner C. Control of fetal hemoglobin: new insights emerging from genomics and clinical implications. Hum Mol Genet. 2009;18:R216-23.
41. Platt OS, Thorington BD, Brambilla DJ, Milner PF, Rosse WF, Vichinsky E, et al. Pain in sickle cell disease. Rates and risk factors. N Engl J Med. 1991;325:11-6.
42. Platt OS. Easing the suffering caused by sickle cell disease. N Engl J Med. 1994;330:783-4.
43. Steinberg MH, Barton F, Castro O, Pegelow CH, Ballas SK, Kutlar A, et al. Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment. JAMA. 2003;289:1645-51.
44. Steinberg MH, Chui DH, Dover GJ, Sebastiani P, Alsultan A. Fetal hemoglobin in sickle cell anemia: a glass half full? Blood. 2014;123:481-5.
45. Wilber A, Nienhuis AW, Persons DA. Transcriptional regulation of fetal to adult hemoglobin switching: new therapeutic opportunities. Blood. 2011;117:3945-53.
46. Sankaran VG, Xu J, Orkin SH. Advances in the understanding of haemoglobin switching. Br J Haematol. 2010;149:181-94.
47. Xu J, Peng C, Sankaran VG, Shao Z, Esrick EB, Chong BG, et al. Correction of sickle cell disease in adult mice by interference with fetal hemoglobin silencing. Science. 2011;334:993-6.
48. Bauer DE, Orkin SH. Update on fetal hemoglobin gene regulation in hemoglobinopathies. Curr Opin Pediatr. 2011;23:1-8.
49. Stamatoyannopoulos G. Control of globin gene expression during development and erythroid differentiation. Exp Hematol. 2005;33:259-71.
50. Bauer DE, Kamran SC, Orkin SH. Reawakening fetal hemoglobin: prospects for new therapies for the beta-globin disorders. Blood. 2012;120:2945-53.
51. Sankaran VG, Orkin SH. The switch from fetal to adult hemoglobin. Cold Spring Harb Perspect Med. 2013;3:a011643.
52. Stamatoyannopoulos G, Veith R, Galanello R, Papayannopoulou T. Hb F production in stressed erythropoiesis: observations and kinetic models. Ann NY Acad Sci. 1985;445:188-97.
53. Xiang J, Wu DC, Chen Y, Paulson RF. In vitro culture of stress erythroid progenitors identifies distinct progenitor populations and analogous human progenitors. Blood. 2015;125:1803-12.
54. Sankaran VG, Xu J, Byron R, Greisman HA, Fisher C, Weatherall DJ, et al. A functional element necessary for fetal hemoglobin silencing. N Engl J Med. 2011;365:807-14.
55. Kulozik AE, Yarwood N, Jones RW. The Corfu delta beta zero thalassemia: a small deletion acts at a distance to selectively abolish beta globin gene expression. Blood. 1988;71:457-62.
56. Prakobkaew N, Fucharoen S, Fuchareon G, Siriratmanawong N. Phenotypic expression of Hb F in common high Hb F determinants in Thailand: roles of alpha-thalassemia, 5' delta-globin BCL11A binding region and 3' beta-globin enhancer. Eur J Haematol. 2014;92:73-9.
57. Orkin SH, Antonarakis SE, Kazazian Jr HH. Polymorphism and molecular pathology of the human beta-globin gene. Prog Hematol. 1983;13:49-73.
58. Antonarakis SE, Kazazian Jr HH, Orkin SH. DNA polymorphism and molecular pathology of the human globin gene clusters. Hum Genet. 1985;69:1-14.
59. Pagnier J, Mears JG, Dunda-Belkhodja O, Schaefer-Rego KE, Beldjord C, Nagel RL, et al. Evidence for the multicentric origin of the sickle cell hemoglobin gene in Africa. Proc Natl Acad Sci USA. 1984;81:1771-3.
60. Labie D, Dunda-Belkhodja O, Rouabhi F, Pagnier J, Ragusa A, Nagel RL. The -158 site 5' to the G gamma gene and G gamma expression. Blood. 1985;66:1463-5.
61. Labie D, Pagnier J, Lapoumeroulie C, Rouabhi F, Dunda-Belkhodja O, Chardin P, et al. Common haplotype dependency of high G gamma-globin gene expression and high Hb F levels in beta-thalassemia and sickle cell anemia patients. Proc Natl Acad Sci USA. 1985;82:2111-4.
62. Miller BA, Olivieri N, Salameh M, Ahmed M, Antognetti G, Huisman TH, et al. Molecular analysis of the high-hemoglobin-F phenotype in Saudi Arabian sickle cell anemia. N Engl J Med. 1987;316:244-50.
63. Thein SL, Menzel S, Peng X, Best S, Jiang J, Close J, et al. 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 USA. 2007;104:11346-51.
64. Lettre G, Sankaran VG, Bezerra MA, Araujo AS, Uda M, Sanna S, et al. DNA polymorphisms at the BCL11A, HBS1L-MYB, and beta-globin loci associate with fetal hemoglobin levels and pain crises in sickle cell disease. Proc Natl Acad Sci USA. 2008;105:11869-74.
65. Galarneau G, Palmer CD, Sankaran VG, Orkin SH, Hirschhorn JN, Lettre G. Fine-mapping at three loci known to affect fetal hemoglobin levels explains additional genetic variation. Nat Genet. 2010;42:1049-51.
66. Perrine RP, Brown MJ, Clegg JB, Weatherall DJ, May A. Benign sickle-cell anaemia. Lancet. 1972;2:1163-7.
67. Pembrey ME, Wood WG, Weatherall DJ, Perrine RP. Fetal haemoglobin production and the sickle gene in the oases of Eastern Saudi Arabia. Br J Haematol. 1978;40:415-29.
68. Alsultan A, Alabdulaali MK, Griffin PJ, Alsuliman AM, Ghabbour HA, Sebastiani P, et al. Sickle cell disease in Saudi Arabia: the phenotype in adults with the Arab-Indian haplotype is not benign. Br J Haematol. 2014;164:597-604.
69. Alsultan A, Ngo D, Bae H, Sebastiani P, Baldwin CT, Melista E, et al. Genetic studies of fetal hemoglobin in the Arab-Indian haplotype sickle cell-beta(0) thalassemia. Am J Hematol. 2013;88:531-2.
70. Miller BA, Salameh M, Ahmed M, Wainscoat J, Antognetti G, Orkin S, et al. High fetal hemoglobin production in sickle cell anemia in the eastern province of Saudi Arabia is genetically determined. Blood. 1986;67:1404-10.
71. Mabaera R, West RJ, Conine SJ, Macari ER, Boyd CD, Engman CA, et al. A cell stress signaling model of fetal hemoglobin induction: what doesn't kill red blood cells may make them stronger. Exp Hematol. 2008;36:1057-72.
72. Alsultan A, Solovieff N, Aleem A, AlGahtani FH, Al-Shehri A, Osman ME, et al. Fetal hemoglobin in sickle cell anemia: Saudi patients from the Southwestern province have similar HBB haplotypes but higher HbF levels than African Americans. Am J Hematol. 2011;86:612-4.
73. Akinsheye I, Alsultan A, Solovieff N, Ngo D, Baldwin CT, Sebastiani P, et al. Fetal hemoglobin in sickle cell anemia. Blood. 2011;118:19-27.
74. Garner C, Tatu T, Reittie JE, Littlewood T, Darley J, Cervino S, et al. Genetic influences on F cells and other hematologic variables: a twin heritability study. Blood. 2000;95:342-6.
75. Gibney GT, Panhuysen CI, So JC, Ma ES, Ha SY, Li CK, et al. Variation and heritability of Hb F and F-cells among beta-thalassemia heterozygotes in Hong Kong. Am J Hematol. 2008;83:458-64.
76. Nuinoon M, Makarasara W, Mushiroda T, Setianingsih I, Wahidiyat PA, Sripichai O, et al. A genome-wide association identified the common genetic variants influence disease severity in beta0-thalassemia/hemoglobin E. Hum Genet. 2010;127:303-14.
77. Uda M, Galanello R, Sanna S, Lettre G, Sankaran VG, Chen W, et al. Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of beta-thalassemia. Proc Natl Acad Sci USA. 2008;105:1620-5.
78. Sedgewick A, Timofeev N, Sebastiani P, So JCC, Ma ESK, Chan LC, et al. BCL11A (2p16) is a major HbF quantitative trait locus in three different populations. Blood Cells Mol & Dis. 2008;41:255-8.
79. Solovieff N, Milton JN, Hartley SW, Sherva R, Sebastiani P, Dworkis DA, et al. Fetal hemoglobin in sickle cell anemia: genome-wide association studies suggest a regulatory region in the 5' olfactory receptor gene cluster. Blood. 2010;115:1815-22.
80. Farrell JJ, Sherva RM, Chen ZY, Luo HY, Chu BF, Ha SY, et al. A 3-bp deletion in the HBS1L-MYB intergenic region on chromosome 6q23 is associated with HbF expression. Blood. 2011;117:4935-45.
81. Galanello R, Sanna S, Perseu L, Sollaino MC, Satta S, Lai ME, et al. Amelioration of Sardinian beta0 thalassemia by genetic modifiers. Blood. 2009;114:3935-7.
82. Sankaran VG, Menne TF, Xu J, Akie TE, Lettre G, Van Handel B, et al. Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A. Science. 2008;322:1839-42.
83. Xu J, Sankaran VG, Ni M, Menne TF, Puram RV, Kim W, et al. Transcriptional silencing of {gamma}-globin by BCL11A involves long-range interactions and cooperation with SOX6. Genes Dev. 2010;24:783-98.
84. Bauer DE, Kamran SC, Lessard S, Xu J, Fujiwara Y, Lin C, et al. An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level. Science. 2013;342:253-7.
85. Sebastiani P, Farrell JJ, Alsultan A, Wang S, Edward HL, Shapell H, Bae H, Milton JN, Baldwin CT, Al-Rubaish AM, et al. BCL11A enhancer haplotypes and fetal hemoglobin in sickle cell anemia Blood Cells Mol Dis 2015;54:224-230.
86. Stadhouders R, Aktuna S, Thongjuea S, Aghajanirefah A, Pourfarzad F, van Ijcken W, et al. HBS1L-MYB intergenic variants modulate fetal hemoglobin via long-range MYB enhancers. J Clin Iinvest. 2014;124:1699-710.
87. Vegiopoulos A, Garcia P, Emambokus N, Frampton J. Coordination of erythropoiesis by the transcription factor c-Myb. Blood. 2006;107:4703-10.
88. Bianchi E, Zini R, Salati S, Tenedini E, Norfo R, Tagliafico E, et al. c-myb supports erythropoiesis through the transactivation of KLF1 and LMO2 expression. Blood. 2010;116:e99-110.
89. Tallack MR, Perkins AC. Three fingers on the switch: Kruppel-like factor 1 regulation of gamma-globin to beta-globin gene switching. Curr Opin Hematol. 2013;20:193-200.
90. Borg J, Papadopoulos P, Georgitsi M, Gutierrez L, Grech G, Fanis P, et al. Haploinsufficiency for the erythroid transcription factor KLF1 causes hereditary persistence of fetal hemoglobin. Nat Genet. 2010;42:801-5.
91. Borg J, Patrinos GP, Felice AE, Philipsen S. Erythroid phenotypes associated with KLF1 mutations. Haematologica. 2011;96:635-8.
92. Arnaud L, Saison C, Helias V, Lucien N, Steschenko D, Giarratana MC, et al. A dominant mutation in the gene encoding the erythroid transcription factor KLF1 causes a congenital dyserythropoietic anemia. Am J Hum Genet. 2010;87:721-7.
93. Jaffray JA, Mitchell WB, Gnanapragasam MN, Seshan SV, Guo X, Westhoff CM, et al. Erythroid transcription factor EKLF/KLF1 mutation causing congenital dyserythropoietic anemia type IV in a patient of Taiwanese origin: review of all reported cases and development of a clinical diagnostic paradigm. Blood Cells, Mol Dis. 2013;51:71-5.
94. Viprakasit V, Ekwattanakit S, Riolueang S, Chalaow N, Fisher C, Lower K, et al. Mutations in Kruppel-like factor 1 cause transfusion-dependent hemolytic anemia and persistence of embryonic globin gene expression. Blood. 2014;123:1586-95.
95. Liu D, Zhang X, Yu L, Cai R, Ma X, Zheng C, et al. KLF1 mutations are relatively more common in a thalassemia endemic region and ameliorate the severity of beta-thalassemia. Blood. 2014;124:803-11.
96. Esteghamat F, Gillemans N, Bilic I, van den Akker E, Cantu I, van Gent T, et al. Erythropoiesis and globin switching in compound Klf1::Bcl11a mutant mice. Blood. 2013;121:2553-62.
97. Zhou D, Liu K, Sun CW, Pawlik KM, Townes TM. KLF1 regulates BCL11A expression and gamma- to beta-globin gene switching. Nat Genet. 2010;42:742-4.
98. Siatecka M, Bieker JJ. The multifunctional role of EKLF/KLF1 during erythropoiesis. Blood. 2011;118:2044-54.
99. Yien YY, Bieker JJ. EKLF/KLF1, a tissue-restricted integrator of transcriptional control, chromatin remodeling, and lineage determination. Mol Cell Biol. 2013;33:4-13.
100. Sebastiani P, Ramoni MF, Nolan V, Baldwin CT, Steinberg MH. Genetic dissection and prognostic modeling of overt stroke in sickle cell anemia. Nat Genet. 2005;37:435-40.
101. Danjou F, Francavilla M, Anni F, Satta S, Demartis FR, Perseu L, et al. A genetic score for the prediction of beta-thalassemia severity. Haematologica. 2014;100:452-7.
102. Milton JN, Gordeuk VR, Taylor JG, Gladwin MT, Steinberg MH, Sebastiani P. Prediction of fetal hemoglobin in sickle cell anemia using an ensemble of genetic risk prediction models. Circulation Cardiovascular Genet. 2014;7:110-5.
103. Ma Q, Abel K, Sripichai O, Whitacre J, Angkachatchai V, Makarasara W, et al. Beta-globin gene cluster polymorphisms are strongly associated with severity of HbE/beta(0)-thalassemia. Clin Genet. 2007;72:497-505.
104. Love PE, Warzecha C, Li L. Ldb1 complexes: the new master regulators of erythroid gene transcription. Trends in Genet: TIG. 2014;30:1-9.
105. Deng W, Lee J, Wang H, Miller J, Reik A, Gregory PD, et al. Controlling long-range genomic interactions at a native locus by targeted tethering of a looping factor. Cell. 2012;149:1233-44.
106. Deng W, Rupon JW, Krivega I, Breda L, Motta I, Jahn KS, et al. Reactivation of developmentally silenced globin genes by forced chromatin looping. Cell. 2014;158:849-60.
107. Kutlar A, Ataga KI, McMahon L, Howard J, Galacteros F, Hagar W, et al. A potent oral P-selectin blocking agent improves microcirculatory blood flow and a marker of endothelial cell injury in patients with sickle cell disease. Am J Hematol. 2012;87:536-9.
108. Adams-Graves P, Kedar A, Koshy M, Steinberg M, Veith R, Ward D, et al. RheothRx (poloxamer 188) injection for the acute painful episode of sickle cell disease: A pilot study. Blood. 1997;90:2041-6.
109. Orringer EP, Casella JF, Ataga KI, Koshy M, Adams-Graves P, Luchtman-Jones L, et al. Purified poloxamer 188 for treatment of acute vaso-occlusive crisis of sickle cell disease: A randomized controlled trial. JAMA. 2001;286:2099-106.
110. Chang J, Patton JT, Sarkar A, Ernst B, Magnani JL, Frenette PS. GMI-1070, a novel pan-selectin antagonist, reverses acute vascular occlusions in sickle cell mice. Blood. 2010;116:1779-86.
111. Rivella S. β-thalassemias: paradigmatic diseases for scientific discoveries and development of innovative therapies. Haematologica. 2015;100:418-30.
112. Ramos E, Ruchala P, Goodnough JB, Kautz L, Preza GC, Nemeth E, et al. Minihepcidins prevent iron overload in a hepcidin-deficient mouse model of severe hemochromatosis. Blood. 2012;120:3829-36.
113. Nai A, Pagani A, Mandelli G, Lidonnici MR, Silvestri L, Ferrari G, et al. Deletion of TMPRSS6 attenuates the phenotype in a mouse model of beta-thalassemia. Blood. 2012;119:5021-9.
114. Li H, Rybicki AC, Suzuka SM, von Bonsdorff L, Breuer W, Hall CB, et al. Transferrin therapy ameliorates disease in beta-thalassemic mice. Nat Med. 2010;16:177-82.
115. Flanagan JM, Frohlich DM, Howard TA, Schultz WH, Driscoll C, Nagasubramanian R, et al. Genetic predictors for stroke in children with sickle cell anemia. Blood. 2011;117:6681-4.
116. Taylor JG, Tang DC, Savage SA, Leitman SF, Heller SI, Serjeant GR, et al. Variants in the VCAM1 gene and risk for symptomatic stroke in sickle cell disease. Blood. 2002;100:4303-9.
117. Hoppe C, Klitz W, Cheng S, Apple R, Steiner L, Robles L, et al. Gene interactions and stroke risk in children with sickle cell anemia. Blood. 2004;103:2391-6.
118. Mendonca TF, Oliveira MC, Vasconcelos LR, Pereira LM, Moura P, Bezerra MA, et al. Association of variant alleles of MBL2 gene with vasoocclusive crisis in children with sickle cell anemia. Blood Cells Mol Dis. 2010;44:224-8.
119. Oliveira MC, Mendonca TF, Vasconcelos LR, Moura P, Bezerra MA, Santos MN, et al. Association of the MBL2 gene EXON1 polymorphism and vasoocclusive crisis in patients with sickle cell anemia. Acta Haematol. 2009;121:212-5.
120. Galarneau G, Coady S, Garrett ME, Jeffries N, Puggal M, Paltoo D, et al. Gene-centric association study of acute chest syndrome and painful crisis in sickle cell disease patients. Blood. 2013;122:434-42.
121. Martinez-Castaldi C, Nolan VG, Baldwin CT, Farrer LA, Steinberg MH, Klings ES. Association of genetic polymorphisms in the TGF-β pathway with the acute chest syndrome of sickle cell anemia. ASH Annual Meeting Abstracts. 2007;110:2247.
122. Bean CJ, Boulet SL, Ellingsen D, Pyle ME, Barron-Casella EA, Casella JF, et al. Heme oxygenase-1 gene promoter polymorphism is associated with reduced incidence of acute chest syndrome among children with sickle cell disease. Blood. 2012;120:3822-8.
123. Sharan K, Surrey S, Ballas S, Borowski M, Devoto M, Wang KF, et al. Association of T-786C eNOS gene polymorphism with increased susceptibility to acute chest syndrome in females with sickle cell disease. Br J Haematol. 2004;124:240-3.
124. de Oliveira Filho RA, Silva GJ, de Farias Domingos I, Hatzlhofer BL, da Silva Araujo A, de Lima Filho JL, et al. Association between the genetic polymorphisms of glutathione S-transferase (GSTM1 and GSTT1) and the clinical manifestations in sickle cell anemia. Blood Cells Mol Dis. 2013;51:76-9.
125. Neonato MG, Lu CY, Guilloud-Bataille M, Lapoumeroulie C, Nabeel-Jassim H, Dabit D, et al. Genetic polymorphism of the mannose-binding protein gene in children with sickle cell disease: identification of three new variant alleles and relationship to infections. Eur J Hum Genet. 1999;7:679-86.
126. Adewoye AH, Nolan VG, Ma Q, Baldwin C, Wyszynski DF, Farrell JJ, et al. Association of polymorphisms of IGF1R and genes in the transforming growth factor- beta /bone morphogenetic protein pathway with bacteremia in sickle cell anemia. Clin Infect Dis. 2006;43:593-8.
127. Dossou-Yovo OP, Zaccaria I, Benkerrou M, Hauchecorne M, Alberti C, Rahimy MC, et al. Effects of RANTES and MBL2 gene polymorphisms in sickle cell disease clinical outcomes: association of the g.In1.1T>C RANTES variant with protection against infections. Am J Hematol. 2009;84:378-80.
128. Tamouza R, Neonato MG, Busson M, Marzais F, Girot R, Labie D, et al. Infectious complications in sickle cell disease are influenced by HLA class II alleles. Hum Immunol. 2002;63:194-9.
129. Tamouza R, Busson M, Fortier C, Diagne I, Diallo D, Sloma I, et al. HLA-E∗0101 allele in homozygous state favors severe bacterial infections in sickle cell anemia. Hum Immunol. 2007;68:849-53.
130. Baldwin C, Nolan VG, Wyszynski DF, Ma QL, Sebastiani P, Embury SH, et al. Association of klotho, bone morphogenic protein 6, and annexin A2 polymorphisms with sickle cell osteonecrosis. Blood. 2005;106:372-5.
131. Ulug P, Vasavda N, Awogbade M, Cunningham J, Menzel S, Thein SL. Association of sickle avascular necrosis with bone morphogenic protein 6. Ann Hematol. 2009;88:803-5.
132. Nolan VG, Baldwin C, Ma Q, Wyszynski DF, Amirault Y, Farrell JJ, et al. Association of single nucleotide polymorphisms in klotho with priapism in sickle cell anaemia. Br J Haematol. 2005;128:266-72.
133. Elliott L, Ashley-Koch AE, De Castro L, Jonassaint J, Price J, Ataga KI, et al. Genetic polymorphisms associated with priapism in sickle cell disease. Br J Haematol. 2007;137:262-7.
134. Nolan VG, Adewoye A, Baldwin C, Wang L, Ma Q, Wyszynski DF, et al. Sickle cell leg ulcers: associations with haemolysis and SNPs in Klotho, TEK and genes of the TGF-beta/BMP pathway. Br J Haematol. 2006;133:570-8.
135. Ofosu MD, Castro O, Alarif L. Sickle cell leg ulcers are associated with HLA-B35 and Cw4. Arch Dermatol. 1987;123:482-4.
136. Ashley-Koch AE, Okocha EC, Garrett ME, Soldano K, De Castro LM, Jonassaint JC, et al. MYH9 and APOL1 are both associated with sickle cell disease nephropathy. Br J Haematol. 2011;155:386-94.
137. 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;82:179-84.
138. Carpenter SL, Lieff S, Howard TA, Eggleston B, Ware RE. UGT1A1 promoter polymorphisms and the development of hyperbilirubinemia and gallbladder disease in children with sickle cell anemia. Am J Hematol. 2008;83:800-3.
139. Ashley-Koch AE, Elliott L, Kail ME, De Castro LM, Jonassaint J, Jackson TL, et al. Identification of genetic polymorphisms associated with risk for pulmonary hypertension in sickle cell disease. Blood. 2008;111:5721-6.
140. Zhang X, Zhang W, Ma SF, Desai AA, Saraf S, Miasniakova G, et al. Hypoxic response contributes to altered gene expression and precapillary pulmonary hypertension in patients with sickle cell disease. Circulation. 2014;129:1650-8.
141. Wong TE, Brandow AM, Lim W, Lottenberg R. Update on the use of hydroxyurea therapy in sickle cell disease. Blood. 2014;124:3850-7.
142. Patthamalai P, Fuchareon S, Chaneiam N, Ghalie RG, Chui DH, Boosalis MS, et al. A phase 2 trial of HQK-1001 in HbE-beta thalassemia demonstrates HbF induction and reduced anemia. Blood. 2014;123:1956-7.
143. Lavelle D, Vaitkus K, Ling Y, Ruiz MA, Mahfouz R, Ng KP, et al. Effects of tetrahydrouridine on pharmacokinetics and pharmacodynamics of oral decitabine. Blood. 2012;119:1240-7.
144. Meiler SE, Wade M, Kutlar F, Yerigenahally SD, Xue Y, Moutouh-de Parseval LA, et al. Pomalidomide augments fetal hemoglobin production without the myelosuppressive effects of hydroxyurea in transgenic sickle cell mice. Blood. 2011;118:1109-12.
145. Johnson J, Hunter R, McElveen R, Qian XH, Baliga BS, Pace BS. Fetal hemoglobin induction by the histone deacetylase inhibitor, scriptaid. Cell Mol Biol. 2005;51:229-38.
146. Hebbel RP, Vercellotti GM, Pace BS, Solovey AN, Kollander R, Abanonu CF, et al. The HDAC inhibitors trichostatin A and suberoylanilide hydroxamic acid exhibit multiple modalities of benefit for the vascular pathobiology of sickle transgenic mice. Blood. 2010;115:2483-90.
147. Campbell AD, Cui S, Shi L, Urbonya R, Mathias A, Bradley K, et al. Forced TR2/TR4 expression in sickle cell disease mice confers enhanced fetal hemoglobin synthesis and alleviated disease phenotypes. Proc Natl Acad Sci US A. 2011;108:18808-13.
148. Suzuki M, Yamamoto M, Engel JD. Fetal globin gene repressors as drug targets for molecular therapies to treat the beta-globinopathies. Mol Cell Biol. 2014;34:3560-9.