An expert review of pharmacogenomics of sickle cell disease therapeutics: Not yet ready for global precision medicine

OMICS A Journal of Integrative Biology

Volumn 20, Issue 10, 2016, Pages 565-574

  Mnika, Khuthala ^a   Pule, Gift D ^a   Dandara, Collet ^a   Wonkam, Ambroise ^a,b  

^a UNIVERSITY OF CAPE TOWN   (South Africa)

^b UNIVERSITY OF CAPE TOWN   (South Africa)

Author keywords

[No Author keywords available]

Indexed keywords

HYDROXYUREA; MORPHINE; ANALGESIC AGENT; NARCOTIC ANALGESIC AGENT;

ANALGESIA; DISEASE PREDISPOSITION; DRUG METABOLISM; DRUG RESPONSE; GENETIC VARIATION; HUMAN; META ANALYSIS; PAIN; PERSONALIZED MEDICINE; PHARMACOGENOMICS; PRIORITY JOURNAL; REVIEW; SICKLE CELL ANEMIA; SYSTEMATIC REVIEW; ANEMIA, SICKLE CELL; GENETICS; PHARMACOGENETIC VARIANT; PHARMACOGENETICS;

ANALGESICS; ANALGESICS, OPIOID; ANEMIA, SICKLE CELL; HUMANS; HYDROXYUREA; PAIN; PAIN MANAGEMENT; PHARMACOGENETICS; PHARMACOGENOMIC VARIANTS; PRECISION MEDICINE;

EID: 84991475814     PISSN: 15362310     EISSN: 15578100     Source Type: Journal    
DOI: 10.1089/omi.2016.0105     Document Type: Review

References (127)

1. Adegbola MA. (2009). Can heterogeneity of chronic sickle-cell disease pain be explained by genomics? A literature review. Biol Res Nurs 11, 81-97.
2. Adekile AD. (2011). Limitations of Hb F as a phenotypic modifier in sickle cell disease: Study of Kuwaiti Arab patients. Hemoglobin 35, 607-617.
3. Alebouyeh M, Moussavi F, Haddad-Deylami H, and Vossough P. (2004).Hydroxyurea in the treatment ofmajorb-Thalassemia and importance of genetic screening. Ann Hematol 83, 430-433.
4. Al-Habboubi HH, Mahdi N, Abu-Hijleh TM, Abu-Hijleh FM, Sater MS, and Almawi WY. (2012). The relation of vascular endothelial growth factor (VEGF) gene polymorphisms on VEGF levels and the risk of vasoocclusive crisis in sickle cell disease. Eur J Haematol 89, 403-409.
5. Alvarez O, Miller ST, Wang WC, et al. (2012). Effect of hydroxyurea treatment on renal function parameters: Results from the multi-center placebo-controlled BABY HUG clinical trial for infants with sickle cell anemia. Pediatr Blood Cancer 59, 668-674.
6. Ballas SK. (2015). Sickle Cell Pain. Lippincott: Williams and Wilkins.
7. Ballas SK, and Lusardi M. (2005). Hospital readmission for adult acute sickle cell painful episodes: Frequency, etiology, and prognostic significance. Am J Hematol 79, 17-25.
8. Ballas SK, Gupta K, and Adams-Graves P. (2012). Sickle cell pain: A critical reappraisal. Blood 120, 3647-3656.
9. Bartolucci P, and Galacteros F. (2012). Clinical management of adult sickle-cell disease. Curr Opin Hematol 19, 149-155.
10. Bean CJ, Boulet SL, Yang G, et al. (2013). Acute chest syndrome is associated with single nucleotide polymorphismdefined beta globin cluster haplotype in children with sickle cell anaemia. Br J Haematol 163, 268-276.
11. Belfer I, Youngblood V, Darbari DS, et al. (2014). A GCH1 haplotype confers sex-specific susceptibility to pain crises and altered endothelial function in adults with sickle cell anemia. Am J Hematol 89, 187-193.
12. Bergman S. (2005). Psychosocial aspects of chronic widespread pain and fibromyalgia. Disabil Rehabil 27, 675-683.
13. Beyer A, Koch T, Schröder H, Schulz S, and Höllt V. (2004). Effect of the A118G polymorphism on binding affinity, potency and agonist-mediated endocytosis, desensitization, and resensitization of the human mu-opioid receptor. J Neurochem 89, 553-560.
14. Bockaert J, and Pin JP. (1999). Molecular tinkering of G protein-coupled receptors: An evolutionary success. EMBO J 18, 1723-1729.
15. Bohn LM, Lefkowitz RJ, Gainetdinov RR, Peppel K, Caron MG, and Lin FT. (1999). Enhanced morphine analgesia in mice lacking beta-Arrestin 2. Science 286, 2495-2498.
16. Bond C, Laforge KS, Tian M, et al. (1998). Single-nucleotide polymorphism in the human mu opioid receptor gene alters bendorphin binding and activity: Possible implications for opiate addiction. Proc Natl Acad Sci USA 95, 9608-9613.
17. Borg J, Phylactides M, Bartsakoulia M, et al. (2012). KLF10 gene expression is associated with high fetal hemoglobin levels and with response to hydroxyurea treatment in bhemoglobinnopathy patients. Pharmacogenomics 13, 1487-1500.
18. Bukar AA, Abjah UAM, Kagu MB, et al. (2013). Seroprevalence of parvovirus B19 and its clinical effect among anaemic SCA patients in Northeastern Nigeria. Am J Sci Ind Res 4, 195-200.
19. Brousseau DC, McCarver DG, Drendel AL, et al. (2007). The effect of CYP2D6 polymorphisms on the response to pain treatment for paediatric sickle cell pain crisis. J Pediatr 150, 623-626.
20. Canver MC, Smith EC, Sher F, et al. (2015). BCL11A enhancer dissection by Cas9-mediated in situ saturating mutagenesis. Nature 527, 192-197.
21. Charache S, Dover GJ, Moore RD. et al. (1992). Hydroxyurea: Effects on hemoglobin F production in patients with sickle cell anemia. Blood 79, 2555-2565.
22. Charache S, Terrin ML, Moore RD, et al. (1995). Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. N Engl J Med 332, 1317-1322.
23. Chaturvedi S, and DeBaun MR. (2016). Evolution of sickle cell disease from a life-Threatening disease of children to a chronic disease of adults: The last 40 years. Am J Hematol 91, 5-14.
24. Chou W, Wang C, Liu P, Liu C, Tseng C, and Jawan, B. (2006). Human opioid receptor A118G polymorphism affects intravenous patient-controlled analgesia morphine consumption after total abdominal hysterectomy. Anesthesiology 105, 334-337.
25. Colombatti R, Perrotta S, Samperi P, et al. (2013). Organizing national responses for rare blood disorders: The Italian experience with sickle cell disease in childhood. Orphanet J Rare Dis 8, 1.
26. Compton P, Geschwind DH, and Alarcon M. (2003). Association between human l-opioid receptor gene polymorphism, pain tolerance, and opioid addiction. Am J Med Genet B Neuropsychiatr Genet 121, 76-82.
27. Cox SE, Makani J, Soka D, et al. (2014). Haptoglobin, alphathalassaemia and glucose-6-phosphate dehydrogenase polymorphisms and risk of abnormal transcranial Doppler among patients with sickle cell anaemia in Tanzania. Br J Haematol 165, 699-706.
28. Darbari DS, Minniti CP, Rana S, and van den Anker J. (2008). Pharmacogenetics of morphine: Potential implications in sickle cell disease. Am J Hematol 83, 233-236.
29. de Montalembert M, Brousse V, Elie C, et al. (2006). Longterm hydroxyurea treatment in children with sickle cell disease: Tolerance and clinical outcomes. Haematologica 91, 125-128.
30. DeBaun MR. (2014). Hydroxyurea therapy contributes to infertility in adult men with sickle cell disease: A review. Expert Rev Hematol 7, 767-773.
31. Dersh J, Polatin PB, and Gatchel RJ. (2002). Chronic pain and psychopathology: Research findings and theoretical considerations. Psychosom Med 64, 773-786.
32. Diatchenko L, Slade GD, Nackley AG, et al. (2005). Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Hum Mol Gen 14, 135-143.
33. Dixit A, Chatterjee T, Mishra P, et al. (2005). Hydroxyurea in thalassemia intermedia-A promising therapy. Ann Hematol 84, 441-446.
34. Duguay Y, Baar C, Skorpen F, and Guillemette C. (2004). A novel functional polymorphism in the uridine diphosphateglucuronosyltransferase 2B7 promoter with significant impact on promoter activity. Clin Pharmacol Ther 75, 223-233.
35. Dzierzynski N, Stojanovic KS, Georgin-Lavialle S, and Lionnet F. (2016). Enjeux et difficultés de la relation entre soignants et patients drépanocytaires au cours de la crise douloureuse aiguë. Rev Med Interne 37, 111-116.
36. Elford HL. (1968). Effect of hydroxyurea on ribonucleotide reductase. Biochem Biophys Res Commun 33, 129-135.
37. Friedrisch JR, Prá D, Maluf SW, et al. (2008). DNA damage in blood leukocytes of individuals with sickle cell disease treated with hydroxyurea. Mutat Res Genet Toxicol Environ Mutagen 649, 213-220.
38. Galarneau G, Coady S, Garrett ME, et al. (2013). Gene-centric association study of acute chest syndrome and painful crisis in sickle cell disease patients. Blood 122, 434-442.
39. Gibbons C, Geoghegan R, Conroy H, et al. (2015). Sickle cell disease: Time for a targeted neonatal screening programme. Ir Med J 8, 43-45.
40. Grosse SD, Odame I, Atrash HK, Amendah DD, Piel FB, and Williams TN. (2011). Sickle cell disease in Africa: A neglected cause of early childhood mortality. Am J Prev Med 41, 398-405.
41. Hamideh D, and Alvarez O. (2013). Sickle cell disease related mortality in the United States (1999-2009). Pediatr Blood Cancer 60, 1482-1486.
42. Hankins JS, Ware RE, Rogers ZR, et al. (2005). Long-Term hydroxyurea therapy for infants with sickle cell anemia: The HUSOFT extension study. Blood 106, 2269-2275.
43. Heeney MM, and Ware RE. (2008). Hydroxyurea for children with sickle cell disease. Pediatr Clin North Am 55, 483-501.
44. Herrick JB. (2000). Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia. Yale J Biol Med 74, 179-184.
45. Höllt V. (2002). A polymorphism (A118G) in the l-opioid receptor gene affects the response to morphine-6-glucuronide in humans. Pharmacogenet Genomics 12, 1-2.
46. Jhun, EH, Yao Y, He Y, et al. (2015). Prevalence of pain-related single nucleotide polymorphisms in patients of African origin with sickle cell disease. Pharmacogenomics 16, 1795-1806.
47. Joly P, Gagnieu, MC, Bardel, C, et al. (2012). Genotypic screening of the main opiate-related polymorphisms in a cohort of 139 sickle cell disease patients. Am J Hematol 87, 534-536.
48. Kanter J, and Kruse-Jarres R. (2013). Management of sickle cell disease from childhood through adulthood. Blood Rev 27, 279-287.
49. Kinney TR, Helms RW, O'Branski EE, et al. (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.
50. Klepstad P, Rakvåg T, Kaasa S, et al. (2004). The 118A> G polymorphism in the human l-opioid receptor gene may increase morphine requirements in patients with pain caused by malignant disease. Acta Anaesthesiol Scand 48, 1232-1239.
51. Knorring LV. (1989). The pathogenesis of chronic pain syndromes. Nord Psykiatr Tidsskr 43, 35-41.
52. Kraus J, Borner C, Giannini E, et al. (2001). Regulation of muopioid receptor gene transcription by interleukin-4 and influence of an allelic variation within a STAT6 transcription factor binding site. J Biol Chem 276, 43901-43908.
53. Kumkhaek C, James G, Taylor VI, et al. (2008). Fetal haemoglobin response to hydroxycarbamide treatment and sar1a promoter polymorphisms in sickle cell anaemia. Br J Haematol 141, 254-259.
54. Kunz JB, Awad S, Happich M, et al. (2015). Significant prevalence of sickle cell disease in Southwest Germany: Results from a birth cohort study indicate the necessity for newborn screening. Ann Hematol 95, 397-402.
55. Lettre G, Sankaran VG, Bezerra MA, et al. (2008). DNA polymorphisms at the BCL11A, HBS1L-MYB, and betaglobin loci associate with fetal hemoglobin levels and pain crises in sickle cell disease. Proc Natl Acad Sci U S A 105, 11869-11874.
56. Loh HH, Liu H, Cavalli A, Yang W, Chen Y, and Wei L. (1998). l Opioid receptor knockout in mice: Effects on ligand-induced analgesia and morphine lethality. Mol Brain Res 54, 321-326.
57. Lotsch J, Sharke C, Grosch S, et al. (2002). The polymorphism A118G of the human mu-opioid receptor gene decreases the pupil constrictory effect of morphine-6-glucuronide but not that of morphine. Pharmacogenetics 12, 3-9.
58. Lotsch J, and Geisslinger G. (2006). Current evidence for a genetic modulation of the response to analgesics. Pain 121, 1-5.
59. Ma Q, Wyszynski DF, Farrell JJ, et al. (2007). Fetal hemoglobin in sickle cell anaemia: Genetic determinants of response to hydroxyurea. Pharmacogenomics J 7, 386-394.
60. Makani J, Menzel S, Nkya S, et al. (2011). Genetics of fetal hemoglobin in Tanzanian and British patients with sickle cell anemia. Blood 117, 1390-1392.
61. Makani J, Ofori-Acquah SF, Nnodu O, Wonkam A, and Ohene-Frempong K. (2013). Sickle cell disease: New opportunities and challenges in Africa. Sci World J 2013.
62. Makubi A, Soka D, and Makani J. (2012). Moyamoya disease, a rare cause of recurrent strokes in an African sickle cell child: Does hydroxyurea have a role in this context? Int J Child Health Nutr 1, 82-85.
63. Mantione KJ, Goumon Y, Esch T, and Stefano GB. (2005). Morphine 6beta glucuronide: Fortuitous morphine metabolite or preferred peripheral regulatory opiate? Med Sci Monitr 11, 43-46.
64. Matthes HW, Maldonado R, Simonin F, et al. (1996). Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the l-opioid-receptor gene. Nature 383, 819-823.
65. McGann PT, Ferris MG, Ramamurthy U, et al. (2013). A prospective newborn screening and treatment program for sickle cell anemia in Luanda, Angola. Am J Hematol 88, 984-989.
66. Meineke I, Freudenthaler S, Hofmann U, et al. (2002). Pharmacokinetic modelling of morphine, morphine-3-glucuronide and morphine-6-glucuronide in plasma and cerebrospinal fluid of neurosurgical patients after short-Term infusion of morphine. Br J Clin Pharmacol 54, 592-603.
67. Mmbando BP, Mgaya J, Cox SE, et al. (2015). Negative epistasis between sickle and foetal haemoglobin suggests a reduction in protection against malaria. PLoS One 10, e0125929.
68. Modell B, and Darlison M. (2008). Global epidemiology of haemoglobin disorders and derived service indicators. Bull WHO 86, 480-487.
69. Mogil JS. (2004). Complex trait genetics of pain in the laboratory mouse. Pain Res Manag 28, 123-150.
70. Mogil JS, and Devor M. (2004). Introduction to pain genetics. Pain Res Manag 28, 1-20.
71. Mtatiro SN, Singh T, Rooks H., et al. (2014). Genome wide association study of fetal hemoglbin in sickle cell anemia in Tanzania. PLoS One 9, e111464.
72. Murthy BP, Pollack GM, and Brouwer KL. (2002). Contribution of morphine-6-glucuronide to antinociception following Intravenous Administration of Morphine to Healthy Volunteers. J Clin Pharmacol 42, 569-576.
73. Nagel RL, Fabry ME, Pagnier J, et al. (1985). Hematologically and genetically distinct forms of sickle cell anemia in Africa: The Senegal type and the Benin type. N Engl J Med 312, 880-884.
74. Nishank SS, Singh MPSS, and Yadav R. (2013). Clinical impact of factor V Leiden, prothrombin G20210A, and MTHFR C677T mutations among sickle cell disease patients of Central India. Eur J Haematol 91, 462-466.
75. Olabode JO, and Shokunbi WA. (2006). Types of crises in sickle cell disease patients presenting at the haematology day care unit (HDCU), University College Hospital (UCH), Ibadan. West Afr J Med 25, 284-288.
76. Orkin SH. (2016). Recent advances in globin research using genome-wide association studies and gene editing. Ann NY Acad Sci 1368, 5-10.
77. Osborne R, Joel S, Trew D, and Slevin M. (1990). Morphine and metabolite behavior after different routes of morphine administration: Demonstration of the importance of the active metabolite morphine-6-glucuronide. Clin Pharmacol Ther 47, 12-19.
78. Piel FB, Patil AP, Howes RE, et al. (2013). Global epidemiology of sickle haemoglobin in neonates: A contemporary geostatistical model-based map and population estimates. Lancet 381, 142-151.
79. Pizzo E, Laverty AA, Phekoo KJ, et al. (2015). A retrospective analysis of the cost of hospitalizations for sickle cell disease with crisis in England, 2010/11. J Public Health (Oxf) 37, 529-539.
80. Platt OS, Orkin SH, Dover G, Beardsley GP, Miller B, and Nathan DG. (1984). Hydroxyurea enhances fetal hemoglobin production in sickle cell anemia. J Clin Invest 74, 652-656.
81. Platt OS, Thorington BD, Brambilla DJ, et al. (1991). Pain in sickle cell disease: Rates and risk factors. N Engl J Med 325, 11-16.
82. Pule GD, Mowla S, Novitzky N, Wiysonge CS, and Wonkam A. (2015). A systematic review of known mechanisms of hydroxyurea-induced fetal hemoglobin for treatment of sickle cell disease. Expert Rev Hematol 8, 669-679.
83. Rahimy MC, Gangbo A, Ahouignan G, et al. (2003). Effect of a comprehensive clinical care program on disease course in severely ill children with sickle cell anemia in a sub-Saharan African setting. Blood 102, 834-838.
84. Rahimy MC, Gangbo A, Ahouignan G, and Alihonou E. (2009). Newborn screening for sickle cell disease in the Republic of Benin. J Clin Pathol 62, 46-48.
85. Rakvåg TT, Klepstad P, Baar C, et al. (2005). The Val158Met polymorphism of the human catechol-O-methyltransferase (COMT) gene may influence morphine requirements in cancer pain patients. Pain 116, 73-78.
86. Rees DC, Williams TN, and Gladwin MT. (2010). Sickle-cell disease. Lancet 376, 2018-2031.
87. Ross JR, Rutter D, Welsh K, et al. (2005). Clinical response to morphine in cancer patients and genetic variation in candidate genes. Pharmacogenomics J 5, 324-336.
88. Rumaney MB, Bitoungui VJN, Vorster AA, et al. (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, e100516.
89. Sheehan VA, Luo Z, Flanagan JM, et al. (2013). Genetic modifiers of sickle cell anaemia in the BABY HUG cohort: Influence on laboratory and clinical phenotypes. Am J Hematol 88, 571-576.
90. Shenoy S. (2011). Hematopoietic stem cell transplantation for sickle cell disease: Current practice and emerging trends. Hematology ASH Educ 2011, 273-279.
91. Shiba HF, El-GhamrawyMK, Shaheen IAE, Ali RAE, andMousa SM. (2014). Glutathione S-Transferase gene polymorphisms (GSTM1, GSTT1, and GSTP1) in Egyptian pediatric patients with sickle cell disease. Pediatr Dev Pathol 17, 265-270.
92. Slade GD, Diatchenko L, Bhalang K, et al. (2007). Influence of psychological factors on risk of temporomandibular disorders. J Dent Res 86, 1120-1125.
93. Smith MT, Watt JA, and Cramond T. (1990). Morphine-3-glucuronide-A potent antagonist of morphine analgesia. Life Sci J 47, 579-585.
94. Solovieff N, Milton JN and Steinberg MH. (2010). Fetal hemaglobin in sickle cell anemia: Genome-wide associated studies suggest a regulatory region in the 5¢ olfactory receptor gene cluster. Blood 4, 1815-1825.
95. Stamer UM, and Stuber F. (2007). Genetic factors in pain and its treatment. Curr Opin Anaesthesiol 20, 478-484.
96. Steinberg MH, Barton F, Castro O, et al. (2003). Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: Risks and benefits up to 9 years of treatment. JAMA 289, 1645-1651.
97. Steinberg MH, Lu ZH, Barton FB, Terrin ML, Charache S, and Dover GJ. (1997). Fetal hemoglobin in sickle cell anemia: Determinants of response to hydroxyurea. Multicenter Study of Hydroxyurea. Blood 89, 1078-1088.
98. Steinberg MH, McCarthy WF, Castro OP, et al. (2010). The risks and benefits of long-Term use of hydroxyurea in sickle cell anemia: A 17.5 year follow-up. Am J Hematol 85, 403-408.
99. Tekola-Ayele F, and Rotimi CN. (2015). Translational genomics in low-And middle-income countries: Opportunities and challenges. Public Health Genomics 18, 242-247.
100. Thein SL, and Menzel S. (2009). Discovering the genetics underlying foetal haemoglobin production in adults. Br J Haematol 145, 455-467.
101. Thornburg CD, Dixon N, Burgett S, et al. (2009). A pilot study of hydroxyurea to prevent chronic organ damage in young children with sickle cell anemia. Pediatr Blood Cancer 52, 609-615.
102. Todd KH. (2005). Chronic Pain and aberrant drug-related behavior in the emergency department. J Law Med Ethics 33, 761-769.
103. Todd KH, Green C, Bonham VL, Haywood C, and Ivy E. (2006). Sickle cell disease related pain: Crisis and conflict. J Pain 7, 453-458.
104. Tshilolo L, Aissi LM, Lukusa D, et al. (2009). Neonatal screening for sickle cell anaemia in the Democratic Republic of the Congo: Experience from a pioneer project on 31 204 newborns. J Clin Pathol 62, 35-38.
105. Tubman VN, Marshall R, Jallah W, et al. (2016). Newborn screening for sickle cell disease in Liberia: A Pilot Study. Pediatr Blood Cancer 63, 671-676
106. Vichinsky EP. (1991). Comprehensive care in sickle cell disease: Its impact on morbidity and mortality. Sem Hematol 28, 220-226.
107. Voskaridou E, Christoulas D, Bilalis A, et al. (2010). The effect of prolonged administration of hydroxyurea on morbidity and mortality in adult patients with sickle cell syndromes: Results of a 17-year, single-center trial (LaSHS). Blood 115, 2354-2363.
108. Ware RE. (2013). Is sickle cell anemia a neglected tropical disease? PLoS Negl Trop Dis 7, e2120.
109. Ware RE, Despotovic JM, Mortier NA, et al. (2011). Pharmacokinetics, pharmacodynamics, and pharmacogenetics of hydroxyurea treatment for children with sickle cell anemia. Blood 118, 4985-4991.
110. Weatherall DJ, and Clegg JB. (2008). The Thalassaemia Syndromes, 4th ed. John Wiley & Sons New Jersey, USA.
111. Weatherall D, Hofman K, Rodgers G, Ruffin J, and Hrynkow S. (2005). A case for developing North-South partnerships for research in sickle cell disease. Blood 105, 921-923.
112. Weinshilboum RM, and Raymond FA. (1977). Inheritance of low erythrocyte catechol-o-methyltransferase activity in man. Am J Hum Genet 29, 125-135.
113. Williams TN, Mwangi TW, Wambua S, et al. (2005). Sickle cell trait and the risk of Plasmodium falciparum malaria and other childhood diseases. Int J Infect Dis 192, 178-186.
114. Wonkam A, Bitoungui VJN, Vorster AA, et al. (2014). Association of variants at BCL11A and HBS1L-MYB with hemoglobin F and hospitalization rates among sickle cell patients in Cameroon. PLoS One 9, e92506.
115. Wonkam A, Mba CZ, Mbanya D, Ngogang J, Ramesar R, and Angwafo FF. (2014). Psychosocial stressors of sickle cell disease on adult patients in Cameroon. J Genet Couns 23, 948-956.
116. Wonkam A, Ponde C, Nicholson N, Fieggen K, Ramesar R, and Davidson A. (2012). The burden of sickle cell disease in Cape Town. SAMJ 102, 753-754.
117. Wonkam A, Rumaney MB, Ngo Bitoungui VJ, Vorster AA, Ramesar R, and Ngogang J. (2014). Coinheritance of sickle cell anemia and a-Thalassemia delays disease onset and could improve survival in cameroonian's patients (Sub-Saharan Africa). Am J Hematol 89, 664-665.
118. Xu J, Peng C, Sankaran VG, et al. (2011). Correction of sickle cell disease in adult mice by interference with fetal hemoglobin silencing. Science 334, 993-996.
119. Xu J, Sankaran VG, Ni M, et al. (2010). Transcriptional silencing of {gamma}-globin by BCL11A involves long-range interactions and cooperation with SOX6. Genes Dev 24, 783-798.
120. Yanni E, Grosse SD, Yang Q, and Olney RS. (2009). Trends in pediatric sickle cell disease-related mortality in the United States, 1983-2002. J Pediatr 154, 541-545.
121. Yavarian M, Karimi M, Bakker E, Harteveld CL, and Giordano PC. (2004). Response to hydroxyurea treatment in Iranian transfusion-dependent beta-Thalassemia patients. Haematologica 89, 1172-1178.
122. Zago M, Silva W, Dalle B, et al. (2000). Atypical beta(s) haplotypes are generated by diverse genetic mechanisms. Am J Hematol 63, 79-84.
123. Zhu J, Chin K, Aerbajinai W, Kumkhaek C, Li H, and Rodgers GP. (2014). Hydroxyurea-inducible SAR1 gene acts through the Gialpha/JNK/Jun pathway to regulate gamma-globin expression. Blood 124, 1146-1156.
124. Zimmerman SA, Schultz WH, Burgett S, Mortier NA, and Ware RE. (2007). Hydroxyurea therapy lowers transcranial Doppler flow velocities in children with sickle cell anemia. Blood 110, 1043-1047.
125. Zimmerman SA, Schultz WH, Davis JS, et al. (2004). Sustained long-Term hematologic efficacy of hydroxyurea at maximum tolerated dose in children with sickle cell disease. Blood 103, 2039-2045.
126. Zubieta JK, Heitzeg MM, Smith YR, et al. (2003). COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain stressor. Science 299, 1240-1243.
127. Zur B. (2016). Increase in genetically determined anemia as a result of migration in Germany. Der Internist 57, 444-445.