Original Article

Fetal Hemoglobin Modulators May Be Associated With Symptomology of Football Players with Sickle Cell Trait

Authors: Carroll Flansburg, MA, MPH, Christina M. Balentine, BS, Ryan W. Grieger, MS, Justin Lund, MA, Michelle Ciambella, BS, Deandre White, BS, Eric Coris, MD, Eduardo Gonzalez, MD, Anne C. Stone, PhD, Lorena Madrigal, PhD

Abstract

Objectives: This study investigates whether genetic modifiers previously shown to influence adult fetal hemoglobin (HbF) levels and glucose-6-phosphate dehydrogenase deficiency were associated with variable symptomology in a small sample of collegiate football players with sickle cell trait.

Methods: Survey data on self-assessed symptoms and genotype data from five single nucleotide polymorphisms (SNPs) related to HbF production and two SNPs that cause glucose-6-phosphate dehydrogenase deficiency were collected from current and former college football players.

Results: In this sample, SNPs found within the β-globin gene cluster were found to be associated with a previous diagnosis of exertional sickling and experience of extreme heat during and after training. rs10189857 in the BCL11A gene was associated with body mass index and weight and with experiencing extreme thirst during and after training. No significant correlations were found between the other SNPs and symptoms within this sample.

Conclusions: These findings show that genetic variation known to affect sickle cell disease symptomology may partly explain why some football players with sickle cell trait experience adverse clinical outcomes during periods of extreme physical exertion and others do not.
Posted in: Hematology7

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References

1. Ingram VM. Gene mutations in human haemoglobin: the chemical difference between normal and sickle cell haemoglobin. Nature 1957;180:326-328.
2. Bauer DE, Kamran SC, Lessard S, et al. An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level. Science 2013;342:253-257.
3. Meier ER, Fasano RM, Levett PR. A systematic review of the literature for severity predictors in children with sickle cell anemia. Blood Cells Mol Dis 2017;65:86-94.
4. Serjeant GR. Fetal hemoglobin in homozygous sickle-cell disease. Clin Haematol 1975;4:109-122.
5. Hardison RC, Blobel GA. Genetics. GWAS to therapy by genome edits? Science 2013;342:206-207.
6. Smith EC, Orkin SH. Hemoglobin genetics: recent contributions of GWAS and gene editing. Hum Mol Genet 2016;25:R99-R105.
7. Steinberg MH. Predicting clinical severity in sickle cell anaemia. Br J Haematol 2005;129:465-481.
8. Tang DC, Ebb D, Hardison RC, et al. Restoration of the CCAAT box or insertion of the CACCC motif activates <corrected] delta-globin gene expression. Blood 1997;90:421-427.
9. Akinsheye I, Alsultan A, Solovieff N, et al. Fetal hemoglobin in sickle cell anemia. Blood 2011;118:19-27.
10. Basak A, Hancarova M, Ulirsch JC, et al. BCL11A deletions result in fetal hemoglobin persistence and neurodevelopmental alterations. J Clin Invest 2015;125:2363-2368.
11. Funnell AP, Prontera P, Ottaviani V, et al. 2p15-p16.1 microdeletions encompassing and proximal to BCL11A are associated with elevated HbF in addition to neurologic impairment. Blood 2015;126:89-93.
12. Uda M, Galanello R, Sanna S, 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 U S A 2008;105:1620-1625.
13. Antoniani C, Romano O, Miccio A. Concise review: epigenetic regulation of hematopoiesis: biological insights and therapeutic applications. Stem Cells Transl Med 2017;6:2106-2114.
14. Martyn GE, Wienert B, Yang L, et al. Natural regulatory mutations elevate the fetal globin gene via disruption of BCL11A or ZBTB7A binding. Nat Genet 2018;50:498-503.
15. Thein SL, Menzel S, Lathrop M, et al. Control of fetal hemoglobin: new insights emerging from genomics and clinical implications. Hum Mol Genet 2009;18:R216-R223.
16. Bhatnagar P, Purvis S, Barron-Casella E, et al. Genome-wide association study identifies genetic variants influencing F-cell levels in sickle-cell patients. J Hum Genet 2011;56:316-323.
17. Galarneau G, Palmer CD, Sankaran VG, et al. Fine-mapping at three loci known to affect fetal hemoglobin levels explains additional genetic variation. Nat Genet 2010;42:1049-1051.
18. Lettre G, Sankaran VG, Bezerra MA, 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 U S A 2008;105:11869-11874.
19. Masuda T, Wang X, Maeda M, et al. Transcription factors LRF and BCL11A independently repress expression of fetal hemoglobin. Science 2016;351:285-289.
20. Thein SL, Menzel S, Peng X, 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 U S A 2007;104:11346-11351.
21. Bauer DE, Orkin SH. Hemoglobin switching' surprise: the versatile transcription factor BCL11A is a master repressor of fetal hemoglobin. Curr Opin Genet Dev 2015;33:62-70.
22. Kulozik AE, Kar BC, Satapathy RK, et al. Fetal hemoglobin levels and beta (s) globin haplotypes in an Indian populations with sickle cell disease. Blood 1987;69:1742-1746.
23. Connes P, Reid H, Hardy-Dessources MD, et al. Physiological responses of sickle cell trait carriers during exercise. Sports Med 2008;38:931-946.
24. National Heart, Lung, and Blood Institute. Questions and answers about sickle cell trait. https://www.nhlbi.nih.gov/news/2010/questions-and-answers-about-sickle-cell-trait. Published September 22, 2010. Accessed February 26, 2019.
25. Tsaras G, Owusu-Ansah A, Boateng FO, et al. Complications associated with sickle cell trait: a brief narrative review. Am J Med 2009;122:507-512.
26. Hayashi TY, Matsuda I, Hagiwara K, et al. Massive splenic infarction and splenic venous thrombosis observed in a patient with acute splenic syndrome of sickle cell traits on contrast-enhanced thin-slice computed tomography. Abdom Radiol (NY) 2016;41:1718-1721.
27. Gupta M, Lehl SS, Singh K, et al. Acute splenic infarction in a hiker with previously unrecognised sickle cell trait. BMJ Case Rep 2013;2013:bcr2013008931.
28. Ferster K, Eichner ER. Exertional sickling deaths in Army recruits with sickle cell trait. Mil Med 2012;177:56-59.
29. Murray MJ, Evans P. Sudden exertional death in a soldier with sickle cell trait. Mil Med 1996;161:303-305.
30. Way A, Ganesan S, McErlain M. Multiple limb compartment syndromes in a recruit with sickle cell trait. J R Army Med Corps 2011;157:182-183.
31. Weisman IM, Zeballos RJ, Martin TW, et al. Effect of Army basic training in sickle-cell trait. Arch Intern Med 1988;148:1140-1144.
32. Harris KM, Haas TS, Eichner ER, et al. Sickle cell trait associated with sudden death in competitive athletes. Am J Cardiol 2012;110:1185-1188.
33. Kark JA, Ward FT. Exercise and hemoglobin S. Semin Hematol 1994;31:181-225.
34. Nelson DA, Deuster PA, Carter R, 3rd et al. Sickle cell trait, rhabdomyolysis, and mortality among U.S. Army soldiers. N Engl J Med 2016;375:435-442.
35. Davis AM. Sickle-cell trait as a risk factor for sudden-death in physical-training-reply. N Engl J Med 1987;317:781-787.
36. Harmon KG, Drezner JA, Klossner D, et al. Sickle cell trait associated with a RR of death of 37 times in National Collegiate Athletic Association football athletes: a database with 2 million athlete-years as the denominator. Br J Sports Med 2012;46:325-330.
37. Oɼ FG, Bergeron MF, Cantrell J, et al. ACSM and CHAMP summit on sickle cell trait: mitigating risks for warfighters and athletes. Med Sci Sports Exerc 2012;44:2045-2056.
38. Mitchell BL. Sickle cell trait and sudden death-bringing it home. J Natl Med Assoc 2007;99:300-305.
39. Guindo A, Traore K, Diakite S, et al. An evaluation of concurrent G6PD (A-) deficiency and sickle cell trait in Malian populations of children with severe or uncomplicated P. falciparum malaria. Am J Hematol 2011;86:795-796.
40. Ouattara AK, Yameogo P, Diarra B, et al. Molecular heterogeneity of glucose-6-phosphate dehydrogenase deficiency in Burkina Faso: G-6-PD Betica Selma and Santamaria in people with symptomatic malaria in Ouagadougou. Mediterr J Hematol Infect Dis 2016;8:e2016029.
41. Sebastiani P, Farrell JJ, Alsultan A, et al. BCL11A enhancer haplotypes and fetal hemoglobin in sickle cell anemia. Blood Cells Mol Dis 2015;54:224-230.
42. Sebastiani P, Solovieff N, Hartley SW, et al. Genetic modifiers of the severity of sickle cell anemia identified through a genome-wide association study. Am J Hematol 2010;85:29-35.
43. Help and Documentation. Cary, NC :SAS Institute; 2002-2004.
44. Akinbami AO, Campbell AD, Han ZJ, et al. Hereditary persistence of fetal hemoglobin caused by single nucleotide promoter mutations in sickle cell trait and Hb SC disease. Hemoglobin 2016;40:64-65.
45. Hariharan P, Sawant M, Gorivale M, et al. Synergistic effect of two β globin gene cluster mutations leading to the hereditary persistence of fetal hemoglobin (HPFH) phenotype. Mol Biol Rep 2017;44:413-417.
46. Al-Allawi NA, Puehringer H, Raheem RA, et al. Genetic modifiers in β-thalassemia intermedia: a study on 102 Iraqi Arab patients. Genet Test Mol Biomarkers 2015;19:242-247.
47. Sokal R, Rohlf F. Biometry: The Principles and Practice of Statistics in Biological Research. New York:WH Freeman;2012.
48. Bacchetti P, Deeks SG, McCune JM. Breaking free of sample size dogma to perform innovative translational research. Sci Transl Med 2011;3:87ps24.