Identifying genetic variants and pathways associated with extreme levels of fetal hemoglobin in sickle cell disease in Tanzania

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dc.contributor.authorNkya, Siana
dc.contributor.authorMwita, Liberata
dc.contributor.authorMgaya, Josephine
dc.contributor.authorKumburu, Happiness
dc.contributor.authorvan Zwetselaar, Marco
dc.contributor.authorMenzel, Stephan
dc.contributor.authorMazandu, Gaston K
dc.contributor.authorSangeda, Raphael
dc.contributor.authorChimusa, Emile
dc.contributor.authorMakani, Julie
dc.date.accessioned2020-06-10T10:46:26Z
dc.date.available2020-06-10T10:46:26Z
dc.date.issued2020-06-05
dc.date.updated2020-06-07T03:46:16Z
dc.description.abstractBackground Sickle cell disease (SCD) is a blood disorder caused by a point mutation on the beta globin gene resulting in the synthesis of abnormal hemoglobin. Fetal hemoglobin (HbF) reduces disease severity, but the levels vary from one individual to another. Most research has focused on common genetic variants which differ across populations and hence do not fully account for HbF variation. Methods We investigated rare and common genetic variants that influence HbF levels in 14 SCD patients to elucidate variants and pathways in SCD patients with extreme HbF levels (≥7.7% for high HbF) and (≤2.5% for low HbF) in Tanzania. We performed targeted next generation sequencing (Illumina_Miseq) covering exonic and other significant fetal hemoglobin-associated loci, including BCL11A, MYB, HOXA9, HBB, HBG1, HBG2, CHD4, KLF1, MBD3, ZBTB7A and PGLYRP1. Results Results revealed a range of genetic variants, including bi-allelic and multi-allelic SNPs, frameshift insertions and deletions, some of which have functional importance. Notably, there were significantly more deletions in individuals with high HbF levels (11% vs 0.9%). We identified frameshift deletions in individuals with high HbF levels and frameshift insertions in individuals with low HbF. CHD4 and MBD3 genes, interacting in the same sub-network, were identified to have a significant number of pathogenic or non-synonymous mutations in individuals with low HbF levels, suggesting an important role of epigenetic pathways in the regulation of HbF synthesis. Conclusions This study provides new insights in selecting essential variants and identifying potential biological pathways associated with extreme HbF levels in SCD interrogating multiple genomic variants associated with HbF in SCD.en_US
dc.identifier.apacitationNkya, S., Mwita, L., Mgaya, J., Kumburu, H., van Zwetselaar, M., Menzel, S., ... Makani, J. (2020). Identifying genetic variants and pathways associated with extreme levels of fetal hemoglobin in sickle cell disease in Tanzania. <i>BMC Medical Genetic</i>, 21(1), 125. http://hdl.handle.net/11427/32062en_ZA
dc.identifier.chicagocitationNkya, Siana, Liberata Mwita, Josephine Mgaya, Happiness Kumburu, Marco van Zwetselaar, Stephan Menzel, Gaston K Mazandu, Raphael Sangeda, Emile Chimusa, and Julie Makani "Identifying genetic variants and pathways associated with extreme levels of fetal hemoglobin in sickle cell disease in Tanzania." <i>BMC Medical Genetic</i> 21, 1. (2020): 125. http://hdl.handle.net/11427/32062en_ZA
dc.identifier.citationNkya, S., Mwita, L., Mgaya, J., Kumburu, H., van Zwetselaar, M., Menzel, S., Mazandu, G.K. & Sangeda, R. et al. 2020. Identifying genetic variants and pathways associated with extreme levels of fetal hemoglobin in sickle cell disease in Tanzania. <i>BMC Medical Genetic.</i> 21(1):125. http://hdl.handle.net/11427/32062en_ZA
dc.identifier.ris TY - Journal Article AU - Nkya, Siana AU - Mwita, Liberata AU - Mgaya, Josephine AU - Kumburu, Happiness AU - van Zwetselaar, Marco AU - Menzel, Stephan AU - Mazandu, Gaston K AU - Sangeda, Raphael AU - Chimusa, Emile AU - Makani, Julie AB - Background Sickle cell disease (SCD) is a blood disorder caused by a point mutation on the beta globin gene resulting in the synthesis of abnormal hemoglobin. Fetal hemoglobin (HbF) reduces disease severity, but the levels vary from one individual to another. Most research has focused on common genetic variants which differ across populations and hence do not fully account for HbF variation. Methods We investigated rare and common genetic variants that influence HbF levels in 14 SCD patients to elucidate variants and pathways in SCD patients with extreme HbF levels (≥7.7% for high HbF) and (≤2.5% for low HbF) in Tanzania. We performed targeted next generation sequencing (Illumina_Miseq) covering exonic and other significant fetal hemoglobin-associated loci, including BCL11A, MYB, HOXA9, HBB, HBG1, HBG2, CHD4, KLF1, MBD3, ZBTB7A and PGLYRP1. Results Results revealed a range of genetic variants, including bi-allelic and multi-allelic SNPs, frameshift insertions and deletions, some of which have functional importance. Notably, there were significantly more deletions in individuals with high HbF levels (11% vs 0.9%). We identified frameshift deletions in individuals with high HbF levels and frameshift insertions in individuals with low HbF. CHD4 and MBD3 genes, interacting in the same sub-network, were identified to have a significant number of pathogenic or non-synonymous mutations in individuals with low HbF levels, suggesting an important role of epigenetic pathways in the regulation of HbF synthesis. Conclusions This study provides new insights in selecting essential variants and identifying potential biological pathways associated with extreme HbF levels in SCD interrogating multiple genomic variants associated with HbF in SCD. DA - 2020-06-05 DB - OpenUCT DP - University of Cape Town IS - 1 J1 - BMC Medical Genetic KW - Sickle cell disease KW - Genetic disorder KW - Fetal hemoglobin KW - Hemoglobinopathy KW - Tanzania LK - https://open.uct.ac.za PY - 2020 T1 - Identifying genetic variants and pathways associated with extreme levels of fetal hemoglobin in sickle cell disease in Tanzania TI - Identifying genetic variants and pathways associated with extreme levels of fetal hemoglobin in sickle cell disease in Tanzania UR - http://hdl.handle.net/11427/32062 ER - en_ZA
dc.identifier.urihttps://doi.org/10.1186/s12881-020-01059-1
dc.identifier.urihttp://hdl.handle.net/11427/32062
dc.identifier.vancouvercitationNkya S, Mwita L, Mgaya J, Kumburu H, van Zwetselaar M, Menzel S, et al. Identifying genetic variants and pathways associated with extreme levels of fetal hemoglobin in sickle cell disease in Tanzania. BMC Medical Genetic. 2020;21(1):125. http://hdl.handle.net/11427/32062.en_ZA
dc.language.isoenen_US
dc.language.rfc3066en
dc.publisher.departmentDepartment of Pathologyen_US
dc.publisher.facultyFaculty of Health Sciencesen_US
dc.rights.holderThe Author(s)
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.sourceBMC Medical Geneticen_US
dc.source.journalissue1en_US
dc.source.journalvolume21en_US
dc.source.pagination125en_US
dc.source.urihttps://bmcmedgenet.biomedcentral.com/
dc.subjectSickle cell diseaseen_US
dc.subjectGenetic disorderen_US
dc.subjectFetal hemoglobinen_US
dc.subjectHemoglobinopathyen_US
dc.subjectTanzaniaen_US
dc.titleIdentifying genetic variants and pathways associated with extreme levels of fetal hemoglobin in sickle cell disease in Tanzaniaen_US
dc.typeJournal Articleen_US
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