Working Paper Article Version 1 This version is not peer-reviewed

Identifying Genetic Variants and Pathways Associated with Extreme Levels of Fetal Hemoglobin in Sickle Cell Disease in Tanzania

Version 1 : Received: 19 September 2019 / Approved: 20 September 2019 / Online: 20 September 2019 (11:47:39 CEST)

How to cite: Nkya, S.; Mwita, L.; Mgaya, J.; Kumburu, H.; van Zwetselaar, M.; Menzel, S.; Mazandu, G.K.; Sangeda, R.Z.; Chimusa, E.R.; Makani, J. Identifying Genetic Variants and Pathways Associated with Extreme Levels of Fetal Hemoglobin in Sickle Cell Disease in Tanzania. Preprints 2019, 2019090239 Nkya, S.; Mwita, L.; Mgaya, J.; Kumburu, H.; van Zwetselaar, M.; Menzel, S.; Mazandu, G.K.; Sangeda, R.Z.; Chimusa, E.R.; Makani, J. Identifying Genetic Variants and Pathways Associated with Extreme Levels of Fetal Hemoglobin in Sickle Cell Disease in Tanzania. Preprints 2019, 2019090239

Abstract

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 variants which differ across populations and hence do not fully account for HbF variation. To investigate rare and common variants influencing HbF levels in SCD, we performed targeted next generation sequencing covering exonic and other significant fetal hemoglobin-associated loci, including BCL11A, MYB, HOXA9, HBB, HBG1, HBG2, CHD4, KLF1, MBD3, ZBTB7A and PGLYRP1. Results revealed a range of functionally relevant genetic variants. Notably, there were significantly more deletions in individuals with high HbF levels (11% vs 0.9%). We identified frameshift deletion 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. This study provides new insights in selecting essential variants associated with extreme HbF levels in SCD.

Subject Areas

Sickle cell disease; genetic disorder; fetal hemoglobin; hemoglobinopathy; Tanzania

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