Identifying genetic variants and pathways associated with extreme levels of fetal hemoglobin in Sickle Cell Disease in Tanzania.

Abstract

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 variants which differ across populations and hence do not fully account for HbF variation. Results: This study investigates rare and common genetic variants that influence HbF levels in 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 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 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. Conclusion: This study provides new insights in selecting essential variants and identifying potential biological pathways associated with extreme HbF levels in SCD using multiple genomic variants associated with HbF in SCD.

Exome sequencing in high and low fetal haemoglobin Arab–Indian haplotype sickle cell disease

“…Our results differ from those of Nkya et al . who studied 14 Tanzanian sickle cell anaemia patients with high ( n = 9, HbF 15–32%) or low HbF ( n = 5; HbF 0·3–2·2%) and found an increased number of pathogenic or non‐synonymous mutations in CHD4 (chromodomain helicase DNA binding protein) in the low‐HbF group 11 . CHD4 is a component of the NuRD (nucleosome remodeling and deacetylase) complex, a transcriptional repressor.…”

Inauguration of the Tanzania Society of Human Genetics: Biomedical Research in Tanzania with Emphasis on Human Genetics and Genomics

“…To date, there is no formal database of genetics-related/influenced diseases in the country. However, some of genetic studies involving samples from Tanzania or conducted in the country include the Human Heredity and Health in Africa (H3A) studies in diabetes, 20 tuberculosis, 21 albinism, 22 sickle cell disease (SCD), 23,24 and malaria. 25 To address this gap, the Tanzania Society of Human Genetics (TSHG) was formed in 2017.…”