Browsing by Subject "Fetal hemoglobin"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Open Access
    Identifying genetic variants and pathways associated with extreme levels of fetal hemoglobin in sickle cell disease in Tanzania
    (2020-06-05) Nkya, Siana; Mwita, Liberata; Mgaya, Josephine; Kumburu, Happiness; van Zwetselaar, Marco; Menzel, Stephan; Mazandu, Gaston K; Sangeda, Raphael; Chimusa, Emile; Makani, Julie
    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.
  • Thumbnail Image
    Item
    Open Access
    SAR1a promoter polymorphisms are not associated with fetal hemoglobin in patients with sickle cell disease from Cameroon
    (BioMed Central, 2017-05-12) Pule, Gift Dineo; Ngo Bitoungui, Valentina Josiane; Chemegni, Bernard Chetcha; Kengne, Andre Pascal; Wonkam, Ambroise
    Background: Reactivation of adult hemoglobin (HbF) is currently a dominant therapeutic approach to sickle cell disease (SCD). In this study, we have investigated among SCD patients from Cameroon, the association of HbF level and variants in the HU-inducible small guanosine triphosphate-binding protein, secretion-associated and RAS-related (SAR1a) protein, previously shown to be associated with HbF after HU treatment in African American SCD patients. Results: Only patients >5 years old were included; hemoglobin electrophoresis and a full blood count were conducted upon arrival at the hospital. RFLP-PCR was used to describe the HBB gene haplotypes and Gap PCR to investigate the 3.7 kb α-globin gene deletion. The iPLEX Gold Sequenom Mass Genotyping Array and cycle sequencing were used for the genotyping of four selected SNPs in SAR1a (rs2310991; rs4282891; rs76901216 and rs76901220). Genetic analysis was performed using an additive genetic model, under a generalized linear regression framework. 484 patients were studied. No associations were observed between any of the promoter variants and baseline HbF, clinical events or other hematological indices. Conclusion: The results of this study could be explained by possible population-specifcity of some tagging genomic variants associated with HbF production and illustrated the complexity of replicating HbF-promoting variants association results across African populations.