SAR1a promoter polymorphisms are not associated with fetal hemoglobin in patients with sickle cell disease from Cameroon

Gift Dineo Pule,Bernard Chetcha Chemegni,Ambroise Wonkam,Andre Pascal Kengne,Valentina Josiane Ngo Bitoungui

doi:10.1186/s13104-017-2502-3

Abstract

BackgroundReactivation 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.ResultsOnly 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.ConclusionThe results of this study could be explained by possible population-specificity of some tagging genomic variants associated with HbF production and illustrated the complexity of replicating HbF-promoting variants association results across African populations.

Highlights

Reactivation of adult hemoglobin (HbF) is currently a dominant therapeutic approach to sickle cell disease (SCD)
Much like variants in B-cell lymphoma/leukemia 11A (BCL11A), myeloblastosis protein family (MYB) and KLF-1 have been shown to be associated to Hb F levels in both HUexposed and HU-naïve conditions [6, 12], in the present study, we have investigated the relationship between the four SAR1a promoter variants and baseline hemoglobin F (HbF) in SCD patients from Cameroon, without any HU treatment
In a previous study of this cohort, the SCD patient cohort was disaggregated based on the technique used for HbF assessment (HPLC vs alkali denaturation test (ADT)) and found similar but independently examined associations between HbF levels and BCL11A and hemoglobin S-1 like translational protein (HBS1L)-MYB intergenic variants [5]

Summary

Introduction

Reactivation of adult hemoglobin (HbF) is currently a dominant therapeutic approach to sickle cell disease (SCD). The expression of adult HbF is a quantitative trait that is subject to several predisposing loci affecting the persistence of HbF in adulthood, three principal loci; BCL11A, HBS1L-MYB intergenic variants and the five sequence polymorphisms along the β-globin gene cluster that confer the SCD haplotype [1,2,3] Taken in sum, these loci have been associated with the disease-ameliorating HbF and account for 10–20% of the. HbF response to hydroxyurea (HU), has been shown to be subject to a myriad of genetic variations (SNPs, signalling pathways and pharmacogenomics interactions) and environmental factors (socio-economic factors, quality of care, exposure to malaria and infections) [12] Some of these variants have been associated with favourable pharmacologic response to HU treatment like the small guanosine triphosphate (GTP)-binding protein, secretion-associated and RAS-related (SAR) protein [13]. Much like variants in BCL11A, MYB and KLF-1 have been shown to be associated to Hb F levels in both HUexposed and HU-naïve conditions [6, 12], in the present study, we have investigated the relationship between the four SAR1a promoter variants and baseline HbF in SCD patients from Cameroon, without any HU treatment

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Discussion

Conclusion