Unique Polymorphisms at BCL11A, HBS1L-MYB and HBB Loci Associated with HbF in Kuwaiti Patients with Sickle Cell Disease.

Nagihan Akbulut-Jeradi,Adekunle Adekile,Jalaja Sukumaran,Maria Jinky Fernandez,Rasha Al Khaldi

doi:10.3390/jpm11060567

Abstract

Patients with sickle cell disease (SCD) in Kuwait have elevated HbF levels ranging from ~10–44%; however, the modulating factors are unclear. We investigated the association of single nucleotide polymorphisms (SNPs) at BCL11A, HBS1L-MYB and HBB with HbF levels in 237 Kuwaiti SCD patients, divided into 3 subgroups according to their HbF levels. Illumina Ampliseq custom DNA panel was used for genotyping and confirmed by arrayed primer extension or Sanger sequencing. In the BCL11A locus, the CC genotype of rs7606173 [χ2 = 16.5] and (GG) of rs10195871 [χ2 = 15.0] were associated with Hb-F1 and HbF-2 subgroups, unlike rs1427404-T [χ2 = 17.3], which showed the highest association across the three subgroups. HBS1L-MYB locus revealed 2 previously-described SNPs (rs66650371 [χ2 = 9.5] and rs35795442 [χ2 = 9.2]) and 2 previously-unreported SNPs, (rs13220662 [χ2 = 6.2] and rs1406811 [χ2 = 6.7]) that were associated with the HbF-3 subgroup, making this the key locus elevating HbF to the highest levels. HBB cluster variants were associated with lower levels of HbF (β = −1.1). We report four previously-unpublished variants showing significant association with HbF. Each of the three quantitative trait loci affects HbF levels differently; unique SNPs, especially in HBS1L-MYB, elevate HbF to the highest levels.

Highlights

Published: 17 June 2021Sickle cell disease (SCD) is the most widespread monogenic disease worldwide with significant morbidity and mortality, associated with the HBB mutation, rs334 (Glu6→Val; GAG→GTG)
Pre-statistical analysis revealed an overestimation of single nucleotide polymorphisms (SNPs) associated with the high HbF levels among the patients, the inclusion of healthy individuals failed to validate true association probably due to the wide significant differences (p ≤ 0.0001) in the HbF levels between patients (HbF mean = 23.3 ± 9.6%) and healthy individuals (HbF mean = 1.9 ± 2.3%) the latter were excluded from genetic association analysis
Our study confirms that polymorphisms in the BCL11A

Summary

Introduction

Sickle cell disease (SCD) is the most widespread monogenic disease worldwide with significant morbidity and mortality, associated with the HBB mutation, rs334 (Glu6→Val; GAG→GTG). Homozygotes for this mutation have HbSS or sickle cell anemia (SCA), which is the most severe form of the disease. Patients with the Arab/Indian (AI) and Senegal (SEN) haplotypes have the highest HbF levels and mildest phenotypes. These are the haplotypes associated with the HBG2, -158 (C→T) XmnI SNP, namely rs7482144

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Conclusion