The role of BCL11A and HMIP-2 polymorphisms on endogenous and hydroxyurea induced levels of fetal hemoglobin in sickle cell anemia patients from southern Brazil

Abstract

High levels of fetal hemoglobin (HbF) reduce sickle cell anemia (SCA) morbidity and mortality. HbF levels vary considerably and there is a strong genetic component that influences HbF production. Genetic polymorphisms at three quantitative trait loci (QTL): Xmn1-HBG2, HMIP-2 and BCL11A, have been shown to influence HbF levels and disease severity in SCA. Hydroxyurea (HU) is a drug that increases HbF. We investigated the influence of single nucleotide polymorphisms (SNPs) at the Xmn1-HBG2 (rs7482144); BCL11A (rs1427407, rs4671393 and rs11886868); and HMIP-2 (rs9399137 and rs9402686) loci on baseline and HU-induced HbF levels in 111 HbSS patients. We found that both BCL11A and HMIP-2 were associated with increased endogenous levels of HbF. Interestingly, we also found that BCL11A was associated with higher induction of HbF with HU. This effect was independent of the effect of BCL11A on baseline HbF levels. Additional studies will be needed to validate these findings and explain the ample inter-individual variations in HbF levels at baseline and HU-induced in patients with SCA.

The association of HBG2, BCL11A, and HMIP polymorphisms with fetal hemoglobin and clinical phenotype in Iraqi Kurds with sickle cell disease

“…This SNP accounted for 13.4% of HbF variability among our Kurdish SCD patients. Similarly, this SNP was found to contribute significantly to HbF variability in several SCD populations including Indians (23%), Eastern Saudi Arabians (7.5%), Cameroonians (6.3%), Southern Brazilian, and African Americans …”

“…In the present study, MAF of rs9399137 is 0.137, which is among the highest frequencies observed in SCD populations (Table ). This SNP has been reported to be associated with HbF levels in other populations, including Indian, African American, Cameroonian, Tanzanian, British, and Eastern and Southern Brazilian patients, but not in Saudi Arabian or North Brazilian SCD patients …”

“…including Indian, African American, Cameroonian, Tanzanian, British, and Eastern and Southern Brazilian patients, 15,19,20,24,28,33 but not in Saudi Arabian or North Brazilian SCD patients. 10,11,23 The current study has revealed that carriers of the minor alleles of each of rs7482144, rs1427407, and rs9399137 had significantly higher hemoglobin and lower transfusion requirements.…”

High fetal hemoglobin level is associated with increased risk of cerebral vasculopathy in children with sickle cell disease in Mayotte.

“…This was the case for Xmn1 in our cohort, which may have resulted from its rarity. A study comparing two cohorts of European and African origin observed differences in allele frequency and correlation with HbF [51]. Another study, conducted in Cameroon, showed identicallelic frequencies between a Cameroonian population and the African-American cohort, but a lower impact on HbF among Africans [52].…”

Combined and differential effects of alpha‐thalassemia and HbF‐quantitative trait loci in Senegalese hydroxyurea‐free children with sickle cell anemia

“…These three loci account for approximately 20–50% of HbF variability in patients with SCA . To date, few works analyzed their associations with clinical and biological parameters but two major limitations could be highlighted: (1) the most severe patients with SCA received hydroxyurea (HU), a well‐known HbF inducer that may have blunted the effects of the HbF‐QTL and (2) no study focused on the differential effects of the HbF‐QTL according to the alpha‐thalassemia status.…”