Single nucleotide polymorphisms (SNPs) of BCL11A gene and HBS1L-MYB intergenic region (named HMIP-2) affect both fetal hemoglobin (HbF) concentration and clinical outcomes in patients with sickle cell anemia (SCA). However, no previous study has examined the interaction among these SNPs in the regulation of HbF. We examined whether HbF-boosting haplotypes combining alleles of functional SNPs of BCL11A and HMIP-2 were associated with clinical outcomes and hematological parameters, and whether they interact to regulate HbF in a cohort of Brazilian children with SCA. The minor haplotype of BCL11A ("TCA", an allele combination of rs1427407, rs766432, and rs4671393) was associated with higher HbF, hemoglobin and lower reticulocytes count compared to reference haplotype "GAG". The minor haplotype of HMIP-2 ("CGC", an allele combination of rs9399137, rs4895441, and rs9494145) was associated with higher HbF and hemoglobin compared to reference haplotype "TAT". Subjects carrying minor haplotypes showed reduced rate of clinical complications compared to reference haplotypes. Non-carriers of both minor haplotypes for BCL11A and HMIP-2 showed the lowest HbF concentration. Subjects carrying only the minor haplotype of BCL11A showed significantly higher HbF concentration than non-carriers of any minor haplotype, which showed no significant difference compared to subjects carrying only the minor haplotype of HMIP-2. Interestingly, subjects carrying both minor haplotypes of BCL11A ("TCA") and HMIP-2 ("CGC") showed significantly higher HbF levels than subjects carrying only the minor haplotype of BCL11A. Our novel findings suggest that HbF-boosting haplotypes of BCL11A and HMIP-2 can predict clinical outcomes and may interact to regulate HbF in patients with SCA.
© 2022. The Author(s), under exclusive licence to The Japan Society of Human Genetics.