Fetal hemoglobin (HbF) ameliorates clinical severity of sickle cell anemia (SCA). The major loci regulating HbF levels are HBB cluster, BCL11A, and HMIP-2 (HBS1L-MYB). However, the impact of noncoding single-nucleotide polymorphisms (SNPs) in these loci on clinical outcomes and their functional role on regulating HbF levels should be better elucidated. Therefore, we performed comprehensive association analyses of 14 noncoding SNPs in five loci with HbF levels and with clinical outcomes in a cohort of 250 children with SCA from Southeastern Brazil, and further performed functional annotation of these SNPs. We found SNPs independently associated with HbF levels: rs4671393 in BCL11A (β-coefficient = 0.28), rs9399137 in HMIP-2A (β-coefficient = 0.16), and rs4895441 in HMIP-2B (β-coefficient = 0.15). Patients carrying minor (HbF-boosting) alleles for rs1427407, rs93979137, rs4895441, rs9402686, and rs9494145 showed reduced count of reticulocytes (p < 0.01), while those carrying the T allele of rs9494145 showed lower white blood cell count (p = 0.002). Carriers of the minor allele for rs9402686 showed higher peripheral saturation of oxygen (p = 0.002). Patients carrying minor alleles in BCL11A showed lower risk of transfusion incidence rate ratio (IRR ≥ 1.3; p < 0.0001). This effect was independent of HbF effect (p = 0.005). Carriers of minor alleles for rs9399137 and rs9402686 showed lower risk of acute chest syndrome (IRR > 1.3; p ≤ 0.01). Carriers of the reference allele for rs4671393 showed lower risk of infections (IRR = 1.16; p = 0.01). In conclusion, patients carrying HbF-boosting alleles of BCL11A and HMIP-2 were associated with milder clinical phenotypes. Higher HbF concentration may underlie this effect.

胎儿血红蛋白 (HbF) 可改善镰状细胞性贫血 (SCA) 的临床严重程度。调节 HbF 水平的主要位点是HBB簇、BCL11A和 HMIP-2 ( HBS1L-MYB )。然而，应该更好地阐明这些基因座中非编码单核苷酸多态性 (SNP) 对临床结果的影响及其在调节 HbF 水平方面的功能作用。因此，我们对来自巴西东南部的 250 名患有 SCA 的儿童队列中的 5 个基因座中的 14 个非编码 SNP 与 HbF 水平和临床结果进行了全面的关联分析，并进一步对这些 SNP 进行了功能注释。我们发现与 HbF 水平独立相关的 SNP：BCL11A 中的rs4671393（β-系数 = 0.28）、HMIP-2A 中的 rs9399137（β 系数 = 0.16）和 HMIP-2B 中的 rs4895441（β 系数 = 0.15）。携带次要（HbF的升压）为rs1427407，rs93979137，rs4895441，rs9402686，和rs9494145等位基因的患者显示出降低的网织红细胞（计数p <0.01），而输送rs9494145的T等位基因显示出较低的白血细胞数（p = 0.002） . rs9402686 次要等位基因的携带者表现出较高的外周氧饱和度 ( p = 0.002)。携带BCL11A次要等位基因的患者输血发生率比率较低（IRR ≥ 1.3；p < 0.0001）。这种效应独立于 HbF 效应（p= 0.005）。rs9399137 和 rs9402686 的次要等位基因携带者患急性胸部综合征的风险较低（IRR > 1.3；p ≤ 0.01）。rs4671393 参考等位基因的携带者感染风险较低（IRR = 1.16；p = 0.01）。总之，携带BCL11A和 HMIP-2 的HbF 增强等位基因的患者与较温和的临床表型相关。较高的 HbF 浓度可能是这种效应的基础。