Global genetic modifiers of fetal hemoglobin in sickle cell disease: Systematic review and meta-analysis

Fetal hemoglobin (Hb F) is the strongest endogenous modifier of sickle cell disease (SCD) severity, but its genetic regulation varies across populations. This review synthesized evidence on genetic determinants of Hb F and quantified effects of key variants through meta-analysis. Following PRISMA 2020 guidelines (PROSPERO: CRD420251042025), MEDLINE, EMBASE, Scopus, and Web of Science were searched through May 2026. Studies evaluating genetic associations with Hb F levels in SCD were included. Narrative synthesis and random-effects meta-analysis were performed. Eighty-four studies identified 80 variants across 32 genes associated with Hb F levels. The most consistently replicated associations involved BCL11A (rs1427407, rs4671393, and rs11886868), the HBS1L-MYB intergenic region (rs4895441, rs28384513), HBG2 (rs7482144), and HMOX1 (rs2071746). Meta-analysis confirmed directionally consistent associations for seven of eight variants. Additional modifiers included SIN3A , ZBTB7A , ANTXR1 , FOXO3 , BACH2 , and HIF-1α . Hb F regulation in SCD is polygenic and influenced by both canonical and secondary modifiers, supporting genotype-guided therapeutic, and genome-editing strategies.