Genetic Polymorphisms Associated with Fetal Hemoglobin (HbF) Levels and F-Cell Numbers: A Systematic Review of Genome-Wide Association Studies

Abstract

Elevated fetal hemoglobin (HbF), which is partly controlled by genetic modifiers, ameliorates disease severity in β hemoglobinopathies. Understanding the genetic basis of this trait holds great promise for personalized therapeutic approaches. PubMed, MedRxiv, and the GWAS Catalog were searched up to May 2024 to identify eligible GWAS studies following PRISMA guidelines. Four independent reviewers screened, extracted, and synthesized data using narrative and descriptive methods. Study quality was assessed using a modified version of the Q-Genie tool. Pathway enrichment analysis was conducted on gene lists derived from the selected GWAS studies. Out of 113 initially screened studies, 62 underwent full-text review, and 16 met the inclusion criteria for quality assessment and data synthesis. A total of 939 significant SNP-trait associations (p-value < 1 × 10^-5) were identified, mapping to 133 genes (23 with overlapping variant positions) and 103 intergenic sequences. Most SNP-trait associations converged around BCL11A (chr.2), HBS1L-MYB, (chr.6), olfactory receptor and beta globin (HBB) gene clusters (chr.11), with less frequent loci including FHIT (chr.3), ALDH8A1, BACH2, RPS6KA2, SGK1 (chr.6), JAZF1 (chr.7), MMP26 (chr.11), COCH (chr.14), ABCC1 (chr.16), CTC1, PFAS (chr.17), GCDH, KLF1, NFIX, and ZBTB7A (chr.19). Pathway analysis highlighted Gene Ontology (GO) terms and pathways related to olfaction, hemoglobin and haptoglobin binding, and oxygen carrier activity. This systematic review confirms established genetic modifiers of HbF level, while highlighting less frequently associated loci as promising areas for further research. Expanding research across ethnic populations is essential for advancing personalized therapies and enhancing outcomes for individuals with sickle cell disease or β-thalassemia.

Keywords: F cells; GWAS; SNP; beta thalassemia; fetal hemoglobin (HbF); genetic modifier; sickle cell disease (SCD); systematic review.

Figure 1

PRISMA flow diagram.

Figure 2

Gene mapping and functional annotation of the selected SNP set (found in ≥two papers) using snpXplorer. (A) Pie plot shows variant annotations, classified as coding (green), eQTL (blue), or annotated by their genomic position (orange). It informs about variant effect, i.e., a direct effect on protein sequence in the case of coding SNPs, or a regulatory effect in the case of eQTLs or intergenic SNPs. (B) Barplot shows the number of genes associated with each SNP. Variant-gene mapping might associate multiple genes to a single SNP, depending on the effect and position of each SNP. (C) Plot shows the chromosomal distribution of SNPs. (D) The circular summary figure shows the type of annotation of each SNP used as input (coding, eQTL, or annotated by their positions) as well as each SNP’s minor allele frequency (MAF) and chromosomal distribution (numbers 1–22 on the outer ring). (E) Fraction of SNPs associated with traits from the GWAS Catalog, estimated by averaging fractions across 500 iterations of sampling one gene per variant to correct for multiple genes being associated with a single variant.

Figure 3

Enrichment analysis in g.Profiler. (A) Gene set from selected SNP list (‘genes_G’); (B) Gene set compiled from experimental evidence (‘genes_E’).

Figure 3

Enrichment analysis in g.Profiler. (A) Gene set from selected SNP list (‘genes_G’); (B) Gene set compiled from experimental evidence (‘genes_E’).