Among individuals diagnosed with sickle cell anemia (SCA), newly discovered regulatory mechanisms for fetal hemoglobin regulation may offer novel avenues for therapeutic intervention, according to research published in Frontiers in Genetics.

SCA, an inherited blood disorder, is defined by a single point mutation in Hbb, which leads to sickling of the red blood cells. There is, however, significant heterogeneity in individuals presenting with SCA, despite the seemingly simple genetic cause.

Previous research has established that a patient’s circulating immune cells play a role in the development of cardiovascular diseases — a finding that may have important implications for patients with SCA, who are at a heightened risk of these diseases.

Continue Reading

For this study, researchers aimed to evaluate whether, among patients with SCA, circulating immune cells express genes different to those mediating the SCA phenotype, and further to identify potential therapeutic targets through peripheral blood whole transcriptome profiling in pediatric patients. All sequencing data were compared with those of a group obtained from healthy controls.

Overall, data from 46 patients with SCA who underwent sequencing were included. The mean age of patients with SCA was 8.4 years, 17 patients were female sex, and mean hemoglobin beta levels were 8.83 g/dL.

Between patients with SCA and controls, 223 genes were differentially expressed, and differential transcript expression was noted in 441 genes (for false discovery rate P <.001). Patients with SCA also had higher gamma globin gene expression (HGB1, 33-fold increase; HGB2, 49-fold increase; P for false discovery rate < .05). The higher gamma globin gene expression did not covary with hemoglobin F protein levels.

The novel non-coding RNA gene, RYR2, may, according to the authors’ analysis, have a regulatory role in both HBG1 and HBG2 expression levels. JHDM1D-AS1(KDM7A-DT), GATA1, and JAK-STAT all independently correlated with HBG1 and HBG2 mRNA levels.

“Taken together, these data show the depth of biological information to be extracted from RNA-sequencing studies of SCA patients,” the authors wrote.


Gee BE, Pearson A, Buchanan-Perry I, Simon RP, Archer DR, Meller R. Whole blood transcriptome analysis in children with sickle cell anemia. Front Genet. 2022;12:737741. doi:10.3389/fgene.2021.737741