Genes regulating fetal hemoglobin could be sickle cell treatment targets
14 genes that regulate fetal hemoglobin in people of African descent discovered
Scientists have discovered more than a dozen genes that regulate the production of fetal hemoglobin in people of African descent, which may be potential treatment targets for sickle cell disease (SCD).
Their findings were reported in the study, “FLT1 and other candidate fetal haemoglobin modifying loci in sickle cell disease in African ancestries,” published in Nature Communications.
SCD is caused by mutations in a gene that’s needed to make hemoglobin, the protein that red blood cells use to carry oxygen through the bloodstream. The mutated hemoglobin is prone to clumping up in red blood cells, deforming them into a sickle-like shape and driving SCD symptoms. SCD affects the adult version of hemoglobin. Fetal hemoglobin, or HbF, is an alternative version of the protein produced during early fetal development. In normal circumstances, HbF’s production is switched off soon after birth, while the adult protein’s is turned on.
Boosting HbF has been used for treating SCD because it can help compensate for the mutated version of the adult protein. For instance, the gene-editing therapy Casgevy (exagamglogene autotemcel), which is approved in the U.S. and other countries, is designed to boost HbF by reducing the activity of BCL11A, a gene that encodes a protein that normally switches off HbF production.
Identifying the genes that regulate HbF production is crucial for designing treatment strategies that seek to increase HbF levels.
Researchers have identified genes that explain roughly 50% of the variance in HbF levels in European populations. But far less has been known about the genetics of HbF regulation in African populations, which is noteworthy given that SCD predominantly affects people of African descent.
Genes linked to fetal hemoglobin in African ancestry patients
Here, scientists analyzed genetic data from 3,751 SCD patients of African descent in Cameroon, Tanzania, and the U.S.
“Finding new genetic variants that could be edited to treat more patients, which would preserve the type of hemoglobin present at birth, is critical for saving more lives,” Ambroise Wonkam, MD, PhD, the study’s corresponding author and professor at the Johns Hopkins University School of Medicine, said in a university press release.
The researchers carried out a genome-wide association study (GWAS), which involves looking for specific genetic variations that are more or less common in people with a particular trait or disease, in this case, higher or lower HbF levels.
The analysis identified several genes previously reported to regulate HbF production, including BCL11A. It also identified 14 genes that hadn’t been reported to regulate HbF production. Taken collectively, they explained more than 90% of the variation in HbF levels.
“Prior to this research, we only knew 10% to 20% of the gene locations that play a role in the production of fetal hemoglobin in African or African-descended individuals, compared with nearly 50% of the variation in genes that regulate fetal hemoglobin in European-descended individuals,” Wonkam said. “With the new genetic markers described in this study, we now know 90% of the genes associated with the production of fetal hemoglobin in sickle cell disease patients of African ancestry.”
Among the newly identified genes, one called FLT1 had the strongest effect. In fact, the association between FLT1 and HbF levels was the third strongest association identified after BCL11A and another previously identified gene called HBS1L-MYB.
“Of the likely new [genes], FLT1 was particularly interesting because it was identified in a population that has not been previously studied genome-wide … and was the third strongest signal after BCL11A and HBS1L-MYB,” the researchers wrote.
The FLT1 gene plays a role in the development of blood cells, lending credence to the idea that it may help control HbF production. Experiments using cell models further supported the idea that it helps regulate HbF. The researchers called for further studies, including mouse experiments and tests using human cells, to characterize the gene’s effects in greater detail and explore its potential as a therapeutic target for SCD.
This study was funded by the National Institutes of Health, the National Cancer Institute, the Childcare Foundation, and the American Lebanese Syrian Associated Charities.
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