Baylor Scientist Uses Ingenuity Variant Analysis for Sickle Cell Discovery

Sheehan, Vivien.

Vivien Sheehan, Assistant Professor of Pediatrics at Texas Children’s Hematology Center

When Baylor’s Vivien Sheehan won a grant competition to use QIAGEN’s Ingenuity Variant Analysis, she found an exciting association in sickle cell anemia patients. It revealed a novel gene that can regulate fetal hemoglobin, and opens the door for a possible new drug target.

Sheehan, an Assistant Professor of Pediatrics at Texas Children’s Hematology Center and Baylor College of Medicine, studied hydroxyurea-induced fetal hemoglobin levels in children with sickle cell disease. Unfortunately, not all individuals produce enough fetal hemoglobin in response to hydroxyurea to achieve clinical improvement. Sheehan’s goal was to use the genomics interpretation platform to mine exome sequence data for genetic variants related to endogenous fetal hemoglobin levels and drug response.

Now, Sheehan has crunched data from nearly 180 exomes generated by Baylor’s Human Genome Sequencing Center. As part of her analysis, she looked for variants associated with endogenous fetal hemoglobin levels. “We didn’t find anything with linear association,” she says. But Ingenuity Variant Analysis lets users perform burden analysis, and “in doing that we found that there were variants in a gene called FOXO3 that were associated with a lower baseline fetal hemoglobin,” she adds.

The gene hadn’t come up in previous genome-wide association studies of the disease; it was the deep dive in Sheehan’s study that allowed her to find the link. “You can’t do a burden analysis unless you have the detail of whole exome or whole genome sequencing,” she says.

Data interpretation with Ingenuity Variant Analysis was able to direct Sheehan to a gene called FOXO3 that appears to be linked to the amount of fetal hemoglobin a sickle cell patient produces naturally. In addition, the analysis tool helped steer Sheehan away from a number of red herrings, saving valuable time and focusing her attention on the findings most likely to matter. She followed up with extensive functional studies and confirmed the biological effect of the FOXO3 mutations.

The FOXO3 research continues, particularly because the gene is already targeted by therapeutics on the market. “FOXO3 potentially could be a drug target,” Sheehan says. “There are some quite benign medications that have been shown to upregulate FOXO3, such as resveratrol and more potent antioxidants.” While still years away from potential clinical use, the finding offers a new path that might one day help ease symptoms for sickle cell patients.

To learn more about Sheehan’s project, as well as how she used Ingenuity Variant Analysis, check out her case study.