Researchers at Providence Research have identified early molecular differences in newborns with sickle cell trait (SCT), challenging a long-held belief that the condition has no measurable biological effects during infancy.
Using a multi-omics approach and data collected from newborns in The Gambia, a study led by Providence Researcher Dr. Abhinav K. Checkervarty found that babies with SCT showed distinct biological changes within their first week of life, including lower levels of several blood proteins by the third day after birth.
The findings provide new insight into a condition that affects millions of people worldwide and highlight Providence Research’s role in advancing early life and blood disorder research. While newborns with SCT do not develop sickle cell disease and typically show no symptoms, the study suggests that measurable biological differences may be present from birth.
Study grew out of vaccine research
Checkervarty’s research did not begin as a sickle cell study, but as part of a project examining how newborns respond to the hepatitis B vaccine. The dataset included blood samples from newborns across the first week of life, specifically four distinct time points: birth (Day of Life (DOL) 0), DOL1, DOL3, and DOL7.
While exploring how blood disorders might influence vaccine response, the team noticed something unexpected: SCT newborns showed consistent molecular changes at DOL3. This observation redirected the study toward a new question: Does SCT leave a measurable biological signature in early life, even before symptoms appear?
Finding new value in discarded data
One of the study’s most innovative contributions was its use of sequencing data that is normally thrown away during genetic analysis. In standard blood transcriptomics, pieces of globin RNA sequence data, known as ‘reads’, are routinely removed because they overwhelm other gene signals. The team realized that these discarded reads could be repurposed to genotype newborns for SCT.
“We looked at the reads that are usually removed, and found it was possible, using RNA, to identify neonates with sickle cell trait,” says Dr. Checkervarty.
Because the approach uses data that has already been collected, it could help researchers learn more about SCT using existing datasets from regions where the trait is common.
Lower protein levels observed on DOL 3
The clearest finding of the study was a broad decrease in plasma protein levels among SCT newborns on DOL3. Four proteins that showed statistically significant changes are linked to liver function, vascular biology, and sickle cell pathophysiology.
“Protein down-regulation at day three was very unexpected,” says Checkervarty. The cause of this shift remains unknown, but the persistence of the pattern – even when the comparison was repeated using size-matched groups, provides an important avenue for future investigation.
Pathways mirror those seen in older SCT and sickle cell disorder patients
The researchers also found differences in gene activity during the first week of life. More than 2,000 groups of genes were active, including 149 linked to biological processes known to play a role in sickle cell conditions, such as blood function, oxidative stress, and pathways associated with the kidneys and liver. These findings suggest that some of the biological changes associated with SCT can be detected from birth and may be connected to effects on the kidneys and liver that have been observed in older individuals with SCT.
One of the strongest signals identified was a biological pathway previously linked to adults with sickle cell disease. Finding this pathway in newborns was unexpected and supports the idea that SCT-associated biology is detectable from birth – even if clinical symptoms do not appear until later.
The study used a “multi-omics” approach, combining information from genes, proteins and other molecules in the body. This allowed researchers to see biological connections that might be missed when examining only one type of data at a time.
“Genes do not work alone,” says Checkervarty. “Multi-omics showed more biologically relevant pathways.”
What the findings could mean
Although the study was exploratory, the findings challenge the long-held belief that SCT has no biological effects in early life. Despite the absence of symptoms, researchers found measurable molecular differences between newborns with SCT and those without the trait within days of birth, including pathways linked to renal, hepatic, and oxidative stress. These are the same systems implicated in adult SCT complications, raising the question of whether these early differences relate to complications reported later in life.
The work also highlights how existing data can reveal new insights. Because the approach does not require additional genetic sequencing, researchers may be able to re-examine datasets that already exist in regions where SCT is common.
In the future, if these early biological signatures are shown to predict later health outcomes, they could help guide how children with SCT are monitored. However, more research is needed before the findings can be used in clinical care.
Limitations and next steps
While these findings are significant, Checkervarty emphasized that this was an exploratory study and not a clinical trial. The researchers did not control for some environmental and social factors, the validation group was relatively small, and the mechanisms underlying the observed protein changes remain unknown.
For Checkervarty, future work includes replicating these findings in other regions where SCT is prevalent, following newborns for months or years to better understand how early molecular signatures relate to later outcomes, and expanding the analysis to other blood disorders such as thalassemia, an inherited blood disorder associated with anaemia.
Checkervarty hopes that “other people working in blood research will pick up on it, that the publicly available dataset will spark collaboration… and take this study further.”
Story by Tyla Casey-Knight, Providence Research
