Now Madrigal and colleagues have proposed one possible reason for this variation. In the May issue of the Southern Medical Journal, Madrigal and a team of biological anthropologists, a geneticist, and medical doctors show that a small set of gene variants might control the severity of SCT’s effects. Monitoring for those genes, they argue, could reveal who is at highest risk and promote understanding of this often overlooked medical problem.
A handful of genes are known to change the medical outcomes for people with sickle cell anemia, in particular those genes that modify the amount of a protein called fetal hemoglobin in the blood. The more fetal hemoglobin patients have (as opposed to adult hemoglobin), the more oxygen their bodies have access to and the better they do in the face of anemia caused by blood sickling. “We have known that for decades,” Madrigal says. Perhaps these same genes, she thought, might also impact outcomes for people with SCT.
Madrigal’s team worked with about 30 U.S. football players with SCT. The researchers asked them whether, in comparison with their non-SCT teammates, they experienced extreme thirst, full-body muscle cramps, or pain more often or more intensely. They also took cheek swabs and tested for seven mutations in each player’s genome that are known to be associated with fetal-hemoglobin levels. The results, Madrigal says, were “dramatic.” Those participants with genetic dispositions for less fetal hemoglobin had more symptoms, including a diagnosis of blood sickling, whereas those with genetic dispositions for more fetal hemoglobin had built up more muscle mass.
Madrigal admits that the study is small, and she says there is much they’d like to study further, including checking any stored tissue from deceased players for these gene variants and directly testing fetal-hemoglobin levels from blood samples. “This is preliminary data,” she says, obtained with a small grant.
It was “very, very difficult” to get participants, Madrigal adds, because SCT is stigmatized in the football community. Athletes are reluctant to be seen or treated differently because of their trait, Madrigal says. “We know there are a lot of athletes that are getting sidelined or not allowed to play because they have SCT,” says Beverley Francis-Gibson, president of the Sickle Cell Disease Association of America, in Baltimore.
“I think it is believable and worthy of further study,” says James Taylor of the new results; Taylor is the director of the Center for Sickle Cell Disease at Howard University Hospital in Washington, D.C. The proposed mechanism is plausible, he notes: “Fetal hemoglobin might provide an extra buffer.” But further work is needed to prove the connection. “For population genetics, this [sample size] is ridiculously small,” he says.
SCT is often misunderstood, even in the medical community, Taylor says. For one, many doctors see SCT as essentially asymptomatic—a belief that the new work could help change. “I think this is something that has been glossed over,” Taylor says. “I don’t think we should make SCT a disease, but it is a risk factor.”