News Room

The gene variants influence blood levels of fetal hemoglobin (HbF), which are known to affect symptom severity in sickle cell disease--with some patients experiencing frequent, severe pain crises and organ damage, while others are scarcely aware of their disease.

"Our study is a first step towards a better understanding of fetal hemoglobin regulation in patients with sickle cell disease," says Guillaume Lettre, PhD, of the Broad Institute and Children's Hospital Boston, and co-first author on the paper. "But further validation experiments are needed before these findings can become useful in the clinic."

"Eventually, understanding the factors giving rise to heterogeneity in HbF levels might allow us to take severely affected patients and make them more like those with more benign symptoms," adds Vijay Sankaran, co-first author on the paper with Lettre and an MD-PhD student in the laboratory of Stuart Orkin, MD. (Orkin is chair of pediatric oncology at DFCI and a Howard Hughes Medical Institute investigator at Children's.)

Previous research had established that retaining high levels of another type of hemoglobin--HbF, found at high levels in the fetus' can ameliorate sickle cell disease symptoms. At birth, HbF comprises between 50 to 95 percent of a child's hemoglobin, gradually declining as the switch is made to adult hemoglobin production--consistent with clinicians' observations that newborns diagnosed with sickle cell disease usually do not become symptomatic until they are about a year old. Population studies in Saudi Arabia and parts of India had identified groups of sickle cell patients with very high levels of HbF and relatively benign forms of the disease, and additional epidemiologic studies led by Orah Platt, MD, chief of laboratory medicine at Children's, showed that HbF is an ameliorating factor. "The more you have, the better off you are," says Sankaran.

The findings need to be validated in large, prospective clinical studies, but the researchers are hopeful about the possible future clinical implications of their work. "As we find gene variants that regulate HbF levels or predict severity, we might eventually want to genotype patients for these variants, to get more predictive information on their disease," Sankaran says.

Finally, once this study is validated, understanding how these variants actually affect HbF levels might someday lead to new drugs that do the same thing. "If we can gain better insight into what these variants are doing, we may eventually have better, more targeted therapies for sickle cell disease," adds Sankaran.

Lettre and Sankaran shared first authorship of the paper. Orkin and Joel Hirschhorn, MD, PhD, of Children's and the Broad Institute, were senior authors.

This study was funded by grants from the National Heart, Lung and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, and the Howard Hughes Medical Institute.

Contact:
Bess Andrews
617-919-3110
elizabeth.andrews@childrens.harvard.edu

Children's Hospital Boston is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 500 scientists, including eight members of the National Academy of Sciences, 11 members of the Institute of Medicine and 12 members of the Howard Hughes Medical Institute comprise Children's research community. Founded as a 20-bed hospital for children, Children's Hospital Boston today is a 397-bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. Children's also is the primary pediatric teaching affiliate of Harvard Medical School. For more information about the hospital and its research visit: www.childrenshospital.org/newsroom.