Five Gene Variants Help Predict Sickle Cell Disease Severity

Although sickle cell disease is a single-gene disorder, its symptoms are highly variable. Some patients experience frequent, severe pain crises and organ damage, whereas others are scarcely aware of the disease.

Retaining high levels of HbF can ameliorate sickle cell disease symptoms. At birth, HbF comprises between 50 to 95% of a child's hemoglobin, gradually declining as the switch is made to adult hemoglobin production. This is consistent with clinicians' observations that newborns diagnosed with sickle cell disease usually do not become symptomatic until they are about a year old.

Scientists studied 1600 patients with sickle cell disease, and found that previously identified DNA sequence variants in three chromosome locations (small regions on chromosome 2, 6, and 11) were associated with high or low HbF levels. When they added these five variants to a model previously designed to predict disease severity, the model's predictive ability was enhanced.

In sickle cell disease, a single genetic mutation results in the production of an abnormal type of hemoglobin, the main component of red blood cells. The abnormal hemoglobin molecules tend to form long chains, causing red blood cells to become stiff and sickle-shaped. The distorted cells have difficulty passing through blood vessels and can block the smaller vessels, resulting in severe pain and eventual organ damage as tissues are robbed of their blood supply. The sickle-shaped red blood cells also have a very short lifespan, causing patients to be chronically anemic.

The study was performed by scientists at Children's Hospital Boston (MA, USA) and the Dana Farber Cancer Institute (DFCI; Boston, MA, USA), in collaboration with the Broad Institute of MIT and Harvard (Boston, MA, USA). It was published online in the July 14, 2008 edition of the Proceedings of the [U.S.] National Academy of Sciences (PNAS).

Our study is a first step towards a better understanding of fetal hemoglobin regulation in patients with sickle cell disease, said Guillaume Lettre, Ph.D., 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.


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