Researchers ID Specific Genetic Marker That Can Lead to SCD Complications

Researchers have pinpointed a specific genetic profile that could help identify sickle cell disease (SCD) patients who are at risk for developing acute chest syndrome (ACS), a common and severe complication of SCD.

One of the major hallmarks of SCD is hemolysis – or breakdown of red blood cells – due to the sickle shape of the cells. As red blood cells contain hemoglobin, when the cells break apart, hemoglobin is released into the blood stream.

When there are high levels of hemoglobin in the blood, it can lead to the development of ACS. In ACS, blood vessels in the lungs become blocked, making it difficult to breathe.

Usually, a protein called haptoglobin will bind the extra hemoglobin and clear it away. However, the effectiveness of haptoglobin depends on the genotype of each patient. Essentially, individuals can have different versions of the same gene. There are three versions, or genotypes, of the haptoglobin (HP) gene in humans: HP1-1, HP1-2, and HP2-2.

The attraction of haptoglobin for free hemoglobin is genotype dependent, and HP2-2 is known to have the lowest binding affinity for hemoglobin and it has been linked to increased cellular damage. So, researchers at Vanderbilt University hypothesized that SCD patients with the HP2-2 genotype will have an increase in occurrence of disease specific complications.

Researchers studied 58 patients between the ages of 19 and 55 and determined that 90% of patients with HP2-2 genotype experience two or more complications, including ACS, pain, stroke, retinal problems in the eyes, kidney disease and high blood pressure in the arteries of the lungs. This was compared to just 46.7% of patients with the HP1-1 genotype and 56.3% with the HP1-2 genotype who experienced two or more complications.

“These findings suggest that adults with the HP2-2 genotype are at an increased risk for SCD complications. Further research is needed to confirm this finding in a larger, prospective fashion and to determine the role of the haptoglobin genotype and the oxidative effect of cell free hemoglobin in the pathophysiology [disease characteristics] of SCD,” the researchers concluded.

Shaina Willen, MD, the study’s lead author, added in a press release, “The impact of the HP2-2 genotype on the ability of haptoglobin to scavenge products of hemolysis may provide therapeutic targets to investigate related to the oxidative effect of cell-free hemoglobin and the pathophysiology of complications in SCD.”

Results from the study were presented at the American Physiological Society’s Physiological and Pathophysiological Consequences of Sickle Cell Disease conference in Washington, D.C., on Nov. 7, in a presentation and an abstract titled, “Haptoglobin Genotype Is Associated with Increased Morbidity in Adults with Sickle Cell Disease.”