July 03, 2017
3 min read

Gene profile may predict risk for stroke in sickle cell anemia

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Sickle cell anemia patients with -thalassemia and the gene expression BCL11A rs1427407 T may be at greater risk for hemolysis and stroke than those without the variants, according to an analysis of three independent cohorts published in Blood Advances.

“Our goals were to incorporate individual genetic predictors of sickle cell disease severity into a risk profile to better predict which patients are at higher risk for sickle cell-related complications,” Santosh L. Saraf, MD, assistant professor of medicine in the department of hematology and oncology at University of Illinois at Chicago, told HemOnc Today. “A high-risk genetic profile can allow us to focus resources, such as hydroxyurea or red blood cell transfusion therapy, in those patients that have a greater likelihood of developing severe complications.”

Sickle cell anemia — an inherited red blood cell disorder that affects more than 25 million people worldwide — is caused by a mutation in the -globin chain that leads to vaso-occlusion and chronic hemolysis.

Coinheritance of α-thalassemia is observed in about one-third of patients with sickle cell anemia and is associated with reduced hemolysis and protection against some sickle cell anemia–related complications. The BCL11A rs1427407 T variant also is commonly observed and may modify sickle cell disease severity by increasing fetal hemoglobin levels.

Saraf and colleagues sought to determine if a genetic risk profile based on the coinheritance of -thalassemia and BCL11A rs1427407 T variants influences laboratory and clinical variables in a cohort of patients treated in three independent cohorts: University of Ibadan in Nigeria (n = 249; median age, 19 years; 53% male), University of Illinois (n = 260; median age, 31 years; 58% female) and the multicenter Walk-Treatment of Pulmonary Hypertension and Sickle Cell Disease with Sildenafil Therapy study (Walk-PHaSST; n = 387; mean age, 35 years; 52% female).

High-risk patients included those without -thalassemia and BCL11A rs1427407 T, whereas standard-risk patients had either allele or both.

-Thalassemia appeared associated with lower white blood cell counts, and BCL11A rs1427407 T appeared associated with higher hemoglobin concentration.

In the University of Ibadan cohort, patients with a high-risk genetic profile had higher reticulocytes (15% vs. 7.8%) and stroke history (6% vs. 1%; P = .02) than standard-risk patients.

Researchers replicated those findings in high-risk patients from University of Illinois (reticulocytes, 13.5% vs. 11.8%; P = .03; stroke history 32% vs. 22%) and Walk-PHaSST (reticulocytes, 9.6% vs. 8.2%; P = .0003; stroke history 14% vs. 7%; P = .01).


On a combined analysis of all three cohorts, a high-risk genetic profile appeared strongly associated with increased markers of hemolysis (hemoglobin = –0.29; 95% CI, –0.5 to –0.09; P = .006; reticulocyte percentage = 2.29; 95% CI, 1.31-3.25; P = 1 x 10–5) and stroke history (OR = 2; 95% CI, 1.3-3; P = .0002) but not with frequent vaso-occlusive crises (3 or more per year).

“The biggest takeaway is that two genetic variants that affect the degree of hemolysis predict stroke risk in three independent cohorts of sickle cell disease patients from Africa, the United States and England,” Saraf said. “This can allow us to risk stratify patients with sickle cell disease and provide insight into the pathophysiology of sickle cell-related complications.”

Future studies to evaluate whether this genetic risk profile can detect patients with sickle cell anemia who have a higher risk for stroke may also help prioritize hydroxyurea therapy and transfusion strategies, particularly in low-resource areas, where sickle cell anemia is most prevalent, Saraf said.

“Our findings have the potential to risk stratify patients for monitoring (eg, neuroimaging or transcranial dopplers) and treatment strategies (hydroxyurea, red blood cell transfusion) for sickle cell-related complications,” Saraf said. – by Chuck Gormley

For more information:

Santosh L. Saraf, MD, can be reached at Division of Hematology and Oncology, Department of Medicine, University of Illinois at Chicago, 820 South Wood St., MC 712, Chicago, IL 60612; email: ssaraf@uic.edu.

Disclosure: Doris Duke Charitable Foundation, NHLBI and NIH funded this study. The researchers report no relevant financial disclosures.