a-Thalassemia and the BCL11A rs1427407 T allele are commonly observed in sickle cell anemia (SCA) patients and are associated with reduced hemolysis and higher hemoglobin F levels, respectively. We investigated whether a high-risk genetic profile, defined as SCA patients who did not inherit either a-thalassemia or the BCL11A rs1427407 T allele, had stronger associations with clinical and laboratory variables than the individual genetic components in the University of Ibadan cohort (N 5 249). We then replicated our findings in SCA cohorts from the University of Illinois at Chicago (UIC) (N 5 260) and the Walk-Treatment of Pulmonary Hypertension and Sickle Cell Disease with Sildenafil Therapy study (Walk-PHaSST) (N 5 387). A high-risk genetic profile was associated with higher reticulocytes (15.0% vs 7.8%, P 5 .08) and stroke history (6% vs 1%, P 5 .02) than standard-risk patients, and these associations were more significant than the individual genetic components in the University of Ibadan cohort. These findings were replicated in high-risk patients from UIC and Walk-PHaSST for reticulocytes (UIC: 13.5% vs 11.8%, P 5 .03; Walk-PHaSST: 9.6% vs 8.2%, P 5 .0003) and stroke history (UIC: 32% vs 22%, P 5 .07; Walk-PHaSST: 14% vs 7%, P 5 .01). On combined analysis, a high-risk genetic profile had strong associations with increased markers of hemolysis (hemoglobin b 5 –0.29, 95% confidence interval [CI]: 20.50 to 20.09; P5.006; reticulocyte% b 5 2.29, 95% CI: 1.31-3.25; P 5 1 3 1025) and stroke history (odds ratio 5 2.0, 95% CI: 1.3-3.0; P 5 .0002), but no association with frequent vaso-occlusive crises ($3 per year). A high-risk genetic profile is associated with increased hemolysis and stroke history in 3 independent cohorts. This profile may help identify patients to prioritize for hydroxyurea and for closer monitoring strategies for stroke.
ASJC Scopus subject areas