Associations of α-thalassemia and BCL11A with stroke in Nigerian, United States, and United Kingdom sickle cell anemia cohorts

Abstract

Alpha-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 α-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=249). We then replicated our findings in SCA cohorts from the University of Illinois at Chicago (UIC)(n=260) and Walk-Treatment of Pulmonary Hypertension and Sickle cell disease with Sildenafil Therapy (Walk-PHaSST)(n=387). High-risk was associated with higher reticulocytes (15.0% vs. 7.8%, P=0.08) and stroke history (6% vs. 1%, P=0.02) 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=0.03; Walk-PHaSST: 9.6% vs. 8.2%, P=0.0003) and stroke history (UIC: 32% vs. 22%, P=0.07; Walk-PHaSST: 14% vs. 7%, P=0.01). On combined analysis, high-risk had strong associations with increased markers of hemolysis (hemoglobin β= −0.29, 95%CI: −0.50 to −0.09; P=0.006; reticulocyte% β=2.29, 95%CI: 1.31 to 3.25; P=1x10−5) and stroke history (OR=2.0, 95%CI: 1.3 to 3.0; P=0.0002), but no association with frequent vaso-occlusive crises (≥3/year). A high-risk genetic profile is associated with increased hemolysis and stroke history in three independent cohorts. This profile may help identify patients to prioritize for hydroxyurea and for closer monitoring strategies for stroke.

Influence of alpha thalassemia on clinical and laboratory parameters among nigerian children with sickle cell anemia

“…The two α‐globin genes on chromosome 16 are located within a 4‐kb duplicated region leading to the possibility of rearrangements including deletions and triplications with many attendant downstream consequences . The present study confirmed earlier reports that the 3.7 κb α‐globin gene deletion is the common α‐thal allele among Africans as none of the participants had the 4.2Kb α‐globin gene deletion.…”

“…The observed hematological profile of patients with α‐thal in this study has been previously described . The increased Hb and red blood cell count are due to the decrease in the intracellular concentration of HbS, and number of dense red blood cells .…”

“…The prevalence of alpha thalassemia among patients in this study (41%) is comparable to between 37% and 46% earlier described among mixed populations of SCA patients from France and West Africa . This is however higher than the 13%‐28% described among patients in the Americas .…”

“…Although several studies have described the possible effects of α‐thal among patients with SCA in the developed world, there is paucity of information about the influence of this genetic factor in African patients with SCA. Although the few available studies from Africa have established that the 3.7 κb α‐globin gene deletion is the common α‐thal allele among the African population, nonetheless, there is lack of consensus on its impacts on the laboratory and clinical manifestations of patients with SCA …”

Genetic modifiers of long‐term survival in sickle cell anemia

“…5 Similarly, co-inheritance of α-thalassemia is protective against some SCD-related complications, such as hemolysis, stroke, and kidney disease. 6,7 Availability of appropriate comprehensive medical care for SCD that combines newborn screening, penicillin prophylaxis, screening for stroke risk, transfusion program, and the use of hydroxyurea, in high income countries, usually mitigates morbidity and facilitates longer survival of SCD patients. 8 This is, however, not the case in most of SSA, due to the combined effect of inappropriate care and often severe clinical complications, 7,9 compounded by other factors such as malaria, malnutrition, infectious diseases of childhood, and poverty.…”