Influence of the βs haplotype and α-thalassemia on stroke development in a Brazilian population with sickle cell anaemia

Abstract

Stroke is a catastrophic complication of sickle cell anaemia (SCA) and is one of the leading causes of death in both adults and children with SCA. Evidence suggests that some genetic polymorphisms could be related to stroke development, but their association remains controversial. Here, we performed genotyping of five published single nucleotide polymorphisms, the α-thalassemia genotype, the G6PD A (-) variant deficiency, and the β(S) haplotype in a large series of SCA patients with well-defined stroke phenotypes. Of 261 unrelated SCA patients included in the study, 67 (9.5 %) presented a documented, primary stroke event. Markers of haemolysis (red blood cell (RBC) counts, p = 0.023; reticulocyte counts, p = 0.003; haemoglobin (Hb) levels, p < 0.001; indirect bilirubin levels, p = 0.006; lactate dehydrogenase (LDH) levels, p = 0.001) were associated with stroke susceptibility. Genetically, only the β(S) haplotype (odds ratio (OR) 2.9, 95 % confidence interval (CI) 1.56 to 4.31; p = 0.003) and the α(3.7kb)-thalassemia genotype (OR 0.31, 95 % CI 0.11 to 0. 83; p = 0.02) were associated with increased and decreased stroke risk, respectively. In multivariate analysis, the β(S) haplotype was independently associated with stroke development (OR 2.26, 95 % CI 1.16 to 4.4; p = 0.016). Our findings suggest that only the β(S) haplotypes and the α(3.7kb)-thalassemia genotype modulate the prevalence of stroke in our SCA population. Genetic heterogeneity among different populations may account for the irreproducibility amongst different studies.

Clinical and haematological risk factors for cerebral macrovasculopathy in a sickle cell disease newborn cohort: a prospective study

“…We did not observe a statistical association between a-thalassaemia and CV as in other studies in which the presence of a-thalassaemia was found to be protective against stroke (Flanagan et al, 2011;Domingos et al, 2014) or CV (Hsu et al, 2003;Bernaudin et al, 2008;Steinberg & Sebastiani, 2012). This could be due to the lack of power of our ancillary analysis, as the number of patients was lower than in the main analysis.…”

Glucose‐6‐Phosphate Dehydrogenase Deficiency in Brazilian Children With Sickle Cell Anemia is not Associated With Clinical Ischemic Stroke or High‐Risk Transcranial Doppler

“…The prevalence of clinical ischemic stroke or high-risk TCD was not significantly different in the groups with and without G6PD molecular deficiency. This lack of association has been reported in almost all studies that used molecular analysis as the method for characterizing G6PD deficiency [5,10,12,13] and is biologically plausible because male A − or female A − A − genotypes (95% of 140 children investigated in these four studies) are known to lead to a mild or moderate reduction in G6PD activity, as demonstrated in our study. A single study reported that 376G or 202A alleles were independent risk factors for intracranial magnetic resonance angiography (MRA) arteriopathy in males with SCA.…”

“…[3] However, contradictory results have been reported and the impact of G6PD deficiency on the phenotype of SCA is unknown, [4][5][6] particularly its influence on cerebral vasculopathy. [6][7][8][9][10][11][12][13][14][15] We aimed to investigate the association of clinical ischemic stroke, high-risk transcranial Doppler measurements (TCD), and hematological features with molecular variants usually linked to G6PD deficiency or with the biochemical activity of G6PD in a cohort of 395 Brazilian children with SCA.…”

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

“…4,12 Furthermore, the effects of α-thalassemia on cerebral vasculopathy and stroke risk in SCA have been mixed with some studies showing a protective benefit 13–18 while others have not. 10,19–21 In the University of Ibadan cohort of SCA patients, α-thalassemia was commonly observed but was not associated with a statistically significant reduction in the frequency of SCA-related complications.…”