Haptoglobin, alpha‐thalassaemia and glucose‐6‐phosphate dehydrogenase polymorphisms and risk of abnormal transcranial Doppler among patients with sickle cell anaemia in Tanzania

Abstract

SummaryTranscranial Doppler ultrasonography measures cerebral blood flow velocity (CBFv) of basal intracranial vessels and is used clinically to detect stroke risk in children with sickle cell anaemia (SCA). Co‐inheritance in SCA of alpha‐thalassaemia and glucose‐6‐phosphate dehydrogenase (G6PD) polymorphisms is reported to associate with high CBFv and/or risk of stroke. The effect of a common functional polymorphism of haptoglobin (HP) is unknown. We investigated the effect of co‐inheritance of these polymorphisms on CBFv in 601 stroke‐free Tanzanian SCA patients aged <24 years. Homozygosity for alpha‐thalassaemia 3·7 deletion was significantly associated with reduced mean CBFv compared to wild‐type (β‐coefficient −16·1 cm/s, P = 0·002) adjusted for age and survey year. Inheritance of 1 or 2 alpha‐thalassaemia deletions was associated with decreased risk of abnormally high CBFv, compared to published data from Kenyan healthy control children (Relative risk ratio [RRR] = 0·53 [95% confidence interval (CI):0·35–0·8] & RRR = 0·43 [95% CI:0·23–0·78]), and reduced risk of abnormally low CBFv for 1 deletion only (RRR = 0·38 [95% CI:0·17–0·83]). No effects were observed for G6PD or HP polymorphisms. This is the first report of the effects of co‐inheritance of common polymorphisms, including the HP polymorphism, on CBFv in SCA patients resident in Africa and confirms the importance of alpha‐thalassaemia in reducing risk of abnormal CBFv.

Minireview: Clinical severity in sickle cell disease: the challenges of definition and prognostication

“…21,22 Its effects on cerebrovascular disease are less clear. Some studies indicate no association between G6PD deficiency and stroke or cerebral vasculopathy, 17,23,24 while others do show an increased frequency of magnetic resonance index (MRI)- or transcranial Doppler (TCD)-defined cerebral vasculopathy. 18,25,26 These conflicting data limit the prognostic utility of G6PD deficiency.…”

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

“…[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.…”

Perspectives in Genetics and Sickle Cell Disease Prevention in Africa: Beyond the Preliminary Data from Cameroon

“…In generalised linear regression models, adjusted for age, sex and HbF-promoting SNPs, the positive effects of the co-inheritance of α-thalassemia on RBC count, MCV and lymphocytes count were still observed among Cameroonian [26]. In addition, among African Americans and Tanzanians, the co-inheritance of α-thalassemia and SCD was associated with a lower stroke risk [27, 28]. …”