Reduced rate of sickle‐related complications in Brazilian patients carrying HbF‐promoting alleles at the BCL11A and HMIP‐2 loci

Abstract

The presence of high levels of fetal haemoglobin (HbF) provides well-validated clinical benefits to patients with sickle cell anaemia (SCA). Nevertheless it has been difficult to show clear direct effects of the known genetic HbF modifiers, such as the enhancer polymorphisms for haematopoietic transcription factors BCL11A and MYB, on SCA severity. Investigating SCA patients from Brazil, with a high degree of European genetic admixture, we have detected strong effects of these variants on HbF levels. Critically, we have shown, for the first time, that the presence of such HbF-promoting variants leads to a reduced rate of SCA complications, especially stroke.

The association of HBG2, BCL11A, and HMIP polymorphisms with fetal hemoglobin and clinical phenotype in Iraqi Kurds with sickle cell disease

“…In the present study, MAF of rs9399137 is 0.137, which is among the highest frequencies observed in SCD populations (Table ). This SNP has been reported to be associated with HbF levels in other populations, including Indian, African American, Cameroonian, Tanzanian, British, and Eastern and Southern Brazilian patients, but not in Saudi Arabian or North Brazilian SCD patients …”

g(HbF): a genetic model of fetal hemoglobin in sickle cell disease

“…10,[22][23][24] To represent the relationship between genetic factors and HbF more accurately and to build a summary variable that is robust across diverse SCD cohorts, we used regression modeling of the effect of 7 known modifier variants (Table 1) on HbF levels in 581 SCD patients with HbSS and HbSb 0 genotypes. We targeted genetic variants at the 3 major HbF loci that have been widely replicated and implicated as causative genetic variants.…”

Clinical and genetic factors are associated with pain and hospitalisation rates in sickle cell anaemia in Cameroon

“…Variants in HbF-promoting loci have been associated with higher total haemoglobin concentrations and lower leucocyte counts (Sheehan et al , 2013; Mtatiro et al , 2014), as well as lower VOC and composite endpoints, such as hospitalisations (Lettre et al , 2008; Sheehan et al , 2013; Leonardo et al , 2016). Co-inheritance of α-thalassaemia is protective against some SCD-related complications, such as acute chest syndrome, leg ulcers and chronic kidney disease (Geard et al , 2017; Higgs et al , 1982; Guasch et al , 1999), but convey similar or higher rates of VOC (Meier et al, 2017; Platt et al , 1991; Darbari et al , 2013; Darbari et al , 2012; Tarer et al , 2006).…”