Genetic modulators of fetal hemoglobin expression and ischemic stroke occurrence in African descendant children with sickle cell anemia
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Sickle cell anemia (SCA) is an autosomal recessive monogenic disease with significant clinical variability. Cerebrovascular disease, particularly ischemic stroke, is one of the most severe complications of SCA in children. This study aimed to investigate the influence of genetic variants on the levels of fetal hemoglobin (Hb F) and biochemical parameters related with chronic hemolysis, as well as on ischemic stroke risk, in ninety-one unrelated SCA patients, children of sub-Saharan progenitors. Our results show that a higher Hb F level has an inverse relationship with the occurrence of stroke, since the group of patients who suffered stroke presents a significantly lower mean Hb F level (5.34 ± 4.57% versus 9.36 ± 6.48%; p = 0.024). Furthermore, the co-inheritance of alpha-thalassemia improves the chronic hemolytic pattern, evidenced by a decreased reticulocyte count (8.61 ± 3.58% versus 12.85 ± 4.71%; p < 0.001). In addition, our findings have confirmed the importance of HBG2 and BCL11A loci in the regulation of Hb F expression in sub-Saharan African SCA patients, as rs7482144_A, rs11886868_C, and rs4671393_A alleles are significantly associated with a considerable increase in Hb F levels (p = 0.019, p = 0.026, and p = 0.028, respectively). Concerning KLF1, twelve different variants were identified, two of them novel. Seventy-three patients (80.2%) presented at least one variant in this gene. However, no correlation was observed between the presence of these variants and Hb F level, severity of hemolysis, or stroke occurrence, which is consistent with their in silico-predicted minor functional consequences. Thus, we conclude that the prevalence of functional KLF1 variants in a sub-Saharan African background does not seem to be relevant to SCA clinical modulation.
KeywordsSickle cell anemia Fetal hemoglobin Cerebrovascular disease KLF1 gene Genetic risk factors
The authors wish to thank the SCA patients and their parents for their participation in this study.
MN, SV, MS, AC, and EF performed the molecular work and analyzed results; SV and AC also collected data and populating database; JM and LV performed NGS experiments and analyzed data; PK, RM, RS, AD, TF, AM, and IMS participated in clinical enrolling/work-up of patients. JL acquired funding and performed a critical revision of the manuscript. PF conceived and designed the experiments, supervised the molecular analysis, and drafted the manuscript. All authors (except AM†) revised and approved the manuscript final version.
This work was partially funded by Fundação para a Ciência e a Tecnologia (FCT) grant PIC/IC/83084/2007, ISAMB, and INSA project 2012DGH720. Additionally, it is a result of the GenomePT project (POCI-01-0145-FEDER-022184), supported by COMPETE 2020 - Operational Programme for Competitiveness and Internationalisation (POCI), Lisboa Portugal Regional Operational Programme (Lisboa2020), Algarve Portugal Regional Operational Programme (CRESC Algarve2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF), FCT.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
This study was conducted in accordance with the ethical standards of the institutional review board and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all patients’ legal representatives for being included in the study.
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