Abstract

BACKGROUND

Sickle cell anemia (SCA) is a clinically heterogeneous, monogenic disorder. Medical care has less-than-optimal impact on clinical outcomes in SCA in Africa due to several factors, including patient accessibility, poor access to resources, and non-availability of specific effective interventions for SCA.

METHODS

Against this background, we investigated 192 African participants who underwent whole exome sequencing. Participants included 105 SCA patients spanning variable clinical expression: a "long survivor" group (age over 40 years), a "stroke" group (at least one episode of overt stroke), and a "random" group (patients younger than 40 years without overt cerebrovascular disease). Fifty-eight ethnically matched homozygous hemoglobin A controls were also studied. Findings were validated in an independently recruited sample of 29 SCA patients. Statistical significance of the mutational burden of deleterious and loss-of-function variants per gene against a null model was estimated for each group, and gene-set association tests were conducted to test differences between groups.

RESULTS

In the "long survivor" group, deleterious/loss-of-function variants were enriched in genes including CLCN6 (a voltage-dependent chloride channel for which rare deleterious variants have been associated with lower blood pressure) and OGHDL (important in arginine metabolism, which is a therapeutic target in SCA). In the "stroke" group, significant genes implicated were associated with increased activity of the blood coagulation cascade and increased complement activation, for example, SERPINC1, which encodes antithrombin. Oxidative stress and glutamate biosynthesis pathways were enriched in "long survivors" group. Published transcriptomic evidence provides functional support for the role of the identified pathways.

CONCLUSIONS

This study provides new gene sets that contribute to variability in clinical expression of SCA. Identified genes and pathways suggest new avenues for other interventions.

MeSH

Stroke, Anemia, Sickle Cell, Cells, Clinical Medicine, Genes, Blood, Hemoglobin A

Cited by

• Clinical characteristics and risk factors of relative systemic hypertension and hypertension among sickle cell patients in Cameroon. Front Med (Lausanne), 2022
• A whole genome sequencing approach to anterior cruciate ligament rupture-a twin study in two unrelated families. PLoS One, 2022
• Distribution of HbS Allele and Haplotypes in a Multi-Ethnic Population of Guinea Bissau, West Africa: Implications for Public Health Screening. Front Pediatr, 2022
• FLT1 and other candidate fetal haemoglobin modifying loci in sickle cell disease in African ancestries. Nat Commun, 2025
• Modulation of blood pressure regulatory genes in the Agtrap-Plod1 locus associated with a deletion in Clcn6. Physiol Rep, 2022
• The future of sickle cell disease therapeutics rests in genomics. Dis Model Mech, 2023
• The dawn of a cure for sickle cell disease through CRISPR-based treatment: A critical test of equity in public health genomics. Ann Hum Genet, 2025
• Genetic Modifiers of Sickle Cell Anemia Phenotype in a Cohort of Angolan Children. Genes (Basel), 2024
• Sickle Cell Disease in Children and Adolescents: A Review of the Historical, Clinical, and Public Health Perspective of Sub-Saharan Africa and Beyond. Int J Pediatr, 2022
• Factors associated with blood pressure variation in sickle cell disease patients: a systematic review and meta-analyses. Expert Rev Hematol, 2022
• Incomplete Penetrance and Variable Expressivity: From Clinical Studies to Population Cohorts. Front Genet, 2022
• Genetic modifiers of long-term survival in sickle cell anemia. Clin Transl Med, 2020
• Whole genome sequencing reveals population diversity and variation in HIV-1 specific host genes. Front Genet, 2024
• Modelling the mortality of sickle cell disease in Africa. Lancet Haematol, 2021