Genetic modifiers of frequent vaso-occlusive hospitalizations among individuals with sickle cell disease (SCD)

Sickle cell disease (SCD) is characterized by painful vaso-occlusive crises (VOC), which occur due to the adhesion of sickled erythrocytes and leukocytes to the endothelium, leading to vascular obstruction and tissue ischemia. Recurrent VOC increases SCD morbidity, reduces quality of life, and results in frequent hospitalizations. While factors like HbF levels and alpha-thalassemia co-occurrence are known to influence the risk of VOC, the genetic basis of this phenotype remains underexplored. To address this, we conducted a Genome-Wide Association Study (GWAS) to identify genetic predictors of frequent VOC in SCD patients. The study focused on patients with the SS genotype, analyzing those who experienced three or more pain crisis hospitalizations annually. To account for population substructure, the top 10 principal components were included. The GWAS was performed using ENCORE and the Saige Logistic Mixed Model, adjusted for hydroxyurea treatment as a covariate, with a genome-wide significance threshold of 5 × 10^-8. The study included 125 cases and 1670 controls, revealing 9 significant SNPs. 8 were associated with the CTNNA2 gene (p-value = 7.77 × 10^-9), and 1 with METTL4 (p-value = 3.39 × 10^-8). These findings highlight the role of CTNNA2 and METTL4 in VOC hospitalizations, providing insights into the genetic underpinnings of SCD pain.