Exploring the impact of haptoglobin gene polymorphisms and severity of sickle cell disease: meta-analysis and gene set enrichment study

Sickle cell disease, a genetic blood disorder marked by vaso-occlusive crises and severe pain, presents a major global health challenge. Haptoglobin, a glycoprotein that binds free hemoglobin in the blood, protects tissues from oxidative damage. This study aims to explore the link between variations in the haptoglobin ( HP ) gene and susceptibility to more severe sickle cell disease. A comprehensive literature search was performed across Scopus, Embase, Google Scholar, Web of Science, and PubMed. Methodological quality was evaluated using the RoB 2 tool. Statistical analyses employed MetaGenyo software with significance being set at a p-value <0.05. Functional enrichment, gene ontologies, and protein-protein interaction networks were mapped using the Enrichr and STRING web platforms. Eight studies were evaluated to determine the association between HP gene polymorphisms and susceptibility to sickle cell disease complications. The results indicate a significant association between HP gene polymorphisms and sickle cell disease severity under the dominant model (odds ratio = 0.76; 95% confidence interval: 0.61–0.94; p-value = 0.01). Additionally, a subgroup analysis based on ethnicity demonstrated associations in the African and South American populations (p-value <0.05) but the Asian population showed no correlation between HP gene polymorphisms and sickle cell disease severity (p-value >0.05). This meta-analysis demonstrates a significant association between HP gene polymorphisms and increased severity of sickle cell disease, suggesting that the HP genotype may serve as a valuable predictive biomarker for clinical outcomes.