Sickle cell anemia Patients (SCA) frequently experience vaso-occlusive crises (VOC) and chronic hemolysis. In Brazil, it is estimated that over 100,000 people are affected, resulting in significant clinical, social, and economic impact. The inflammatory microenvironment characteristic of SCA leads to the release of hemolysis byproducts into the bloodstream, stimulating the production of inflammatory cytokines that exacerbate endothelial activation, cellular recruitment, and chronic pain. Among these cytokines, IL-1β, IL-8, and IL-18 stand out due to their significant roles in modulating clinical severity and systemic inflammation.

We evaluated inflammatory cytokine levels of inflammatory cytokines and genotyped single nucleotide variants (SNVs) in the promoter regions of the IL-1β, IL-8, and IL-18 genes in patients SCA patients and healthy individuals.

This case-control study involved patients under the care of HEMOAM and healthy blood donors. Cytokine concentrations were analyzed using the BD Symphony S6 flow cytometer. Single nucleotide variants (SNVs) (IL-1B c.-31C>T; IL-8 c.-251A>T; and IL-18 c.-607A>C) were analyzed by real-time PCR. Statistical analyses were conducted using SPSS v19, considering p-values less than 0.05 as significant.

As expected, cytokine levels were significantly elevated (up to 10 × ) in patients compared to controls. Strongly expressive results were observed among patients. Homozygous mutant genotypes for IL-1B (c.-31TT) and IL-8 (c.-607AA) showed significantly elevated levels, whereas the homozygous mutant genotype for IL-8 (c.-251TT) showed significantly reduced levels of their respective interleukins when compared to heterozygous and wild-type genotypes (p < 0.001; p < 0.023; p < 0.001, respectively). Although cytokine concentrations in the control group were considerably lower, significant differences were also observed between genotypes.

Our findings confirm previous studies in the literature showing that SCA patients have elevated levels of inflammatory cytokines. The substantial increase in IL-1β among individuals with the c.-31TT genotype reinforces its role in inflammatory activation and VOC episodes. For IL-8, patients with the c.-251AA genotype also exhibited higher levels than control groups. When elevated, this cytokine is associated with more severe clinical manifestations. These findings support the hypothesis that SNVs in IL-8 may intensify inflammation and worsen the clinical condition of patients. In IL-18, elevated levels were identified, especially in individuals with the c.-607AA genotype, suggesting that this cytokine may serve as an indicator of more severe inflammation. Collectively, these results support the notion that SNVs in the promoter regions of IL-1β, IL-8, and IL- 18 influence the magnitude of the inflammatory immune response in SCA. Conclusion: We believe the obtained data obtained may contribute to a better understanding of chronic inflammation in SCA and serve as a foundation for personalized therapeutic strategies. Further studies are necessary to support diagnostic and treatment approaches, particularly for patients in the northern region of Brazil.