Association of interleukin-33 gene polymorphisms with susceptibility to Plasmodium falciparum infection

Host immune genetic variation contributes to inter-individual differences in susceptibility to Plasmodium falciparum malaria and parasite-burden response. Interleukin-33 (IL-33), an IL-1 family alarmin signaling through ST2, regulates innate and adaptive immune responses during infection. Although IL-33/ST2 signaling has been implicated in malaria-related immune regulation, the contribution of IL-33 genetic variation to human P. falciparum susceptibility remains insufficiently defined.

This case-control study included 250 individuals with active P. falciparum malaria and 200 healthy controls from the Jazan region of Southwestern Saudi Arabia. Thirteen IL-33 SNPs were genotyped, and associations were evaluated in relation to malaria susceptibility, parasite-density strata, age-defined patient groups, haplotypes, and luciferase reporter activity.

rs10118795 CT was associated with increased malaria susceptibility (OR = 1.584, 95% CI 1.068-2.350; p = 0.022), whereas rs55726619 CT showed a protective association (OR = 0.042, 95% CI 0.002-0.725; p < 0.001). rs55726619 showed the most consistent parasite-burden association, including with the highest parasite-density category. In children aged 1-5 years, rs10815393 CC was strongly enriched compared with patients aged ≥ 6 years (100.0% vs. 2.1%; χ² = 100.8; p < 0.001; adjusted OR = 650.46, 95% CI 32.88-12869.02; Fisher's p = 7.12 × 10⁻¹¹), as was rs55726619 CC (100.0% vs. 7.8%; χ² = 62.04; p < 0.001; adjusted OR = 172.69, 95% CI 9.50-3138.11; Fisher's p = 5.91 × 10⁻⁸). rs1332290 GG showed a nominal age-associated difference (28.6% vs. 16.5%; OR = 0.098, 95% CI 0.005-2.093; p = 0.046). Haplotype set 4 was significantly associated with malaria susceptibility (p = 2.76 × 10⁻⁶), and luciferase reporter assays showed allele-dependent differences in IL-33 regulatory activity.

IL-33 variants, particularly rs55726619 and rs10815393, may influence P. falciparum susceptibility, parasite-burden response, and age-dependent host genetic effects, supporting IL-33/ST2 signaling as a relevant pathway for further validation.