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%; χ 2 = 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%; χ 2 = 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.