Hyperlipidemia and hypercholesterolemia are metabolic conditions that elevate cardiovascular disease risk and frequently co-occur with obesity, insulin resistance, and other metabolic disturbances. Toll-like receptor 4 (TLR4), a key mediator of innate immune responses, has been proposed as a link between lipid metabolism and inflammatory pathways; however, the extent to which TLR4 genetic variation influences hyperlipidemia susceptibility remains inadequately defined. This investigation examined whether the TLR4 polymorphisms rs4986790 (Asp299Gly) and rs1927914 are associated with hyperlipidemia risk in a Palestinian cohort. The study employed a case-control design comprising 55 diagnosed hyperlipidemia/hypercholesterolemia patients and 50 age- and sex-matched healthy individuals. Genomic DNA was extracted from peripheral blood, and TLR4 variants were genotyped using PCR-RFLP with BccI and SphI enzymes. Genotype and allele frequency comparisons were performed using chi-square analysis, with associations quantified through odds ratios (ORs) and 95% confidence intervals (CIs). No statistically significant relationship emerged between rs4986790 and hyperlipidemia susceptibility (P > 0.05). In contrast, rs1927914 demonstrated a robust association with disease risk. Relative to the TT genotype, TC genotype carriers exhibited elevated susceptibility (OR = 17.63, 95% CI: 3.85–81.20, P < 0.001), and the CC genotype likewise conferred increased risk (OR = 10.06, 95% CI: 1.15–88.40, P = 0.03). Dominant model analysis and allele-based comparisons confirmed a significant relationship between the C allele and hyperlipidemia (P < 0.001). These observations suggest that TLR4 rs1927914, but not rs4986790, may influence genetic predisposition to hyperlipidemia among Palestinians and could potentially serve as a biomarker for identifying individuals at heightened disease risk.
