ABSTRACT

Background: Research has indicated links between pure hypercholesterolemia (PH) and multiple cancers; however, its direct effect on gastric cancer remains uncertain. Methods: To investigate the potential direct effect of PH on gastric cancer, this study employed a two-sample MR approach, utilizing data from genome-wide association studies. Instrumental variables were identified based on single nucleotide polymorphisms associated with PH at a genome-wide significance level (p < 5 × 10⁻⁸) and with linkage disequilibrium (r² < 0.001). Causal inference was drawn using methods including IVW, MR-Egger, and the WM approach, with a significance threshold set at p < 0.05. Heterogeneity and horizontal pleiotropy were evaluated through Cochran’s Q-test and the MR-Egger intercept, respectively. Robustness checks were conducted via omission diagnostics. Results: The MR analysis indicated a causal link between PH and a reduced risk of gastric cancer [IVW: OR: 0.84, p = 0.019; MR-Egger: OR: 0.813, p = 0.268; WM: OR: 0.838, p = 0.013]. The absence of significant heterogeneity and horizontal pleiotropy affirmed the reliability of these findings. Conclusion: The findings suggest a significant inverse relationship between PH and the risk of gastric cancer, indicating that elevated serum cholesterol levels may decrease the risk or slow the progression of gastric cancer, whereas lower levels may expedite cancer progression and are associated with a worse prognosis.