Genetically predicted circulating polyunsaturated fatty acids and Crohn’s disease susceptibility

Crohn disease (CD) remains an increasing global health burden. Omega-3 and omega-6 polyunsaturated fatty acids participate in lipid metabolism and inflammatory regulation, but previous observational and interventional studies have produced inconsistent findings. This study aimed to assess whether genetically predicted circulating omega-3, omega-6, and the omega-6/omega-3 ratio are associated with CD susceptibility using a two-sample Mendelian randomization (MR) design. Genome-wide association study summary data for circulating omega-3, omega-6, and the omega-6/omega-3 ratio were obtained from the IEU Open GWAS project (each n = 114,999), while CD outcome data included 12,194 cases and 28,072 controls. Genome-wide significant single-nucleotide polymorphisms ( P < 5 × 10 −8 ) were clumped at r 2 = 0.001 within 10,000 kb, and all retained instruments had F-statistics > 10. Multiplicative random-effects inverse-variance weighting was used as the primary analysis, supplemented by MR-Egger, weighted median, simple mode, and weighted mode methods. Heterogeneity, horizontal pleiotropy, and robustness were evaluated using Cochran’s Q test, the MR-Egger intercept, leave-one-out analysis, and funnel plots. A total of 46 single-nucleotide polymorphisms for omega-3, 51 for omega-6, and 34 for the omega-6/omega-3 ratio were included. Higher genetically predicted circulating omega-3 levels were associated with lower odds of CD (odds ratio [OR] = 0.823, 95% confidence interval [CI] 0.721–0.939, P =.004), whereas omega-6 showed no statistically significant association (OR = 0.885, 95% CI 0.727–1.061, P =.186). A higher genetically predicted omega-6/omega-3 ratio was associated with increased odds of CD (OR = 1.211, 95% CI 1.069–1.372, P =.003). Complementary MR methods showed generally concordant directions, and MR-Egger intercept tests provided no statistical evidence of directional horizontal pleiotropy. However, substantial between-instrument heterogeneity was observed for all three exposures. These findings suggest that genetically predicted higher circulating omega-3 levels and a lower omega-6/omega-3 ratio are associated with lower CD susceptibility, whereas omega-6 alone shows no statistically significant association. Given the substantial between-instrument heterogeneity, these results should be regarded as suggestive genetic evidence rather than definitive proof of causality and should not be interpreted as evidence that dietary omega-3 intake or supplementation prevents CD.