Genetically predicted circulating polyunsaturated fatty acids and Crohn's disease susceptibility: A two-sample mendelian randomization study.

Authors

Tingting Zhu, Qiang Hu, Kaifeng Zhu

Published in

Medicine. Volume 105. Issue 39. Pages e50897. Sep 25, 2026.

Abstract

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 r2 = 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.

PMID:
42798115
Bibliographic data and abstract were imported from PubMed on 26 Sep 2026.

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