Association between omega-3/6 fatty acids and cholelithiasis: A mendelian randomization study

Area of Science:

• Nutritional Epidemiology
• Genetic Epidemiology
• Metabolic Health

Background:

• The potential protective role of omega-3 and omega-6 fatty acids against cholelithiasis (gallstones) is suggested but not clearly established.
• Investigating the causal relationship between these fatty acids and gallstone formation is essential for understanding preventative strategies.

Purpose of the Study:

• To elucidate the causal relationship between omega-3 and omega-6 fatty acid levels and the risk of cholelithiasis using Mendelian randomization (MR).
• To assess the protective effects of omega-3 and omega-6 fatty acids on gallstone disease.

Main Methods:

• Utilized a large-scale Mendelian randomization study employing data from UK Biobank (discovery, n=114,999), an independent GWAS (validation, n=13,544), and FinnGen (cholelithiasis cases/controls, n=19,023/195,144).
• Primary analysis used the inverse variance weighting (IVW) method, with sensitivity analyses including MR-Egger, weighted median, MR-PRESSO, and outlier methods to ensure robustness and detect pleiotropy.

Main Results:

• Higher omega-3 levels demonstrated a significant inverse association with cholelithiasis risk in both discovery (P=1.49 × 10⁻⁵) and validation (P=5.49 × 10⁻⁴) stages, confirming a protective effect.
• Increased omega-6 levels were also negatively associated with cholelithiasis risk across discovery (P=4.37 × 10⁻³) and validation (P=3.44 × 10⁻²) phases.
• Sensitivity analyses supported the main findings, indicating a stable causal link between omega-3/6 fatty acids and reduced gallstone risk.

Conclusions:

• Mendelian randomization analysis strongly suggests that higher levels of omega-3 and omega-6 fatty acids are causally associated with a reduced risk of cholelithiasis.
• Clinical attention towards individuals with low serum omega-3/6 levels is warranted for proactive cholelithiasis risk management.