Association of polyunsaturated fatty acids with cholelithiasis risk and the role of plasma lipid mediators: insights from NHANES 2017-2020 and Mendelian randomization

Abstract Background & aims Previous studies have suggested a potential link between polyunsaturated fatty acid (PUFA) intake and the risk of cholelithiasis. Omega–3 fatty acids, a key subfamily of PUFAs, have been identified in observational studies as playing a role in lipid regulation and potentially serving as a protective factor against cholelithiasis. In this study, we aim to investigate this association further by analyzing data from the 2017 – 2020 National Health and Nutrition Examination Survey (NHANES) and conducting Mendelian randomization (MR) analyses. Methods We employed weighted multivariate–adjusted logistic regression analyses to examine the association between PUFAs and cholelithiasis risk using data from NHANES 2017 – 2020. Additionally, a two–sample Mendelian randomization (MR) study was conducted utilizing pooled data from Genome-Wide Association Studies (GWAS) to establish the causal relationship between PUFAs and cholelithiasis. Following this, we performed two–step MR mediation analyses to investigate the mediating role of plasma lipids in the pathway, focusing on the strongly positive subfamily of PUFAs, Omega–3, in relation to plasma circulating lipids and cholelithiasis. Results Our observational study in NHANES included 7,527 participants. Weighted multivariate–adjusted logistic regression analyses initially revealed a negative association between PUFAs, their subclasses, and cholelithiasis. However, this association became nonsignificant after adjusting for multiple covariates. In contrast, MR analyses identified a significant negative association between PUFAs (OR=0.75 [95% CI, 0.58~0.98]) and Omega–3 (OR=0.79 [95% CI, 0.7~0.9]) and the risk of cholelithiasis. Specifically, Omega–3 was associated with a reduced risk of developing cholelithiasis (OR=0.77 [95% CI, 0.65~0.91]), possibly due to the upregulation of LDL–C levels (Beta=0.24 [95% CI, 0.1~0.38]). This upregulation of LDL–C subsequently lowered the risk of cholelithiasis (OR=0.77 [95% CI, 0.65~0.91]), with the mediating effect of LDL–C accounting for 28% of the overall association. Conclusions Both cross–sectional observational analyses and Mendelian randomization (MR) analyses demonstrated a negative correlation between polyunsaturated fatty acids (PUFAs) and cholelithiasis. Omega–3 fatty acids seem to play a key role in this association by increasing plasma LDL–C levels, which in turn may help reduce the risk of cholelithiasis.