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

Background & aimsPrevious 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. MethodsWe 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. ResultsOur 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. ConclusionsBoth 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.