Two-sample Mendelian randomization analysis of the causal relationship between lipid metabolism/fatty acid metabolism and pre-eclampsia.

Objectives: A causal relationship has been found between the abundance of some flora in the gut microbiota and the development of pre-eclampsia (PE). Short-chain fatty acids in gut microbes are an important source of lipids. The causal effect of lipid metabolism/fatty acid metabolism pathways on PE exposure is unknown.

Material and methods: This study was based on single nucleotide polymorphism (SNP) data related to lipid metabolism/fatty acid metabolism and PE from the genome-wide association study (GWAS) in the GWAS Catalog database and finngen database, and a two-sample mendelian randomization (MD) analysis was performed to explore the causal relationship between lipid/fatty acid metabolism and PE exposure. Five MD analysis methods were used in this study, inverse-variance weighted (IVW), MR-Egger regression, weighted median (WM), weighted median estimator (WME), MR-PRESSO. The intercept term of MR-Egger regression was tested for the presence of genetic pleiotropy between SNPs and PEs. Cochran's Q test was performed to investigate the heterogeneity between variables. The leave-one-out method was used for sensitivity analysis to determine the robustness of the results.

Results: Inverse-variance weighted results showed that gamma-glutamyl glutamine levels [odds ratio (OR) = 0.40, 95% confidence interval (CI): 0.21-0.78; p = 0.01], 1-arachidonoylglycerophosphocholine [1-arachidonoyl-sn-glycero-3-phosphocholine levels (OR = 0.57; 95% CI: 0.38-0.87; p = 0.01), X-14304--leucylalanine levels (OR = 0.72; 95% CI :0.56-0.93; p = 0.01), citrulline levels (OR = 0.48; 95% CI: 0.26-0.89; p = 0.02), inosine levels (OR = 0.88; 95% CI: 0.78-0.98; p = 0.02), and HWESASXX levels (OR = 0.64; 95% CI: 0.42-1.00; p = 0.05) were negatively correlated with PE. There was a positive trend for X-14205--alpha-glutamyltyrosine levels (OR = 1.55; 95% CI: 1.12-2.14; p = 0.01), X-11787 levels (OR = 3.29; 95% CI: 1.23-8.78; p = 0.02) to be associated with PE. No significant heterogeneity or pleiotropy was found for instrumental variables or levels pleiotropy.

Conclusions: This study demonstrated a causal relationship between eight fatty acid metabolisms and PE. Follow-up in-depth randomized controlled trials are needed to reveal the promotional or protective effects of fatty acid metabolism on PE.