Abstract
Inguinal hernia (IH) is a common condition with a substantial health burden and emerging evidence suggests that lipid metabolism-related indicators may contribute to its risk. However, the exact role of specific lipid types in causing IH is still unclear. This study aims to investigate whether any of 179 distinct lipid species have a causal impact on IH risk using causal inference. We applied a two-sample Mendelian randomization (MR) framework, integrating lipidomic genome-wide association studies (GWAS) data from 7,174 Finnish individuals with IH summary statistics from the UK Biobank (16,749 cases and 439,599 controls). Linkage disequilibrium pruning and genome-wide significance (P < 5E-8) were used to choose genetic instruments. Primary causal estimates were derived with inverse-variance weighted (IVW) method, and further supported by weighted median (WM) and robust adjusted profile score (RAPS). We employed sensitivity tests, like Cochran's Q for heterogeneity, MR-Egger for directional pleiotropy, Radial MR for outlier detection, and leave-one-out analysis to measure the impact of individual variants. Among 179 lipid species, 162 had valid IVs, and 94 met the criteria for causal inference. IVW analysis identified 25 lipid species with nominal significance, 24 of which were supported by WM and RAPS. Sensitivity analyses consistently provided robust evidence supporting a causal relationship between four lipid species and increased IH risk: diacylglycerol (18:1_18:1) (OR = 1.16, P = 0.005), diacylglycerol (18:1_18:2) (OR = 1.12, P = 0.006), phosphatidylinositol (18:0_20:4) (OR = 1.10, P = 1.47E-04), and triacylglycerol (54:6) (OR = 1.21, P = 0.001). Our findings provides genetic molecular evidence that four lipid species are causally linked to an increased IH susceptibility, offering novel insights into lipid-centered interventions for disease prevention and highlighting the importance of metabolic health in hernia pathogenesis.