179 Plasma lipids and risk of intracranial aneurysms: A genetic study of association and causality

Abstract Background Current evidence suggests that genetic factors, hemodynamic abnormalities, and chronic inflammation of the vascular wall contribute to the onset of intracranial aneurysms (IAs). The deposition of lipid plaques is frequently observed in the walls of IAs. Therefore, the objective of this research was to determine the causal link between plasma lipids and IAs. Methods Genetic instrumental variables for 179 plasma lipids were acquired from a genome-wide association study (GWAS) of 7174 unrelated Finnish individuals. Outcome data for individuals with IAs were retrieved from a GWAS involving 23 cohorts, comprising 79,429 individuals of European ancestry. This dataset included 7,495 cases and 71,934 controls. Three databases were utilized for the implementation of Mendelian Randomization (MR) analysis. This included an aSAH group with 5,140 aSAH cases and 71,952 controls, a uIA group with 2,070 uIA cases and 71,952 controls, and an IAs group with 7,495 IAs cases and 71,934 controls. An inverse-variance weighted (IVW) method was employed as the key analysis method. To ensure the reliability of the findings, MR-Egger regression, weighted-median, and weighted-mode methods were employed. Sensitivity analyses included Cochran’s Q test, MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO), Radial MR test, MR-Egger intercept test, and Leave-one-out (LOO) analysis. The MR-Steiger test was conducted to avoid reverse causality. Results Following rigorous screening, MR tests, and Bonferroni correction, the genetically predicted level of Phosphatidylethanolamine(18:2_0:0)(LPE(18:2))(OR:1.28,95CI:1.13-1.46, P=1.42×10−4) ,Phosphatidylcholine (PC) (16:0_20:4)(OR:0.86,95CI:0.86-0.93, P=1.38×10−4),Phosphatidylcholine (PC) (18:0_20:3)(OR:1.29,95CI:1.12-1.47, P=2.33×10−4)and Phosphatidylcholine (PC) (O-16:0_20:4)(OR:0.83,95CI:0.75-0.91, P=2.22×10−4) showed significant causal relationships with aSAH. Two plasma lipids, LPE (18:2)(OR:1.22,95CI:1.11-1.34, P=3.14×10−5) and PC (16:1_18:2)(OR:1.19,95CI:1.09-1.31, P=1.53×10−4) exhibited a positive correlation with the risk of IAs. No significant causal link was found between uIA and 179 plasma lipids. Conclusion Genetically determined LPE (18:2) ,PC(18:0_20:3) and PC (16:1_18:2) can increase the risk of IAs rupture;while PC(16:0_20:4) and PC (O-16:0_20:4) can reduce the risk of IAs rupture.PCs with arachidonic acid (AA) chains and the metabolism of AA may be crucially involved in the occurrence and development of IAs.