Tables 1and Supplementary Table 3 delineate a total of 921, 24, 128, 18, 11, and 161 cis-eQTLs identified from eQTLGen or the GTEx Consortium for the genes HMGCR, PCSK9, CETP, LDLR, NPC1L1, and APOB, respectively. The most significant cis-eQTL SNP was chosen as the genetic instrument for each respective target gene. Additionally, we meticulously selected 7, 12, 4, 11, 3, and 7 SNPs within or in close proximity to genes HMGCR, PCSK9, CETP, LDLR, NPC1L1, and APOB, respectively, from a GWAS summary dataset on LDL-C levels obtained from the GLGC. Notably, all instrument variants manifested F-Statistics surpassing 20, thereby ensuring effective mitigation of any potential bias arising from weak instruments in our study (Supplementary Table 4). Substantiating the robustness of the selected genetic instruments, positive control analyses established significant associations between exposures, including genes HMGCR, PCSK9, CETP, LDLR, NPC1L1, APOB and LDL-C levels when utilising proposed eQTL-based instruments (Supplementary Table 5), as well as between exposures and coronary heart disease when employing LDL-C GWAS-proposed instruments (Supplementary Table 6).

The results depicted in Fig. 1 and Supplementary Table 7 unveil substantial associations between augmented expression of HMGCR and an escalated risk of aortic aneurism (odds ratio [OR] = 1.603, 95% confidence interval [CI] = 1.209–2.124; p = 0.0008), thoracic aortic aneurism (OR = 1.666, 95% CI = 1.122–2.475; p = 0.0103), and abdominal aortic aneurism (OR = 1.910, 95% CI = 1.278–2.856; p = 0.0013). Similarly, heightened expression of PCSK9 exhibited an association with an elevated risk of aortic aneurism (OR = 1.290, 95% CI = 1.064–1.564; p = 0.0058) and abdominal aortic aneurism (OR = 1.498, 95% CI = 1.132–1.983; p = 0.0023), while amplified expression of CETP was related to a higher risk of aortic aneurism (OR = 1.417, 95% CI = 1.088–1.847; p = 0.0089) and abdominal aortic aneurism (OR = 2.138, 95% CI = 1.453–3.147; p = 0.0001). These findings suggest potential advantages of HMGCR inhibitors in reducing the risk of aortic aneurism, encompassing both abdominal and thoracic subtypes. Furthermore, PCSK9 and CETP inhibitors might also contribute to a reduced risk of abdominal aortic aneurism. Encouragingly, there were suggestive findings of a negative association between LDLR expression and the risk of aortic aneurism (OR = 0.562, 95% CI = 0.321–0.983; p = 0.0359). However, no significant association was discerned between the expression of NPC1L1, APOB, and various types of arterial aneurisms.

Summary-data-based Mendelian randomization (SMR) analysis illustrating the correlation between the expression of genes HMGCR, PCSK9, LDLR, CETP, NPC1L1, and APOB, and various types of aneurisms

Fig. 2 and Supplementary Table 8 illustrate the IVW-MR analysis, offering suggestive evidence for the link between HMGCR-mediated LDL-C (equivalent to a 1 mmol/l increase) and an augmented risk of aortic aneurism (OR = 2.228, 95% CI = 1.702–2.918; p = 5.75E-09), thoracic aortic aneurism (OR = 1.751, 95% CI = 1.191–2.575; p = 0.0044), abdominal aortic aneurism (OR = 4.784, 95% CI = 3.257–7.028; p = 1.48E-15), and nonruptured aortic aneurism (OR = 1.993, 95% CI = 1.277–3.110; p = 0.0024). These findings further bolster the potential protective impact of HMGCR inhibitors against various types of arterial aneurisms. Additionally, a robust positive correlation surfaced between PCSK9-mediated LDL-C and the risk of aortic aneurism (OR = 1.226, 95% CI = 1.095–1.464; p = 0.0015), abdominal aortic aneurism (OR = 1.631, 95% CI = 1.318–2.018; p = 6.61E-06), and other aneurism (OR = 1.813, 95% CI = 1.319–2.491; p = 0.0002). Furthermore, CETP-mediated LDL-C was positively related to the risk of aortic aneurism (OR = 2.928, 95% CI = 1.863–4.600; p = 3.18E-06) and abdominal aortic aneurism (OR = 7.867, 95% CI = 4.115–15.040; p = 4.42E-10). Moreover, LDLR-mediated LDL-C was favourably associated with the risk of abdominal aortic aneurism (OR = 2.217, 95% CI = 1.750–2.809; p = 4.16E-11), while exhibiting an unfavourable association with the risk of thoracic aortic aneurism (OR = 0.634, 95% CI = 0.504–0.797; p = 9.67E-05). However, the IVW-MR analysis failed to furnish any corroboration for the association between NPC1L1-mediated LDL-C, APOB-mediated LDL-C, and various types of arterial aneurisms. Furthermore, all causal inferences obtained through the IVW-MR method exhibit statistical power exceeding 0.8, with a Type I error rate of 0.05 (Supplementary Table 8). In addition, the results of the MVMR analysis (Fig. 3), controlling for conventional aneurysm risk factors, including hypertension, BMI, and smoking, further underscore the independent impact of HMGCR-mediated LDL-C levels on the heightened risk of aortic aneurysm (OR = 1.920, 95% CI = 1.450–2.542; p = 5.20E-06), thoracic aortic aneurysm (OR = 1.519, 95% CI = 1.026–2.249; p = 0.036) and abdominal aortic aneurysm (OR = 3.697, 95% CI = 2.542–5.378; p = 8.05E-12).

Inverse-variance-weighted Mendelian randomization (IVW-MR) analysis delineating the connexion between LDL-C levels influenced by genes HMGCR, PCSK9, LDLR, CETP, NPC1L1, or APOB and diverse forms of aneurisms

Relationship between LDL-C levels modulated by the gene HMGCR and diverse forms of aneurisms, adjusted for BMI, hypertension, and smoking in multivariable MR (MVMR) analysis

In the SMR analysis, the HEIDI test indicated that all observed associations remained uninfluenced by potential linkage scenarios (p > 0.01) (Supplementary Table 7). To delve further into the prospective presence of horizontal pleiotropy in the association between HMGCR expression and different types of arterial aneurisms, we probed whether any link existed between the expression of neighbouring genes significantly associated with the top eQTL SNP (rs6453133) of HMGCR and various types of arterial aneurisms. Amongst the six identified genes, including POC5 centriolar protein (POC5), ankyrin repeat and death domain containing 1B (ANKDD1B), ceramide transporter 1 (CERT1, also known as COL4A3BP), DNA polymerase kappa (POLK), ankyrin repeat domain 31 (ANKRD31), and HMGCR, whose expression was linked to the instrument variant of rs6453133 (Supplementary Table 9), only HMGCR, ANKDD1B, POLK and POC5 displayed available eQTLs at a genome-wide significance level (p < 5.0 × 10− 8). Significantly, amongst these genes, solely HMGCR expression portrayed a significant relationship with aortic aneurisms, comprising both thoracic and abdominal subtypes, thus suggesting a delimited role of horizontal pleiotropy in the observed associations (Supplementary Table 10).

In the IVW-MR analysis, the Cochran Q test did not yield any evidence of heterogeneity for all reported results (all p > 0.05; Supplementary Table 8). Likewise, both the intercept term in MR-Egger regression and MR-PRESSO analysis suggested no significant overall horizontal pleiotropy (all p > 0.05; Supplementary Table 8). Furthermore, traditional risk factors, encompassing smoking, hypertension, and body mass index (BMI), showcased notable positive correlations with various types of arterial aneurisms (Supplementary Table 11). Moreover, in the MVMR analysis, on accounting for BMI, smoking, and hypertension, a substantial positive relationship was established between HMGCR-mediated LDL-C levels and the development of aortic aneurisms, comprising both thoracic and abdominal subtypes (Supplementary Table 12).