A Mendelian randomisation, propensity score matching study to investigate causal association between serum homocysteine and intracranial aneurysm.

Background and purpose: Recent observational studies have reported that serum total homocysteine (tHcy) is associated with intracranial aneurysms (IAs). However, the causal effect of tHcy on IAs is unknown. We leveraged large-scale genetic association and real-world data to investigate the causal effect of tHcy on IA formation.

Methods: We performed a two-sample Mendelian randomisation (MR) using publicly available genome-wide association studies summary statistics to investigate the causal relationship between tHcy and IAs, following the recommendations of the Strengthening the Reporting of Observational Studies in Epidemiology-MR statement. Furthermore, a propensity score matching (PSM) analysis was conducted to evaluate the detailed effects of tHcy on risk of IA formation by utilizing real-world multicentre data, including 9902 patients with and without IAs (1:1 matched). Further interaction and subgroup analyses were performed to elucidate how tHcy affects risk of IA formation.

Results: MR analyses indicated that genetically determined tHcy was causally associated with IA risk (OR, 1.38, 95% CI 1.07 to 1.79; p=0.018). This is consistent with the more conservative weighted median analysis (OR, 1.41, 95% CI 1.03 to 1.93; p=0.039). Further sensitivity analyses showed no evidence of horizontal pleiotropy or heterogeneity of single nucleotide polymorphisms in causal inference. According to the PSM study, we found that, compared with low tHcy (≤15 µmol/L), moderate tHcy (>15-30 µmol/L) (OR 2.13, 95% CI 1.93 to 2.36) and high tHcy (>30 µmol/L) (OR 3.66, 95% CI 2.71 to 4.95) were associated with a higher IA risk (p trend <0.001). Subgroup analyses demonstrated significant ORs of tHcy in each subgroup when stratified by traditional cardiovascular risk factors. Furthermore, there was also a synergistic effect of tHcy and hypertension on IA risk (p interaction <0.001; the relative excess risk due to interaction=1.65, 95% CI 1.29 to 2.01).

Conclusion: Both large-scale genetic evidence and multicentre real-world data support a causal association between tHcy and risk of IA formation. Serum tHcy may serve as a biomarker to identify high-risk individuals who would particularly benefit from folate supplementation.