Atherosclerosis, Intracranial Aneurysms, and Intermediate Biomarkers: Real-World Observational and Mendelian Randomization Research

BackgroundThe causal relationship between atherosclerosis and the development of aneurysms remains controversial. This study aims to analyze the genetic predictive association between atherosclerosis and intracranial aneurysms, as well as to explore intermediate biomarkers that may mediate the causal relationship between these two conditions. MethodsThis study utilized head imaging data for a cross-sectional analysis, investigating the prevalence of cerebral atherosclerosis and intracranial aneurysms in 13,739 patients. We performed Mendelian randomization analysis on two samples to explore the genetic predictive association between atherosclerosis and intracranial aneurysms. Furthermore, we examined the role of the matrix metalloproteinase family as an intermediary biomarker in the causal relationship between these two conditions and validated biomarker in serum and in situ samples from clinical patients. ResultsCross-sectional study revealed that patients with intracranial aneurysms exhibited a higher prevalence of cerebral atherosclerosis compared to controls (14.155% vs. 7.069%, P<0.001). Two-sample Mendelian randomization analysis demonstrated that genetically predicted peripheral atherosclerosis significantly increased the risk of intracranial aneurysms, encompassing both unruptured (ORIVW = 1.711, PIVW = 0.002) and ruptured intracranial aneurysms (ORIVW = 1.533, PIVW = 9.41x10^-4). Mendelian randomization further indicated that peripheral atherosclerosis leads to elevated circulating MMP12 levels ({beta}IVW = 0.083, PIVW = 0.008), which were subsequently associated with increased risks of unruptured (ORIVW = 1.136, PIVW = 0.010) and ruptured intracranial aneurysms (ORsimple-mode = 1.217, Psimple-mode = 0.038). ELISA assays confirmed elevated MMP12 levels in the plasma of patients with carotid artery stenosis and intracranial aneurysms. In situ analyses revealed upregulated MMP12 expression in both plaques and intracranial aneurysm tissues. ConclusionOur research clarifies the causal relationship between atherosclerosis and intracranial aneurysms, identifies and validates MMP12 as a key biomarker, and provides new methods and evidence to explain the association between these two diseases. What is already known on this topicPrevious studies have suggested a significant association between atherosclerosis and the development of aneurysms. What this study addsThis study provides robust evidence and causal inferences regarding this relationship, identifying intermediate biomarkers of the diseases. How this study might affect research, practice or policyThese findings suggest that preventing atherosclerosis and controlling MMP12 levels may help reduce the risk of intracranial aneurysms.