In the present study, we have embarked on an explorative journey to understand the potential impact of dietary factors on the risk of intracranial aneurysms, employing a MR analysis. Utilizing data from the extensive IEU Open GWAS project, the causal association of the intake of cooked vegetables and intracranial aneurysm was established. While the frequency of alcohol intake and intake of dried fruit initially indicated a potential risk factor, this association did not maintain its statistical significance following correction for multiple comparisons, suggesting the need for cautious interpretation of its role. The intake of various types of meat (oily fish, pork, lamb/mutton, beef and poultry), vegetarian food comprising raw vegetables (salad), fresh and dried fruits were not associated with intracranial aneurysm. To our knowledge, there have been other MR studies on the risk of intracranial aneurysm[18, 19]. However, this study stands as one of the few attempts to apply Mendelian randomization in dissecting the relationship between a wide range of dietary habits and the risk of developing intracranial aneurysms.
Ruptured intracranial aneurysm causing subarachnoid hemorrhage have a high rate of disability[5], which imposes a heavy economic burden on the world every year. Ruptured intracranial aneurysm are a serious threat to the quality of life and even the lives of patients. Our findings may help clinicians to improve health education and encourage dietary changes in at-risk populations. For people at high risk of intracranial aneurysm, dietary modifications can also reduce the risk of developing an intracranial aneurysm. Therefore, this study is important to deepen the understanding of risk factors and protective factors of intracranial aneurysm.
The Mediterranean diet, deeply rooted in the traditional eating habits of the Mediterranean region, is characterized by a high intake of plant-based foods, such as fruits, vegetables, whole grains, legumes, nuts, and seeds, along with olive oil as the primary source of monounsaturated fats[20, 21]. It promotes moderate consumption of fish and poultry, limits red meat and processed foods, and includes wine in moderation. This dietary pattern, rich in antioxidants and anti-inflammatory agents, is known for its benefits for vascular health and a series of diseases[22–24]. Numerous studies have shown that inflammation plays an important role in the development and progression of intracranial aneurysm[25, 26]. As its components help reduce key risk factors like hypertension and oxidative stress, the Mediterranean diet shed potential light on the prevention of intracranial aneurysm.
In our study, the dietary factors analyzed broadly encompassed aspects of the Mediterranean diet. It is well known that endothelial cell dysfunction is implicated in the pathogenesis of intracranial aneurysm and that oxidative stress is an important mechanism of endothelial cell injury[27]. Interestingly, our results revealed a causal link between cooked vegetable intake and the occurrence of intracranial aneurysms. This association may be attributed to the potential degradation of essential nutrients during the cooking process. Cooking, especially at high temperatures or for prolonged periods, can lead to the breakdown of vital antioxidants and phytonutrients present in vegetables. The collective findings from these studies underscore the significant impact of cooking methods on the antioxidant properties and phytochemical content of vegetables. These studies revealed that different cooking techniques, such as boiling, microwaving, and frying, can lead to varying degrees of retention or loss of valuable antioxidants and other phytochemicals[28, 29]. Specifically, water-based cooking methods like boiling generally result in greater losses of these beneficial compounds[30]. These antioxidants are crucial in inhibiting inflammatory responses and thus play a key role in protecting against the formation of intracranial aneurysms. These nutrients, such as certain vitamins, flavonoids, and polyphenols, are known for their antioxidant properties. Excessive cooking can degrade these antioxidants, thereby diminishing both their nutritional value and their preventive effects against the development of aneurysms. The loss of these protective elements in cooked vegetables might explain their association with an increased risk of intracranial aneurysms, contrasting with the typically protective nature of the raw or less-processed components of the Mediterranean diet.
The potential protective value of dried fruit, as indicated by our findings, may stem from the nutrient concentration achieved through the dehydration process, which not only prolongs shelf life but also enhances the presence of essential antioxidants and anti-inflammatory agents[31]. Dried fruits serve as nutrient-rich snacks, brimming with dietary fiber, essential minerals, vitamins, and bioactive elements like flavonoids and carotenoids. They offer notable health benefits such as antioxidant, anti-inflammatory, anti-atherosclerotic, and anticancer properties[32–35]. These concentrated nutrients in dried fruits can play a significant role in combating oxidative stress and inflammation, two key factors in the development and exacerbation of various health conditions, including intracranial aneurysms. The antioxidants present in dried fruits, like flavonoids and phenolic acids, are known for their capacity to neutralize free radicals and reduce oxidative damage, which can contribute to the weakening of arterial walls and the formation of aneurysms[27, 36, 37]. Thus, the regular consumption of dried fruits, as part of a balanced diet, could be a simple yet effective way to ingest these beneficial compounds, potentially offering a protective effect against intracranial aneurysms.
In this study, while we did not establish a clear link between current alcohol consumption and the risk of developing intracranial aneurysm, our findings do hint at a potential association. This nuanced result stands in contrast to a study conducted in the United States, which identified a significant correlation between the current intensity of alcohol consumption and ruptured intracranial aneurysms[38]. However, this study also did not emphasis on the frequency of alcohol consumption. It's important to contextualize these findings within the broader framework of research methodologies. MR offers a means to mitigate bias introduced by confounding factors and serves as a valuable complement to randomized controlled trials (RCTs), yet it is not a replacement for them[13]. Consequently, while our results suggest a suggestive relationship between alcohol consumption and intracranial aneurysms, they should be interpreted with caution. Further validation through more comprehensive RCTs is necessary to elucidate the nature of this potential link fully.
Consumption of red meat increases the incidence of cerebrovascular disease[39, 40]. Numerous studies have shown that eating large amounts of red meat is associated with a higher risk of stroke[41, 42]. In an animal trial it was shown that iron intake was associated with greater infarct size, an effect associated with an increased inflammatory response to iron[43]. Red and processed meats are the main sources of iron in the diet[44], which may increase the inflammatory response in the blood vessels, thus increasing the risk of aneurysms. However, this MR analysis did not find an increased risk of intracranial aneurysm with the intake of red meats. Therefore, more observational studies and more skillful MR studies are needed in the future to further reveal the relationship between red meat intake and intracranial aneurysm.
In discussing the findings of this Mendelian randomization study, it's essential to highlight the rigorous methodologies employed to validate our results. While the association between cooked vegetable intake and increased risk of intracranial aneurysm is counterintuitive, we ensured the reliability of these findings through a comprehensive approach. This included using the IVW model for causality assessment, conducting heterogeneity checks with Cochran's Q test, employing the MR-Egger method for pleiotropy adjustment, and implementing the MR-PRESSO method for outlier detection. Additionally, leave-one-out analyses were conducted for each genetic variant to further confirm the robustness of our results. These extensive measures collectively reinforce the credibility of our findings. However, the mechanisms by which dietary factors contribute to the increased risk of intracranial aneurysm are not fully understood. MR analysis should be interpreted with more caution. First, the causal relationships found by MR analysis reflect the effects of long-term exposure and associated factors. Thus, short-term exposures may not be clinically relevant. Second, univariate MR analyses reveal only the overall effect between exposure and outcome, not the direct effect between them. Extremely complex mechanisms may exist between exposure and outcome. Third, another noteworthy issue is MR's inability to distinguish causality between periods. For example, MR analysis found a causal relationship between vitamin D and multiple sclerosis[45]. However, this effect was only present in childhood or earlier[46].
In this study, we utilized Mendelian Randomization (MR) with genetic variants as instrumental variables, leveraging the largest intracranial aneurysm database to date, a significant strength that provides a robust basis for our analysis. This approach effectively reduces biases associated with reverse causality and confounding factors, with the reliability of our results further enhanced by comprehensive multiplicity and sensitivity analyses. However, the study faces limitations, notably in the lack of granularity in dietary intake analysis and the absence of gender-specific GWAS data, which restricts our ability to conduct gender-stratified analyses—important considering potential gender variations in dietary effects and aneurysm risks. While our MR analyses suggest associations with certain dietary factors, cautious interpretation is needed due to MR's limitations in detailing complex causality mechanisms. Therefore, while offering valuable insights into dietary factors affecting intracranial aneurysm risk, these findings must be viewed in light of these limitations, underscoring the need for more detailed future research.