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Background: Observational studies have shown that modifiable risk factors are associated with aortic valve stenosis (AVS). However, the causality behind these associations remains largely unknown. Objectives: To explore the associations of modifiable risk factors, including metabolic factors, biochemical measures, education, and lifestyles with AVS and their potential causal associations. Methods: We enrolled 361,930 British white people with genetic data in the UK biobank. Cox proportional risk regression models were used to estimate the hazard ratios between 28 modifiable risk factors and AVS. We used genetic instruments for modifiable risk factors to determine the potential causal relationships using a one-sample Mendelian randomization (MR) approach. Results: A total of 1602 participants developed AVS during an 8.4-year follow-up. Observational analyses showed higher adiposity, blood pressure, heart rate, low-density lipoprotein, urate, C-reactive protein, creatinine, albumin, and glycated hemoglobin, but lower serum vitamin D, and education, unhealthy lifestyle, and poor sleep quality were related to a higher risk of AVS after adjusting for the Bonferroni correction (p < 0.0013). Genetically predicted 1-SD higher levels of body mass index [HR: 1.09, 95% CI: 1.03 to 1.16], body fat percentage (1.17, 1.03 to 1.33), triglyceride (TG) [1.08, 1.00 to 1.16], low-density lipoprotein (LDL) (1.15, 1.08 to 1.21) and serum total cholesterol (TC) (1.13, 1.02 to 1.25) were associated with a higher risk of AVS, respectively. Genetically determined per category higher insomnia (1.32, 1.13 to 1.55) was also associated with AVS. The abovementioned genetic associations with the incident AVS showed an increasing relationship pattern. Conclusions: This study provides strong evidence for the potential causal roles of cardiometabolic factors in developing AVS, highlighting that an idea of metabolic status through a healthy lifestyle may help prevent AVS.

Previous studies have suggested a close but inconsistent relationship between essential nutrients and the risk of amyotrophic lateral sclerosis (ALS), and whether this association is causal remains unknown. We aimed to investigate the potential causal relation between essential nutrients (essential amino acids, essential fatty acids, essential minerals, and essential vitamins) and the risk of ALS using Mendelian randomization (MR) analysis. Large-scale European-based genome-wide association studies’ (GWASs) summary data related to ALS (assembling 27,205 ALS patients and 110,881 controls) and essential nutrient concentrations were separately obtained. MR analysis was performed using the inverse variance–weighted (IVW) method, and sensitivity analysis was conducted by the weighted median method, simple median method, MR–Egger method and MR–PRESSO method. We found a causal association between genetically predicted linoleic acid (LA) and the risk of ALS (OR: 1.066; 95% CI: 1.011–1.125; p = 0.019). An inverse association with ALS risk was noted for vitamin D (OR: 0.899; 95% CI: 0.819–0.987; p = 0.025) and for vitamin E (OR: 0.461; 95% CI: 0.340–0.626; p = 6.25 × 10−7). The sensitivity analyses illustrated similar trends. No causal effect was observed between essential amino acids and minerals on ALS. Our study profiled the effects of diet-derived circulating nutrients on the risk of ALS and demonstrated that vitamin D and vitamin E are protective against the risk of ALS, and LA is a suggested risk factor for ALS.