Dietary antioxidants: a challenge or an opportunity for asthma? Genetic insights from a Two-sample mendelian randomization study

Oxidative stress is crucial in the immune response and airway inflammatory process associated with asthma. While the relationship between dietary antioxidants and asthma remains debated in observational studies, this study uses two-sample Mendelian randomization (MR) to explore a potential causal link. We acquired six distinct categories of absolute circulating antioxidants and five different types of metabolic circulating antioxidants from the most recent genome-wide association study data of the European population, including vitamin A (retinol), vitamin C (ascorbic acid), vitamin E (tocopherol), β-carotene, lycopene, and urate. The latest data regarding asthma was obtained from the FinnGen database. We utilized single nucleotide polymorphisms as instrumental variables to conduct five MR methods. To confirm the accuracy of the results, additional sensitivity analyses were performed to eliminate any potential confounding factors, such as heterogeneity and pleiotropy. MR and sensitivity analyses revealed an association between circulating urate and asthma, suggesting a potential increase in asthma risk (OR = 1.090; 95% CI = 1.030–1.150; <i>p</i> = 0.004). No causal relationship was found for other antioxidants. This MR analysis suggested that genetically determined circulating urate may increase asthma risk. Further large-scale randomized controlled trials and mediated MR analysis are needed to explore underlying mechanisms.

氧化应激在哮喘相关的免疫应答与气道炎症过程中发挥关键作用。尽管观察性研究中膳食抗氧化剂与哮喘的关联仍存在争议，本研究采用双样本孟德尔随机化（two-sample Mendelian randomization, MR）方法探讨二者间潜在的因果关联。我们从欧洲人群最新的全基因组关联研究（genome-wide association study, GWAS）数据中获取了6类不同的循环绝对抗氧化剂与5类不同的循环代谢型抗氧化剂，涵盖维生素A（视黄醇）、维生素C（抗坏血酸）、维生素E（生育酚）、β-胡萝卜素、番茄红素与尿酸盐。哮喘相关的最新数据取自FinnGen数据库。我们以单核苷酸多态性作为工具变量，开展了5种孟德尔随机化分析方法。为验证结果的可靠性，本研究额外开展了敏感性分析以排除潜在混杂因素，包括异质性与多效性。孟德尔随机化与敏感性分析结果显示，循环尿酸盐与哮喘存在关联，提示哮喘风险可能升高（比值比OR=1.090；95%置信区间CI=1.030~1.150；P=0.004）。其余抗氧化剂未发现存在因果关联。本项孟德尔随机化分析表明，由遗传因素决定的循环尿酸盐水平可能升高哮喘发病风险。未来需开展大规模随机对照试验与中介孟德尔随机化分析，以探索其潜在作用机制。