Second Department of Cardiovascular Medicine, Shaanxi Provincial People' Hospital, Xi'an City, 710068, Shaanxi Province, People's Republic of China.
Sci Rep. 2024 Aug 17;14(1):19052. doi: 10.1038/s41598-024-69728-2.
Atherosclerosis (AS) is one of the most common causes of death from cardiovascular disease, and low folic acid (FA) levels have been reported to be strongly associated with an increased risk of AS. We aimed to obtain causal estimates of the association between FA and AS and to quantify the mediating role of known modifiable risk factors. Based on the largest genome-wide association study (GWAS) from the IEU Open GWAS Project for all human studies, we conducted a two-sample Mendelian randomization (MR) study of genetically predicted FA and AS. A two-step MR design was then used to assess the causal mediating effect of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) on the relationship between FA and AS. This MR analysis showed that genetically determined FA levels [IVW: Odds Ratio (OR) = 0.623, 95% CI 0.421-0.924, P = 0.018] were associated with a reduced risk of AS. Inverse variance weighted (IVW) MR analysis also showed that genetically predicted FA was positively correlated with HDL-C levels (OR = 1.358, 95% CI 1.029-1.792, P = 0.031) and negatively correlated with LDL-C (OR = 0.956, 95% CI 0.920-0.994, P = 0.023) and TG levels (OR = 0.929, 95% CI 0.886-0.974, P = 0.003). LDL-C, HDL-C, and TG mediate 3.00%, 6.80%, and 4.40%, respectively, of the total impact of FA on AS. The combined effect of these three factors accounts for 13.04% of the total effect. Sensitivity analysis verifies the stability and reliability of the results. These results support a potential causal protective effect of FA on AS, with considerable mediation through many modifiable risk factors. Thus, interventions on levels of LDL-C, HDL-C, and TG have the potential to substantially reduce the burden of AS caused by low FA.
动脉粥样硬化 (AS) 是心血管疾病死亡的最常见原因之一，低叶酸 (FA) 水平与 AS 风险增加密切相关。我们旨在确定 FA 与 AS 之间的关联的因果估计，并量化已知可改变的危险因素的中介作用。基于 IEU Open GWAS 项目对所有人类研究的最大全基因组关联研究 (GWAS)，我们进行了一项基于遗传预测的 FA 和 AS 的两样本孟德尔随机化 (MR) 研究。然后使用两步 MR 设计来评估 LDL-C、HDL-C 和甘油三酯 (TG) 对 FA 与 AS 之间关系的因果中介效应。这项 MR 分析表明，遗传决定的 FA 水平 [IVW：比值比 (OR) = 0.623，95%置信区间 0.421-0.924，P = 0.018] 与 AS 风险降低相关。逆方差加权 (IVW) MR 分析还表明，遗传预测的 FA 与 HDL-C 水平呈正相关 (OR = 1.358，95%置信区间 1.029-1.792，P = 0.031)，与 LDL-C (OR = 0.956，95%置信区间 0.920-0.994，P = 0.023) 和 TG 水平呈负相关 (OR = 0.929，95%置信区间 0.886-0.974，P = 0.003)。LDL-C、HDL-C 和 TG 分别介导 FA 对 AS 的总影响的 3.00%、6.80%和 4.40%。这三个因素的综合效应占总效应的 13.04%。敏感性分析验证了结果的稳定性和可靠性。这些结果支持 FA 对 AS 具有潜在的因果保护作用，并且通过许多可改变的危险因素进行了大量的中介作用。因此，干预 LDL-C、HDL-C 和 TG 水平有可能大大降低由低 FA 引起的 AS 负担。
