Abstract：
This study aimed to investigate the causal role of diabetes mellitus (DM), glycemic traits, and sodium-glucose cotransporter 2 (SGLT2) inhibition in pulmonary arterial hypertension (PAH). Utilizing a two-sample two-step Mendelian randomization (MR) approach, we determined the causal influence of DM and glycemic traits (including insulin resistance, glycated hemoglobin, and fasting insulin and glucose) on the risk of PAH. Moreover, we examined the causal effects of SGLT2 inhibition on the risk of PAH. Genetic proxies for SGLT2 inhibition were identified as variants in the SLC5A2 gene that were associated with both levels of gene expression and hemoglobin A1c. Results showed that genetically inferred DM demonstrated a causal correlation with an increased risk of PAH, exhibiting an odds ratio (OR) of 1.432, with a 95% confidence interval (CI) of 1.040-1.973, and a p-value of 0.028. The multivariate MR analysis revealed comparable outcomes after potential confounders (OR = 1.469, 95%CI = 1.021-2.115, p = 0.038). Moreover, genetically predicted SGLT2 inhibition was causally linked to a reduced risk of PAH (OR = 1.681*10-7, 95%CI = 7.059*10-12-0.004, p = 0.002). Therefore, our study identified the suggestively causal effect of DM on the risk of PAH, and SGLT2 inhibition may be a potential therapeutic target in patients with PAH.
摘要：
本研究旨在探讨糖尿病（DM）的因果作用，血糖性状，和钠-葡萄糖协同转运蛋白2（SGLT2）在肺动脉高压（PAH）中的抑制作用。利用两样本两步孟德尔随机化(MR)方法，我们确定了DM和血糖性状(包括胰岛素抵抗，糖化血红蛋白,和空腹胰岛素和葡萄糖）对PAH的风险。此外，我们研究了SGLT2抑制对PAH风险的因果效应.SGLT2抑制的遗传代理被鉴定为SLC5A2基因中的变体,其与基因表达水平和血红蛋白A1c两者相关。结果显示，遗传推断的DM显示出与PAH风险增加的因果关系，比值比（OR）为1.432，95%置信区间（CI）为1.040-1.973，p值为0.028。多变量MR分析显示潜在混杂因素后的结果具有可比性（OR=1.469，95CI=1.021-2.115，p=0.038）。此外，基因预测的SGLT2抑制与PAH风险降低有因果关系(OR=1.681*10-7,95CI=7.059*10-12-0.004,p=0.002).因此,我们的研究确定了DM对PAH风险的暗示因果关系，和SGLT2抑制可能是PAH患者的潜在治疗靶点。
