SGLT2 Inhibition, Choline Metabolites, and Cardiometabolic Diseases: A Mediation Mendelian Randomization Study.
SGLT2 Inhibition, Choline Metabolites, and Cardiometabolic Diseases: A Mediation Mendelian Randomization Study.
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SGLT2 抑制、胆碱代谢物和心脏代谢疾病：孟德尔中介随机化研究
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采用孟德尔随机化（MR）研究胆碱代谢物介导钠-葡萄糖协同转运蛋白2（SGLT 2）抑制在冠状动脉疾病（CAD）和2型糖尿病（T2 D）中的因果作用。使用双样本两步MR确定1）SGLT 2抑制对CAD和T2 D的因果效应; 2）三种胆碱代谢产物（总胆碱、磷脂酰胆碱和甘氨酸）对CAD和T2 D的因果效应; 3）这些代谢产物的介导效应。SGLT 2抑制的遗传代理被确定为与基因表达和血红蛋白A1 c水平相关的SLC 5A 2基因变体。代谢物的汇总统计量来自UK Biobank，CAD来自CARDIOGRAMplusC 4D（冠状动脉疾病全基因组复制和荟萃分析[CARDIOGRAMplusC 4D]遗传学）联盟，T2 D来自DIAbetes遗传学复制和荟萃分析（DIAGRAM）和FinnGen研究。sglt 2抑制（每1 SD，HbA 1c降低6.75 mmol/mol [1.09%]）与T2 D和CAD风险降低相关（比值比[OR]分别为0.25 [95% CI 0.12，0.54]和0.51 [0.28，0.94]），与总胆碱呈正相关（β 0.39 [95% CI 0.06，0.72]）、磷脂酰胆碱（0.40 [0.13，0.67]）和甘氨酸（0.34 [0.05，0.63]）。总胆碱（OR 0.78 [95% CI 0.68，0.89]）和磷脂酰胆碱（OR 0.81 [0.72，0.91]）与T2 D相关，但与CAD无关，而甘氨酸与CAD相关（0.94 [0.91，0.98]），但与T2 D无关。中介分析显示SGLT 2抑制通过总胆碱对T2 D产生间接影响的证据（0.91 [0.83，0.99]）和磷脂酰胆碱（0.93 [0.87，0.99]），介导比例分别为总效应的8%和5%，通过甘氨酸对CAD的影响（0.98 [0.96，1.00]），介导比例为2%。这些结果在至少一个独立的数据集中得到了很好的验证。我们的研究确定了SGLT 2抑制在胆碱代谢物中的因果作用。SGLT 2抑制可能通过不同的胆碱代谢物影响T2 D和CAD。
To investigate the causal role of choline metabolites mediating sodium–glucose cotransporter 2 (SGLT2) inhibition in coronary artery disease (CAD) and type 2 diabetes (T2D) using Mendelian randomization (MR). A two-sample two-step MR was used to determine 1) causal effects of SGLT2 inhibition on CAD and T2D; 2) causal effects of three choline metabolites, total choline, phosphatidylcholine, and glycine, on CAD and T2D; and 3) mediation effects of these metabolites. 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. Summary statistics for metabolites were from UK Biobank, CAD from CARDIoGRAMplusC4D (Coronary ARtery DIsease Genome wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) consortium, and T2D from DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) and the FinnGen study. SGLT2 inhibition (per 1 SD, 6.75 mmol/mol [1.09%] lowering of HbA1c) was associated with lower risk of T2D and CAD (odds ratio [OR] 0.25 [95% CI 0.12, 0.54], and 0.51 [0.28, 0.94], respectively) and positively with total choline (β 0.39 [95% CI 0.06, 0.72]), phosphatidylcholine (0.40 [0.13, 0.67]), and glycine (0.34 [0.05, 0.63]). Total choline (OR 0.78 [95% CI 0.68, 0.89]) and phosphatidylcholine (OR 0.81 [0.72, 0.91]) were associated with T2D but not with CAD, while glycine was associated with CAD (0.94 [0.91, 0.98]) but not with T2D. Mediation analysis showed evidence of indirect effect of SGLT2 inhibition on T2D through total choline (0.91 [0.83, 0.99]) and phosphatidylcholine (0.93 [0.87, 0.99]) with a mediated proportion of 8% and 5% of the total effect, respectively, and on CAD through glycine (0.98 [0.96, 1.00]) with a mediated proportion of 2%. The results were well validated in at least one independent data set. Our study identified the causal roles of SGLT2 inhibition in choline metabolites. SGLT2 inhibition may influence T2D and CAD through different choline metabolites.