Xu Qian, Liang Xinyu, Shi Wei, Zhang Huafeng
School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, People's Republic of China.
Department of Orthopedics, Tianjin Medical University General Hospital, Tianjin, 300052, People's Republic of China.
Int Urol Nephrol. 2025 Jun 6. doi: 10.1007/s11255-025-04594-z.
The strong association between hyperuricemia and cardiovascular diseases prompts this study to investigate the effects of uric acid-lowering drugs, GLUT9 and URAT1 inhibitors (GLUT9i and URAT1i), on cardiovascular diseases using Mendelian randomization (MR) analyses.
In GWAS data, SNPs strongly associated with blood uric acid within 100 kb regions around the GLUT9 and URAT1 genes are identified, serving as proxies for the targeted effects of genes on uric acid. Subsequently, these SNPs were utilized for MR analyses with gout, common cardiovascular diseases (heart failure, myocardial infarction, ischemic stroke, venous thromboembolism), and their risk factors (blood glucose, lipid levels, blood pressure). MR-Egger was employed for pleiotropy testing, and Cochran's Q test was utilized for heterogeneity testing to ensure the robustness of the MR analysis.
Both URAT1i and GLUT9i are effective drugs for gout. URAT1i is associated with a reduced risk of heart failure (OR 0.76, 95% CI 0.63, 0.92, P = 0.004), decreased diastolic blood pressure (β = - 0.07, 95% CI - 0.13, 0.00, P = 0.048), reduced high-density lipoprotein levels (β = - 0.05, 95% CI - 0.10, - 0.01, P = 0.016), and increased fasting blood glucose levels (β = 0.07, 95% CI 0.02, 0.13, P = 0.006). Conversely, GLUT9i leads to reductions in fasting blood glucose (β = - 0.03, 95% CI - 0.05, - 0.01, P = 0.013) and diastolic blood pressure (β = - 0.03, 95% CI - 0.05, - 0.01, P = 0.005), and increases in high-density lipoprotein (β = 0.02, 95% CI 0.00, 0.03, P = 0.011).
For patients suffering from gout in conjunction with conditions like hyperglycemia, dyslipidemia, and hypertension, GLUT9i may represent a more promising therapeutic approach.
高尿酸血症与心血管疾病之间的密切关联促使本研究采用孟德尔随机化（MR）分析来探究降尿酸药物、葡萄糖转运蛋白9（GLUT9）和尿酸盐转运体1（URAT1）抑制剂（GLUT9i和URAT1i）对心血管疾病的影响。
在全基因组关联研究（GWAS）数据中，识别出GLUT9和URAT1基因周围100 kb区域内与血尿酸密切相关的单核苷酸多态性（SNP），作为基因对尿酸靶向作用的替代指标。随后，将这些SNP用于痛风、常见心血管疾病（心力衰竭、心肌梗死、缺血性中风、静脉血栓栓塞）及其危险因素（血糖、血脂水平、血压）的MR分析。采用MR-Egger进行多效性检验，采用 Cochr an Q检验进行异质性检验，以确保MR分析的稳健性。
URAT1i和GLUT9i都是治疗痛风的有效药物。URAT1i与心力衰竭风险降低相关（比值比[OR]0.76，95%置信区间[CI]0.63，0.92，P = 0.004），舒张压降低（β = -0.07，95% CI -0.13，0.00，P = 0.048），高密度脂蛋白水平降低（β = -0.05，95% CI -0.10，-0.01，P = 0.016），空腹血糖水平升高（β = 0.07，95% CI 0.02，0.13，P = 0.006）。相反，GLUT9i可导致空腹血糖降低（β = -0.03，95% CI -0.05，-0.01，P = 0.013）和舒张压降低（β = -0.03，95% CI -0.05，-0.01，P = 0.005），以及高密度脂蛋白升高（β = 0.02，95% CI 0.00，0.03，P = 0.011）。
对于患有痛风并伴有高血糖、血脂异常和高血压等疾病的患者，GLUT9i可能是一种更有前景的治疗方法。
