PDF(Pubmed)
Abstract：
Although uric acid-lowering agents such as xanthine oxidase inhibitors have potential cardioprotective effects, studies on their use in preventing cardiovascular diseases are lacking. We investigated the genetically proxied effects of reducing uric acid on ischemic cardiovascular diseases in a lipid-level-stratified population. We performed drug-target Mendelian randomization (MR) analyses using UK Biobank data to select genetic instruments within a uric acid-lowering gene, xanthine dehydrogenase (XDH), and construct genetic scores. For nonlinear MR analyses, individuals were stratified by lipid level. Outcomes included acute myocardial infarction (AMI), ischemic heart disease, cerebral infarction, transient cerebral ischemic attack, overall ischemic disease, and gout. We included 474,983 non-gout individuals with XDH-associated single-nucleotide polymorphisms. The XDH-variant-induced uric acid reduction was associated with reduced risk of gout (odds ratio [OR], 0.85; 95% confidence interval [CI], 0.78-0.93; P < 0.001), cerebral infarction (OR, 0.86; 95% CI, 0.75-0.98; P = 0.023), AMI (OR, 0.79; 95% CI, 0.66-0.94; P = 0.010) in individuals with triglycerides ≥ 188.00 mg/dL, and cerebral infarction in individuals with low-density lipoprotein cholesterol (LDL-C) ≤ 112.30 mg/dL (OR, 0.76; 95% CI, 0.61-0.96; P = 0.020) or LDL-C of 136.90-157.40 mg/dL (OR, 0.67; 95% CI, 0.49-0.92; P = 0.012). XDH-variant-induced uric acid reduction lowers the risk of gout, AMI for individuals with high triglycerides, and cerebral infarction except for individuals with high LDL-C, highlighting the potential heterogeneity in the protective effects of xanthine oxidase inhibitors for treating AMI and cerebral infarction depending on the lipid profiles.
摘要：
尽管降低尿酸的药物如黄嘌呤氧化酶抑制剂具有潜在的心脏保护作用,缺乏关于它们在预防心血管疾病中的应用的研究。我们研究了降低尿酸对脂质水平分层人群缺血性心血管疾病的遗传代理作用。我们使用UKBiobank数据进行药物靶向孟德尔随机化（MR）分析，以选择降低尿酸的基因中的遗传工具。黄嘌呤脱氢酶（XDH），并构建遗传评分。对于非线性MR分析，个体按血脂水平分层。结果包括急性心肌梗死（AMI），缺血性心脏病,脑梗塞,短暂性脑缺血发作,整体缺血性疾病，还有痛风.我们纳入了474,983名具有XDH相关单核苷酸多态性的非痛风个体。XDH变体诱导的尿酸降低与痛风风险降低相关（比值比[OR]，0.85；95%置信区间[CI]，0.78-0.93；P<0.001），脑梗死（OR，0.86；95%CI，0.75-0.98；P=0.023），AMI(或,0.79；95%CI，0.66-0.94；P=0.010）在甘油三酯≥188.00mg/dL的个体中，低密度脂蛋白胆固醇（LDL-C）≤112.30mg/dL（OR，0.76；95%CI，0.61-0.96；P=0.020）或LDL-C为136.90-157.40mg/dL（OR，0.67；95%CI，0.49-0.92；P=0.012）。XDH变体诱导的尿酸降低降低了痛风的风险，高甘油三酯的个体的AMI，和脑梗塞，除了高LDL-C的个体，强调黄嘌呤氧化酶抑制剂治疗AMI和脑梗死的保护作用的潜在异质性取决于血脂谱。
