Basgenbio Inc., Seoul, Republic of Korea.
Department of Statistics and Actuarial Science, College of Natural Sciences, Soongsil University, Seoul, Republic of Korea.
Sci Rep. 2024 Jan 16;14(1):1338. doi: 10.1038/s41598-024-51724-1.
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.
虽然黄嘌呤氧化酶抑制剂等尿酸降低剂具有潜在的心脏保护作用，但关于其在预防心血管疾病中的应用的研究还很缺乏。我们在一个按脂质水平分层的人群中研究了降低尿酸对缺血性心血管疾病的遗传相关性影响。我们使用英国生物库（UK Biobank）的数据进行了药物靶点孟德尔随机化（MR）分析，以在尿酸降低基因黄嘌呤脱氢酶（XDH）内选择遗传工具，并构建遗传评分。对于非线性 MR 分析，根据脂质水平对个体进行分层。结果包括急性心肌梗死（AMI）、缺血性心脏病、脑梗死、短暂性脑缺血发作、整体缺血性疾病和痛风。我们纳入了 474983 名患有 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）、甘油三酯≥188.00mg/dL 的个体中 AMI（OR，0.79；95%CI，0.66-0.94；P=0.010），以及 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）的个体中的脑梗死。XDH 变体诱导的尿酸降低降低了高甘油三酯个体的痛风、AMI 以及除高 LDL-C 个体以外的脑梗死风险，突出了黄嘌呤氧化酶抑制剂治疗 AMI 和脑梗死的保护作用在不同的脂质谱下可能存在异质性。
