State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao, China.
Clinical Trial Research Center, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China.
Eur J Neurol. 2024 Dec;31(12):e16506. doi: 10.1111/ene.16506. Epub 2024 Oct 10.
Previous observational studies have identified correlations between liver enzyme levels and stroke risk. However, the strength and consistency of these associations vary. To comprehensively evaluate the relationship between liver enzymes and stroke risk, we conducted meta-analyses complemented by Mendelian randomization (MR) analyses.
Following the PRISMA guidelines, we performed meta-analyses of prospective studies and conducted subgroup analyses stratified by sex and stroke subtype. Subsequently, adhering to the STROBE-MR guidelines, we performed two-sample bidirectional univariable MR (UVMR) and multivariable MR (MVMR) analyses using the largest genome-wide association studies summary data. Finally, the single-nucleotide polymorphisms associated with liver enzymes on sex differences underwent gene annotation, gene set enrichment, and tissue enrichment analyses.
In the meta-analyses of 17 prospective studies, we found the relative risks for serum γ-glutamyl transferase (GGT) and alkaline phosphatase (ALP) were 1.23 (95% CI: 1.16-1.31) and 1.3 (95% CI: 1.19-1.43), respectively. Subgroup analyses revealed sex and stroke subtype differences in liver enzyme-related stroke risk. Bidirectional UVMR analyses confirmed that elevated GGT, alanine aminotransferase, and aspartate aminotransferase levels were associated with increased stroke occurrence. The primary results from the MVMR analyses revealed that higher ALP levels significantly increased the risk of stroke and ischemic stroke. Gene set and tissue enrichment analyses supported genetic differences in liver enzymes across sexes.
Our study provides evidence linking liver enzyme levels to stroke risk, suggesting liver enzymes as potential biomarkers for early identification of high-risk individuals. Personalized, sex-specific interventions targeting liver enzymes could offer new strategies for stroke prevention.
先前的观察性研究已经确定了肝酶水平与中风风险之间的相关性。然而，这些关联的强度和一致性存在差异。为了全面评估肝酶与中风风险之间的关系，我们进行了荟萃分析，并辅以孟德尔随机化（MR）分析。
根据 PRISMA 指南，我们对前瞻性研究进行了荟萃分析，并按性别和中风亚型进行了亚组分析。随后，根据 STROBE-MR 指南，我们使用最大的全基因组关联研究汇总数据进行了两样本双向单变量 MR（UVMR）和多变量 MR（MVMR）分析。最后，对与肝酶性别差异相关的单核苷酸多态性进行基因注释、基因集富集和组织富集分析。
在 17 项前瞻性研究的荟萃分析中，我们发现血清 γ-谷氨酰转移酶（GGT）和碱性磷酸酶（ALP）的相对风险分别为 1.23（95%CI：1.16-1.31）和 1.3（95%CI：1.19-1.43）。亚组分析显示，肝酶相关中风风险存在性别和中风亚型差异。双向 UVMR 分析证实，升高的 GGT、丙氨酸氨基转移酶和天冬氨酸氨基转移酶水平与中风发生风险增加相关。MVMR 分析的主要结果表明，较高的 ALP 水平显著增加了中风和缺血性中风的风险。基因集和组织富集分析支持了男女之间肝酶的遗传差异。
我们的研究提供了肝酶水平与中风风险相关的证据，表明肝酶可能是识别高危个体的潜在生物标志物。针对肝酶的个性化、性别特异性干预措施可能为中风预防提供新策略。
