肥胖导致中风风险的高凝机制：一项孟德尔随机化研究。

Mechanisms of Hypercoagulability Driving Stroke Risk in Obesity: A Mendelian Randomization Study.

机构信息

From the Department of Neurology (I.D.), University of California, San Francisco; and Department of Epidemiology and Biostatistics (D.G.), School of Public Health, Imperial College London, United Kingdom.

出版信息

Neurology. 2024 Jul 9;103(1):e209431. doi: 10.1212/WNL.0000000000209431. Epub 2024 Jun 11.

DOI:10.1212/WNL.0000000000209431

PMID:38861688

Abstract

BACKGROUND AND OBJECTIVES: Obesity is hypothesized to induce a hypercoagulable state that increases stroke risk. The molecular mechanisms underlying this association are largely uncharacterized. We aimed to apply mendelian randomization to identify whether the association of genetically proxied body mass index (BMI) with cardioembolic stroke risk is mediated by changes in levels of circulating coagulation factors. METHODS: Genetic proxies for BMI and levels of circulating coagulation factors were obtained, respectively, from the Genetic Investigation of ANthropometric Traits consortium (n = 694,649) and deCODE cohort (n = 35,559). Genetic associations with cardioembolic stroke risk were obtained from the GIGASTROKE consortium (10,804 cases and 1,234,804 controls). We performed a two-sample mendelian randomization analysis testing the association of genetically proxied BMI with cardioembolic stroke risk, genetically proxied BMI with levels of coagulation factors, and genetically proxied levels of coagulation factors with cardioembolic stroke risk. These estimates were carried forward to mediation and sensitivity analyses. RESULTS: A 1-SD increase in genetically proxied BMI associated with increased cardioembolic stroke risk (OR of cardioembolic stroke per 1-SD of BMI 1.20, 95% CI 1.08-1.33, = 8.65 × 10) with similar findings in statistical sensitivity analyses more robust to the inclusion of pleiotropic variants. Genetically proxied BMI was further associated with increased levels of Factor VII, Factor Xa, Factor XI, and Protein S (all < 5.9 × 10). Of these factors, genetically proxied levels of Factor XI were associated with cardioembolic stroke risk (OR of cardioembolic stroke per 1-SD increase in Factor XI levels 1.32, 1.19-1.46, = 6.18 × 10). The mediated effect of genetically proxied BMI through Factor XI accounted for 26% (6%-49%) of the total effect of BMI on cardioembolic stroke. DISCUSSION: Human genetic data support increased levels of Factor XI as a mechanistic explanation for how obesity increases cardioembolic stroke risk. The clinical relevance of this association warrants further investigation within ongoing clinical trials of Factor XI inhibition.

摘要

背景与目的：肥胖被认为会导致高凝状态，从而增加中风风险。但这种关联的分子机制在很大程度上仍未被描述。我们旨在应用孟德尔随机化来确定与遗传性 BMI 相关的心血管栓塞性中风风险是否由循环凝血因子水平的变化介导。

方法：分别从遗传因素与人体测量特征研究（Genetic Investigation of ANthropometric Traits consortium，GIGASTROKE）联盟（n=694649）和 deCODE 队列（n=35559）中获得了遗传上与 BMI 相关的代表性指标和循环凝血因子水平的遗传代表性指标。从 GIGASTROKE 联盟（10804 例病例和 1234804 例对照）中获得了与心血管栓塞性中风风险相关的遗传关联。我们进行了两样本孟德尔随机化分析，以检验遗传上与 BMI 相关的代表性指标与心血管栓塞性中风风险的关联、遗传上与凝血因子相关的代表性指标与凝血因子水平的关联以及遗传上与凝血因子相关的代表性指标与心血管栓塞性中风风险的关联。这些估计值被进一步用于中介和敏感性分析。

结果：遗传上与 BMI 相关的代表性指标每增加 1 个标准差，与心血管栓塞性中风风险增加相关（每增加 1 个 BMI 标准差，心血管栓塞性中风的比值比为 1.20，95%CI 为 1.08-1.33， = 8.65×10），且在更稳健的统计敏感性分析中也有类似的发现，这些分析对包含多效性变异的情况更具包容性。遗传上与 BMI 相关的代表性指标还与因子 VII、因子 Xa、因子 XI 和蛋白 S 水平升高相关（所有<5.9×10）。在这些因子中，遗传上与因子 XI 相关的代表性指标与心血管栓塞性中风风险相关（每增加 1 个因子 XI 水平标准差，心血管栓塞性中风的比值比为 1.32，1.19-1.46， = 6.18×10）。遗传上与 BMI 相关的代表性指标通过因子 XI 介导的效应占 BMI 对心血管栓塞性中风总效应的 26%（6%-49%）。

讨论：人类遗传数据支持因子 XI 水平升高是肥胖增加心血管栓塞性中风风险的机制解释。这一关联的临床意义需要在正在进行的因子 XI 抑制临床试验中进一步研究。