血细胞特征和心脏代谢疾病风险的遗传决定因素：孟德尔随机化和观察分析的三角测量证据

IF 4.9 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Atherosclerosis Pub Date : 2025-06-12 DOI:10.1016/j.atherosclerosis.2025.120409

Jingxian Huang , Devendra Meena , Alexander Smith , Verena Zuber , Rui Climaco Pinto , Marie-Joe Dib , Ioanna Tzoulaki , Abbas Dehghan

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引用次数: 0

摘要

背景和目的血细胞特征（bct）通过炎症、血栓形成、内皮功能障碍和脂质代谢等机制与心脏代谢疾病（cmd）相关。bct可以作为易于获得的、具有成本效益的生物标志物来增强CVD风险预测，如果证实因果关系，也可能成为新的治疗靶点。本研究检测了29个bct和20个cmd之间的遗传结构和潜在的因果关系。方法采用单变量孟德尔随机化（UVMR），以反方差加权为主要方法，MR-Egger和加权中位数为敏感性分析，MR-PRESSO检测多效异常值。采用多变量MR贝叶斯模型平均（MR- bma）对最可能的因果因素进行优先排序。为了验证研究结果，我们对约40万英国生物银行参与者进行了观察性分析。结果vmr显示血小板栓塞与心源性卒中相关（对数比值比[logORUVMR]: 2.63），这一发现也被MR-BMA优先考虑（边际包含概率（MIP）： 0.96），并得到观察性分析的支持（危险比（HR）： 1.11）。我们发现了中性粒细胞和红细胞分布宽度与小血管卒中（logORUVMR: 0.10）和冠状动脉疾病（logORUVMR: 0.06）之间潜在因果关系的证据，这一发现进一步得到了观察性数据分析的支持(hr小血管卒中：1.22；冠状动脉疾病：1.16)。此外，较高的血红蛋白浓度与较低的脉压（θUVMR:−0.64）有关，MR-BMA （MIP: 0.97）进一步支持了这一点。此外，网状红细胞指数与低密度脂蛋白胆固醇（θUVMR: 1.22）和总胆固醇（θUVMR: 1.06）相关，并且被确定为MR-BMA中这些结果的首要危险因素。结论本研究为bct对慢性阻塞性肺疾病的潜在因果效应提供了支持证据，为精准医学方法的新生物标志物和治疗靶点的开发奠定了基础。

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Genetic determinants of blood-cell traits and the risk of cardiometabolic Diseases: Triangulating evidence from Mendelian randomization and observational analyses

Background and aims

Blood cell traits (BCTs) are linked to cardiometabolic diseases (CMDs) through mechanisms such as inflammation, thrombosis, endothelial dysfunction, and lipid metabolism. BCTs could serve as readily available, cost-effective biomarkers to enhance CVD risk prediction and, if proven causal, may also emerge as novel therapeutic targets. This study examined the genetic architecture and tested potential causal relations between 29 BCTs and 20 CMDs.

Methods

We employed univariable Mendelian randomization (UVMR) using inverse-variance weighting as the primary method, MR-Egger and weighted-median as sensitivity analyses, and MR-PRESSO to detect pleiotropic outliers. Multivariable MR Bayesian Model Averaging (MR-BMA) was applied to prioritize the most likely causal factors. To validate findings, we conducted observational analyses among ∼0.4 million UK Biobank participants.

Results

UVMR demonstrated that plateletcrit is associated with cardioembolic stroke (log odds ratio [logOR_UVMR]: 2.63), a finding also prioritized by MR-BMA (marginal inclusion probability (MIP): 0.96) and supported by observational analysis (hazard ratio (HR): 1.11). We found evidence supporting a potential causal association of neutrophils and red cell distribution width with small-vessel stroke (logOR_UVMR: 0.10) and coronary artery disease (logOR_UVMR: 0.06), a finding that was further supported by observational data analyses (HR_{small-vessel stroke}: 1.22; HR_{coronary artery disease}: 1.16). Additionally, higher haemoglobin concentration was linked to lower pulse pressure (θ_UVMR: −0.64), with further support from MR-BMA (MIP: 0.97). Furthermore, reticulocyte indices were associated with both low-density lipoprotein cholesterol (θ_UVMR: 1.22) and total cholesterol (θ_UVMR: 1.06), and it was identified as a top-ranked risk factor for these outcomes in MR-BMA.

Conclusions

Our study provides supporting evidence for a potential causal effect of BCTs on CMDs, which might pave the way for novel biomarkers and therapeutic targets for precision medicine approaches.

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来源期刊

Atherosclerosis 医学-外周血管病

CiteScore

9.80

自引率

3.80%

发文量

1269

审稿时长

36 days

期刊介绍： Atherosclerosis has an open access mirror journal Atherosclerosis: X, sharing the same aims and scope, editorial team, submission system and rigorous peer review. Atherosclerosis brings together, from all sources, papers concerned with investigation on atherosclerosis, its risk factors and clinical manifestations. Atherosclerosis covers basic and translational, clinical and population research approaches to arterial and vascular biology and disease, as well as their risk factors including: disturbances of lipid and lipoprotein metabolism, diabetes and hypertension, thrombosis, and inflammation. The Editors are interested in original or review papers dealing with the pathogenesis, environmental, genetic and epigenetic basis, diagnosis or treatment of atherosclerosis and related diseases as well as their risk factors.