位于人类6号染色体上的VEGF - A顺式定位单核苷酸多态性与冠心病队列中的VEGF - A血浆水平及生存率相关。

VEGF-A cis-located SNPs on human chromosome 6 associated with VEGF-A plasma levels and survival in a coronary disease cohort.

作者信息

Meza-Alvarado J C, Pilbrow A P, Frampton C M, Cameron V A, Richards A M, Troughton R W, Doughty R N, Page R A, Mallard B, Bromhead C, Palmer B R

机构信息

School of Health Sciences, School of Health Sciences, Massey University, Wellington, New Zealand.

The Christchurch Heart Institute, University of Otago, Christchurch, New Zealand.

出版信息

BMC Cardiovasc Disord. 2025 Apr 17;25(1):290. doi: 10.1186/s12872-025-04751-3.

DOI:10.1186/s12872-025-04751-3

PMID:40247170

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12004769/

Abstract

BACKGROUND

Cardiovascular disease (CVD) is the leading cause of death worldwide. Risk stratification of CVD patients may be improved by predictive biomarkers, including genetic markers. Elevated circulating vascular endothelial growth factor A (VEGF-A) levels have been linked to CVD development. We explored whether single nucleotide polymorphisms (SNPs) at the VEGFA locus on human chromosome 6 were associated with VEGF-A levels and clinical outcomes in established CVD. VEGF-A levels were compared between coronary heart disease patients and heart healthy controls.

METHODS

Imputed genotypes of 30 SNPs from the VEGFA region for 1935 patients from the Coronary Disease Cohort Study (CDCS) and 1183 individuals from the Canterbury Healthy Volunteers Study (HVOL) were analysed for associations with cardiometabolic parameters. Association with clinical endpoints was assessed using Kaplan-Meier analysis and multivariate regression models. To validate the findings from imputed data, DNA samples of 2027 CDCS patients and 227 HVOL participants were manually genotyped for variants rs6921438 and rs7767396. Baseline plasma VEGF-A assayed by ELISA in 227 HVOL participants was compared with levels in 549 CDCS patients.

RESULTS

Manual genotyping showed rs6921438 AA and rs7767396 GG genotype groups had lower VEGF-A levels at baseline (CDCS: rs6921438 AA (27.7 pg/mL), AG (43.3 pg/mL), GG (63.2 pg/mL), p = 4.49 × 10; rs7767396: GG (27.4 pg/mL), AG (42.8 pg/mL), AA (61.5 pg/mL) p = 3.47 × 10; HVOL rs6921438 AA (12.8 pg/mL), GA (19.9 pg/mL), GG (26.4 pg/mL) p = 0.021; rs7767396 GG (12.6 pg/mL), AG (19.6 pg/mL), AA (25.9 pg/mL) p = 0.029). In the CDCS cohort rs6921438 AA was associated with increased risk of all-cause death (p = 0.03); non ST-elevated myocardial infarction (NSTEMI, p = 0.0003), heart failure (HF, p = 0.035) and major adverse cardiovascular events (p = 0.032); rs7767396 GG was associated with increased NSTEMI (p = 0.001) and HF (p = 0.023) risk; rs6921438 AA (Hazard Ratio (HR) = 6.55 p = 0.017), rs7767396 GG (HR = 0.149, p = 0.017) and VEGF-A (HR = 2.55, p = 0.018) were independent HF admission risk predictors.

CONCLUSIONS

Variants rs6921438 and rs7767396 are associated with plasma VEGF-A levels. Both SNPs and VEGF-A may be useful in prognosis for HF after acute coronary events.

摘要

背景

心血管疾病（CVD）是全球主要的死亡原因。包括基因标记在内的预测性生物标志物可能会改善CVD患者的风险分层。循环血管内皮生长因子A（VEGF-A）水平升高与CVD的发展有关。我们探讨了人类6号染色体上VEGFA基因座的单核苷酸多态性（SNP）是否与已确诊CVD患者的VEGF-A水平及临床结局相关。比较了冠心病患者与心脏健康对照者的VEGF-A水平。

方法

对来自冠心病队列研究（CDCS）的1935例患者和坎特伯雷健康志愿者研究（HVOL）的1183例个体的VEGFA区域的30个SNP的推算基因型进行分析，以确定其与心脏代谢参数的关联。使用Kaplan-Meier分析和多变量回归模型评估与临床终点的关联。为了验证推算数据的结果，对2027例CDCS患者和227例HVOL参与者的DNA样本进行手动基因分型，检测rs-6921438和rs7767396变异。采用酶联免疫吸附测定法（ELISA）检测227例HVOL参与者的基线血浆VEGF-A水平，并与549例CDCS患者的水平进行比较。

结果

手动基因分型显示，rs6921438 AA和rs7767396 GG基因型组在基线时VEGF-A水平较低（CDCS：rs6921438 AA（27.7 pg/mL），AG（43.3 pg/mL），GG（63.2 pg/mL），p = 4.49×10；rs7767396：GG（27.4 pg/mL），AG（42.8 pg/mL），AA（61.5 pg/mL）p = 3.47×10；HVOL rs6921438 AA（12.8 pg/mL），GA（19.9 pg/mL），GG（26.4 pg/mL）p = 0.021；rs7767396 GG（12.6 pg/mL），AG（19.6 pg/mL），AA（25.9 pg/mL）p = 0.029）。在CDCS队列中，rs6921438 AA与全因死亡风险增加相关（p = 0.03）；非ST段抬高型心肌梗死（NSTEMI，p = 0.0003）、心力衰竭（HF，p = 0.035）和主要不良心血管事件（p = 0.032）；rs7767396 GG与NSTEMI风险增加相关（p = 0.001）和HF（p = .023）风险；rs6921438 AA（风险比（HR）= 6.55，p = 0.017）、rs7767396 GG（HR = 0.149，p = 0.017）和VEGF-A（HR = 2.55，p = 0.018）是HF入院风险的独立预测因素。