常见变异可增加 ASCEND-HF 试验心衰患者的死亡率或再住院风险。
Common Variants on Increase Hazard of Mortality or Rehospitalization in Patients With Heart Failure From the ASCEND-HF Trial.
机构信息
Center for Individualized and Genomics Medicine Research (H.G., J.A.L., L.K.W., D.E.L.), Henry Ford Hospital, Detroit, MI.
Department of Cardiovascular Medicine, Cleveland Clinic, OH (W.H.W.T., P.B.).
出版信息
Circ Heart Fail. 2023 Sep;16(9):e010438. doi: 10.1161/CIRCHEARTFAILURE.122.010438. Epub 2023 Jul 26.
BACKGROUND
Heart failure remains a global health burden, and patients hospitalized are particularly at risk, but genetic associates for subsequent death or rehospitalization are still lacking.
METHODS
The genetic substudy of the ASCEND-HF trial (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) was used to perform genome-wide association study and transethnic meta-analysis. The overall trial included the patients of self-reported European ancestry (n=2173) and African ancestry (n=507). The end point was death or heart failure rehospitalization within 180 days. Cox models adjusted for 11 a priori predictors of rehospitalization and 5 genetic principal components were used to test the association between single-nucleotide polymorphisms and outcome. Summary statistics from the 2 populations were combined via meta-analysis with the significance threshold considered <5×10.
RESULTS
Common variants (rs2342882 and rs35850039 in complete linkage disequilibrium) located in were significantly associated with the primary outcome in both ancestry groups (European Americans: hazard ratio [HR], 1.38; =2.42×10; African ancestry: HR, 1.51; =4.43×10; HR in meta-analysis, 1.41; =4.25×10). encodes a regulator of VEGF (vascular endothelial growth factor)-mediated angiogenesis, and in silico investigation revealed several previous genome-wide association study hits in this gene, among which rs748431 was associated with our outcome (HR, 1.20; meta <0.01). Sensitivity analysis proved common variants survival association did not appear to operate via coronary artery disease or nesiritide treatment (>0.05); and the signal was still significant when changing the censoring time from 180 to 30 days (HR, 1.39; =1.59×10).
CONCLUSIONS
In this multiethnic genome-wide association study of ASCEND-HF, single-nucleotide polymorphisms in were associated with increased risk of death or rehospitalization. Additional investigation is required to examine biological mechanisms and whether could be a therapeutic target.
REGISTRATION
URL: https://www.
CLINICALTRIALS
gov; Unique identifier: NCT00475852.
背景
心力衰竭仍然是全球健康负担，住院患者尤其面临风险，但随后死亡或再住院的遗传相关性仍不清楚。
方法
ASCEND-HF 试验（急性心力衰竭中奈西立肽临床疗效的研究）的遗传子研究用于进行全基因组关联研究和跨种族荟萃分析。整个试验包括报告有欧洲血统（n=2173）和非洲血统（n=507）的患者。终点为 180 天内死亡或心力衰竭再住院。使用调整了再住院 11 个先验预测因子和 5 个遗传主成分的 Cox 模型来检验单核苷酸多态性与结果之间的关联。通过荟萃分析合并来自 2 个群体的汇总统计数据，显著阈值<5×10。
结果
位于 （血管内皮生长因子介导的血管生成调节剂）的常见变体（完全连锁不平衡的 rs2342882 和 rs35850039）在两个血统组中与主要结果显著相关（欧洲裔美国人：危险比 [HR]，1.38；=2.42×10；非洲裔美国人：HR，1.51；=4.43×10；荟萃分析中的 HR，1.41；=4.25×10）。 编码 VEGF（血管内皮生长因子）介导的血管生成调节剂，体内研究显示该基因中存在多个先前的全基因组关联研究命中，其中 rs748431 与我们的结果相关（HR，1.20；荟萃分析<0.01）。敏感性分析表明，常见变体的生存关联似乎并非通过冠状动脉疾病或奈西立肽治疗（>0.05）发挥作用；当将截止时间从 180 天更改为 30 天时，信号仍然显著（HR，1.39；=1.59×10）。
结论
在 ASCEND-HF 的这项多民族全基因组关联研究中，位于 的单核苷酸多态性与死亡或再住院风险增加相关。需要进一步研究以检查生物学机制以及 是否可以成为治疗靶点。
注册
临床试验
gov；唯一标识符：NCT00475852。
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