遗传易感性导致欧洲人慢性疾病引发心力衰竭：白细胞端粒长度的影响。
Genetic susceptibility to chronic diseases leads to heart failure among Europeans: the influence of leukocyte telomere length.
机构信息
Epidemiology and Community Health Branch, National Heart Lung and Blood Institute, 10 Center Drive, Bethesda, MD 20892, United States.
Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Rockville, MD 20850, United States.
出版信息
Hum Mol Genet. 2024 Jul 6;33(14):1262-1272. doi: 10.1093/hmg/ddae063.
BACKGROUND
Genetic susceptibility to various chronic diseases has been shown to influence heart failure (HF) risk. However, the underlying biological pathways, particularly the role of leukocyte telomere length (LTL), are largely unknown. We investigated the impact of genetic susceptibility to chronic diseases and various traits on HF risk, and whether LTL mediates or modifies the pathways.
METHODS
We conducted prospective cohort analyses on 404 883 European participants from the UK Biobank, including 9989 incident HF cases. Multivariable Cox regression was used to estimate associations between HF risk and 24 polygenic risk scores (PRSs) for various diseases or traits previously generated using a Bayesian approach. We assessed multiplicative interactions between the PRSs and LTL previously measured in the UK Biobank using quantitative PCR. Causal mediation analyses were conducted to estimate the proportion of the total effect of PRSs acting indirectly through LTL, an integrative marker of biological aging.
RESULTS
We identified 9 PRSs associated with HF risk, including those for various cardiovascular diseases or traits, rheumatoid arthritis (P = 1.3E-04), and asthma (P = 1.8E-08). Additionally, longer LTL was strongly associated with decreased HF risk (P-trend = 1.7E-08). Notably, LTL strengthened the asthma-HF relationship significantly (P-interaction = 2.8E-03). However, LTL mediated only 1.13% (P < 0.001) of the total effect of the asthma PRS on HF risk.
CONCLUSIONS
Our findings shed light onto the shared genetic susceptibility between HF risk, asthma, rheumatoid arthritis, and other traits. Longer LTL strengthened the genetic effect of asthma in the pathway to HF. These results support consideration of LTL and PRSs in HF risk prediction.
背景
遗传易感性与各种慢性疾病相关，其被证实会影响心力衰竭（HF）的发病风险。然而，潜在的生物学途径，尤其是白细胞端粒长度（LTL）的作用，在很大程度上仍不清楚。我们研究了遗传易感性与慢性疾病和各种特征对 HF 风险的影响，以及 LTL 是否介导或修饰了这些途径。
方法
我们对英国生物库中 404883 名欧洲参与者进行了前瞻性队列分析，包括 9989 例 HF 病例。使用多变量 Cox 回归来估计 HF 风险与之前使用贝叶斯方法生成的 24 种多基因风险评分（PRS）之间的关联，这些 PRS 涉及各种疾病或特征。我们使用 UK Biobank 中之前测量的定量 PCR 评估了 PRS 与 LTL 之间的乘法交互作用。进行因果中介分析以估计 PRS 通过 LTL（生物老化的综合标志物）间接作用的总效应的比例。
结果
我们确定了 9 种与 HF 风险相关的 PRS，包括与各种心血管疾病或特征、类风湿关节炎（P=1.3E-04）和哮喘（P=1.8E-08）相关的 PRS。此外，较长的 LTL 与 HF 风险降低显著相关（P 趋势=1.7E-08）。值得注意的是，LTL 显著增强了哮喘与 HF 之间的关系（P 交互作用=2.8E-03）。然而，LTL 仅介导了哮喘 PRS 对 HF 风险的总效应的 1.13%（P<0.001）。
结论
我们的研究结果阐明了 HF 风险、哮喘、类风湿关节炎和其他特征之间的共同遗传易感性。较长的 LTL 增强了哮喘在 HF 发病途径中的遗传效应。这些结果支持在 HF 风险预测中考虑 LTL 和 PRS。
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