PDF(Pubmed)
Abstract：
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.
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.
摘要：
背景：已证明对各种慢性疾病的遗传易感性会影响心力衰竭（HF）的风险。然而,潜在的生物学途径，特别是白细胞端粒长度（LTL）的作用，基本上是未知的。我们调查了慢性疾病的遗传易感性和各种性状对HF风险的影响，以及LTL是否介导或修饰途径。
方法：我们对来自英国生物库的404883名欧洲参与者进行了前瞻性队列分析，包括9989例HF事件。多变量Cox回归用于估计HF风险与先前使用贝叶斯方法生成的各种疾病或性状的24个多基因风险评分（PRS）之间的关联。我们使用定量PCR评估了先前在UK生物库中测量的PRS和LTL之间的乘法相互作用。进行了因果调解分析，以估计通过LTL间接作用的PRS在总影响中的比例，生物衰老的综合标记。
结果：我们确定了9个与HF风险相关的PRS，包括各种心血管疾病或特征，类风湿性关节炎（P=1.3E-04），哮喘（P=1.8E-08）。此外,长期LTL与HF风险降低密切相关(P趋势=1.7E-08).值得注意的是,LTL显著增强了哮喘与HF的关系(P-交互作用=2.8E-03)。然而,LTL仅介导哮喘PRS对HF风险的总效应的1.13%(P<0.001)。
结论：我们的发现揭示了HF风险之间的共同遗传易感性，哮喘,类风湿性关节炎,和其他特征。较长的LTL加强了哮喘在HF通路中的遗传效应。这些结果支持在HF风险预测中考虑LTL和PRS。
方法：我们对来自英国生物库的404883名欧洲参与者进行了前瞻性队列分析，包括9989例HF事件。多变量Cox回归用于估计HF风险与先前使用贝叶斯方法生成的各种疾病或性状的24个多基因风险评分（PRS）之间的关联。我们使用定量PCR评估了先前在UK生物库中测量的PRS和LTL之间的乘法相互作用。进行了因果调解分析，以估计通过LTL间接作用的PRS在总影响中的比例，生物衰老的综合标记。
结果：我们确定了9个与HF风险相关的PRS，包括各种心血管疾病或特征，类风湿性关节炎（P=1.3E-04），哮喘（P=1.8E-08）。此外,长期LTL与HF风险降低密切相关(P趋势=1.7E-08).值得注意的是,LTL显著增强了哮喘与HF的关系(P-交互作用=2.8E-03)。然而,LTL仅介导哮喘PRS对HF风险的总效应的1.13%(P<0.001)。
结论：我们的发现揭示了HF风险之间的共同遗传易感性，哮喘,类风湿性关节炎,和其他特征。较长的LTL加强了哮喘在HF通路中的遗传效应。这些结果支持在HF风险预测中考虑LTL和PRS。
