Genetic susceptibility to chronic diseases leads to heart failure among Europeans: the influence of leukocyte telomere length.

IF 3.1 2区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Human molecular genetics Pub Date : 2024-07-06 DOI:10.1093/hmg/ddae063

Jason Y Y Wong, Batel Blechter, Zhonghua Liu, Jianxin Shi, Véronique L Roger

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引用次数: 0

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.

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慢性病遗传易感性导致欧洲人心力衰竭：白细胞端粒长度的影响。

背景：各种慢性疾病的遗传易感性已被证明会影响心力衰竭（HF）的风险。然而，其潜在的生物学途径，尤其是白细胞端粒长度（LTL）的作用，在很大程度上还不为人所知。我们研究了慢性病遗传易感性和各种特征对心力衰竭风险的影响，以及LTL是否介导或改变了这些途径：我们对英国生物库中的 404 883 名欧洲参与者进行了前瞻性队列分析，其中包括 9989 例高血压病例。我们使用多变量 Cox 回归估算了心房颤动风险与贝叶斯方法生成的 24 种疾病或性状的多基因风险评分 (PRS) 之间的关联。我们使用定量 PCR 评估了 PRS 与之前在英国生物库中测量的 LTL 之间的乘法交互作用。我们还进行了因果中介分析，以估算通过LTL（生物衰老的综合标志物）间接作用的PRSs总效应的比例：结果：我们发现了 9 个与高频风险相关的 PRS，包括与各种心血管疾病或特征、类风湿性关节炎（P = 1.3E-04）和哮喘（P = 1.8E-08）相关的 PRS。此外，较长的LTL与HF风险的降低密切相关（P-趋势=1.7E-08）。值得注意的是，LTL 显著加强了哮喘与 HF 的关系（P-交互作用 = 2.8E-03）。然而，LTL 只介导了 1.13% 的关系（P 结论：LTL 与哮喘-高血压的关系并不明显：我们的研究结果揭示了高血压风险、哮喘、类风湿性关节炎和其他特征之间的共同遗传易感性。较长的LTL加强了哮喘在高血压发病途径中的遗传效应。这些结果支持在预测高频风险时考虑 LTL 和 PRS。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Human molecular genetics 生物-生化与分子生物学

CiteScore

6.90

自引率

2.90%

发文量

294

审稿时长

2-4 weeks

期刊介绍： Human Molecular Genetics concentrates on full-length research papers covering a wide range of topics in all aspects of human molecular genetics. These include: the molecular basis of human genetic disease developmental genetics cancer genetics neurogenetics chromosome and genome structure and function therapy of genetic disease stem cells in human genetic disease and therapy, including the application of iPS cells genome-wide association studies mouse and other models of human diseases functional genomics computational genomics In addition, the journal also publishes research on other model systems for the analysis of genes, especially when there is an obvious relevance to human genetics.