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.
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.