Researchers performed a prospective cohort study to investigate the shared genetic etiology between chronic diseases, such as cardiovascular diseases (CVDs), asthma, rheumatoid arthritis (RA), and pathogenesis of heart failure (HF) and whether leukocyte telomere length (LTL), a biomarker of biological aging, modified these relationships.
They performed all study analyses on the clinical and genetic data of a cohort of 404,883 European participants from the United Kingdom (UK) Biobank.
Study
In the present study, researchers used a multi-step approach to explore the associations between genetic susceptibility to chronic diseases, LTL, and HF risk in the UK Biobank data of 404,883 European participants, of which 9,989 were incident HF cases, as observed through the 12.3-year follow-up.
To this end, they first used multivariable Cox regression to prospectively evaluate the associations between 24 previously derived cancer-, inflammation-, and CVD-related polygenic risk scores (PRSs) and future HF risk.
Next, the team used quantitative polymerase chain reaction (qPCR) to investigate how the identified PRSs interacted with measured LTL to modify HF risk. They further analyzed PRSs showing multiplicative interactions with LTL, stratified by LTL quartiles.
Additionally, they evaluated measured associations between LTL and 24 PRSs to determine qualitatively overlapping results with the PRS-HF analyses. Finally, the researchers pursued evidence of the effect of altered LTL (reflecting the aging process) on significant PRSs of HF risk. Mediation analyses helped them estimate the PRSs acting indirectly through LTL.
Findings
The researchers identified nine PRSs associated with HF risk, including those for various CVDs, RA, and asthma, in a dose-dependent manner. Increased genetic susceptibility to asthma was markedly associated with increased HF risk (P=1.8E-08).
In agreement with previous analyses, they also found evidence that longer phenotypic LTL mediated and strengthened the positive association between asthma genetic susceptibility and HF risk independent of the PRSs. They attributed its role as an effect modifier to the environmentally-determined LTL components (not genetic components). Thus, future studies should incorporate LTL and genetic data into risk stratification analyses.
Intriguingly, the asthma PRS exhibited a super-multiplicative interaction with LTL even though phenotypic LTL was inversely associated with HF. However, LTL mediated 1.13% of the total effect of the asthma PRS on HF risk.
Nonetheless, the study findings reinstate the notion that there is a link between pulmonary diseases, cardiac function, and inflammation. Future studies should elucidate the molecular mechanisms by which LTL exerts its effects and the nature of biological interactions between PRSs and LTL components.
Furthermore, the authors noted a significant overlap between the PRSs for asthma, CVD, CAD, ischemic stroke (ISS) and associations identified in the PRS-HF analyses, indicating potential associations between genetic susceptibility to cardiovascular and pulmonary diseases, phenotypic LTL, and future HF risk.
Conclusion
To summarize, the researchers discovered a high-risk subpopulation for HF comprising people with longer LTL and increased genetic susceptibility to asthma.
The study also highlighted that non-malignant respiratory diseases and LTLs act as effect modifiers in the pathogenesis of HF, a fatal downstream consequence of cardiac dysfunction with a mortality rate as high as some cancers.
Thus, future studies should further investigate the role of LTL and genetics in future HF risk stratification analyses.
Source:
https://www.news-medical.net/news/20230810/Study-examines-shared-genetic-etiology-of-chronic-diseases-and-links-leukocyte-telomere-length-to-heart-failure-risk.aspx