Smoking behaviour, altered DNA methylation, and heart failure risk: evidence from a prospective cohort and epigenetic...

To date, there is still a lack of studies focusing on the interactions between tobacco smoking, epigenetic modifications, and heart failure (HF) risk.

We first performed a prospective cohort study in the UK Biobank to assess the causal relationship between smoking behaviours and HF incidence. Subsequently, we applied two-sample Mendelian Randomization (MR) and epigenetic MR to further investigate the causal effects of smoking behaviours and related DNA methylation on HF, including its subtypes: heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF).

In the UK Biobank cohort, former, ever, and current smoking were all associated with a higher risk of HF, with a clear dose-response relationship observed for pack-years of smoking. Additionally, earlier smoking cessation was linked to a lower risk of HF. Two-sample MR validated these observational findings and further identified the harmful effects of smoking behaviours on both HFpEF and HFrEF. In the epigenetic MR analysis, we found that DNA methylation alteration at cg15234271 [HPN] was associated with a reduced risk of HF, whereas cg16071219 [LPAR6], cg19593285 [E2F1], and cg01305745 [VKORC1] were linked to an elevated risk. For HF subtypes, cg26161820 [PPP1R1B] and cg26716839 [UNC119B] were associated with a lowered risk of HFrEF, while cg08548559 [PIK3IP1] was linked to an increased risk of HFpEF.

Our study demonstrates associations between smoking behaviours, related DNA methylation, and HF incidence, offering novel insights into the pathogenesis of HF.