Effect of smoking behaviour and related blood DNA methylation on visceral adipose tissues.

Abstract

Background: Recent studies have found that tobacco smoking is associated with fat distribution, yet limited research has focused on its relationship with visceral adipose tissues (VATs). Furthermore, the cellular and molecular mechanisms underlying the interactions among smoking, epigenetic modifications, and VATs remain unknown.

Method: We performed univariable Mendelian randomization (MR) analysis to elucidate the causal relationship between smoking behaviours and VATs, including epicardial and pericardial adipose tissue (EPAT), liver fat (LF), and pancreas fat (PF). This approach could minimize the impact of confounders and reverse causality through utilizing genetic variants to proxy the smoking behaviours. Mediation MR analysis were conducted to detect potential mediators. Additionally, summary-data-based MR (SMR) and colocalization analysis were performed to explore the association between smoking-related DNA methylation and VATs.

Results: We identified a convincing association between smoking initiation and increased EPAT (beta: 0.15, 95% CI: 0.06, 0.23, p = 7.01 × 10^-4) and LF area (beta: 0.15, 95% CI = 0.05, 0.24, p = 2.85 × 10^-3), respectively. Further mediation analysis suggested type 2 diabetes mellitus (T2DM) as a potential mediator within these co-relationships. When further exploring the associations between the smoking related DNA methylation and VATs, we identified that WT1 methylation at cg05222924 was significantly linked to a lower EPAT area (beta: -0.12, 95% CI: -0.16, -0.06, P_FDR = 2.24 × 10^-3), while GPX1 methylation at cg18642234 facilitated the deposition of EPAT (beta: 0.15, 95% CI: 0.10, 0.20, P_FDR = 1.66 × 10^-4).

Conclusion: Our study uncovered a significant causal effect between smoking and VATs, with T2DM identified as a potential mediator. Further investigation into DNA methylation yielded novel insights into the pathogenic role of smoking on EPAT.