Tobacco smoking is a well-known modifiable risk factor for many chronic diseases, including cardiovascular disease (CVD). One of the proposed underlying mechanism linking smoking to disease is via epigenetic modifications, which could affect the expression of disease-associated genes. Here, we conducted a three-way association study to identify the relationship between smoking-related changes in DNA methylation and gene expression and their associations with cardio-metabolic traits. We selected 2549 CpG sites and 443 gene expression probes associated with current versus never smokers, from the largest epigenome-wide association study and transcriptome-wide association study to date. We examined three-way associations, including CpG versus gene expression, cardio-metabolic trait versus CpG, and cardio-metabolic trait versus gene expression, in the Rotterdam study. Subsequently, we replicated our findings in The Cooperative Health Research in the Region of Augsburg (KORA) study. After correction for multiple testing, we identified both cis- and trans-expression quantitative trait methylation (eQTM) associations in blood. Specifically, we found 1224 smoking-related CpGs associated with at least one of the 443 gene expression probes, and 200 smoking-related gene expression probes to be associated with at least one of the 2549 CpGs. Out of these, 109 CpGs and 27 genes were associated with at least one cardio-metabolic trait in the Rotterdam Study. We were able to replicate the associations with cardio-metabolic traits of 26 CpGs and 19 genes in the KORA study. Furthermore, we identified a three-way association of triglycerides with two CpGs and two genes (GZMA; CLDND1), and BMI with six CpGs and two genes (PID1; LRRN3). Finally, our results revealed the mediation effect of cg03636183 (F2RL3), cg06096336 (PSMD1), cg13708645 (KDM2B), and cg17287155 (AHRR) within the association between smoking and LRRN3 expression. Our study indicates that smoking-related changes in DNA methylation and gene expression are associated with cardio-metabolic risk factors. These findings may provide additional insights into the molecular mechanisms linking smoking to the development of CVD.

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吸烟相关的 DNA 甲基化和基因表达变化与心脏代谢特征相关

吸烟是众所周知的许多慢性疾病的可改变危险因素，包括心血管疾病 (CVD)。将吸烟与疾病联系起来的潜在机制之一是通过表观遗传修饰，这可能会影响疾病相关基因的表达。在这里，我们进行了一项三向关联研究，以确定与吸烟相关的 DNA 甲基化和基因表达变化之间的关系及其与心脏代谢特征的关联。我们从迄今为止最大的表观基因组范围关联研究和转录组范围关联研究中选择了 2549 个 CpG 位点和 443 个与当前吸烟者和从不吸烟者相关的基因表达探针。我们检查了三方面的关联，包括 CpG 与基因表达、心脏代谢特征与 CpG 以及心脏代谢特征与基因表达，在鹿特丹研究中。随后，我们在奥格斯堡地区的合作健康研究 (KORA) 研究中复制了我们的发现。在对多重测试进行校正后，我们确定了血液中的顺式和反式表达数量性状甲基化 (eQTM) 关联。具体而言，我们发现 1224 个与吸烟相关的 CpG 与 443 个基因表达探针中的至少一个相关，以及 200 个与吸烟相关的基因表达探针与 2549 个 CpG 中的至少一个相关。在鹿特丹研究中，其中 109 个 CpG 和 27 个基因与至少一种心脏代谢特征相关。我们能够在 KORA 研究中复制与 26 个 CpG 和 19 个基因的心脏代谢特征的关联。此外，我们确定了甘油三酯与两个 CpG 和两个基因（GZMA；CLNDD1）的三向关联，和具有六个 CpG 和两个基因（PID1；LRRN3）的 BMI。最后，我们的结果揭示了 cg03636183 (F2RL3)、cg06096336 (PSMD1)、cg13708645 (KDM2B) 和 cg17287155 (AHRR) 在吸烟和 LRRN3 表达之间的关联中的中介作用。我们的研究表明，与吸烟相关的 DNA 甲基化和基因表达变化与心脏代谢危险因素有关。这些发现可能为将吸烟与 CVD 发展联系起来的分子机制提供更多见解。我们的研究表明，与吸烟相关的 DNA 甲基化和基因表达变化与心脏代谢危险因素有关。这些发现可能为将吸烟与 CVD 发展联系起来的分子机制提供更多见解。我们的研究表明，与吸烟相关的 DNA 甲基化和基因表达变化与心脏代谢危险因素有关。这些发现可能为将吸烟与 CVD 发展联系起来的分子机制提供更多见解。