Smoking Status and Type 2 Diabetes, and Cardiovascular Disease: A Comprehensive Analysis of Shared Genetic Etiology and Causal Relationship

Abstract

ObjectiveThis study aimed to explore shared genetic etiology and the causality between smoking status and type 2 diabetes (T2D), cardiovascular diseases (CVDs), and related metabolic traits.MethodsUsing summary statistics from publicly available genome-wide association studies (GWASs), we estimated genetic correlations between smoking status and T2D, 6 major CVDs, and 8 related metabolic traits with linkage disequilibrium score regression (LDSC) analysis; identified shared genetic loci with large-scale genome-wide cross-trait meta-analysis; explored potential shared biological mechanisms with a series of post-GWAS analyses; and determined causality with Mendelian randomization (MR).ResultsWe found significant positive genetic associations with smoking status for T2D (Rg = 0.170, p = 9.39 × 10−22), coronary artery disease (CAD) (Rg = 0.234, p = 1.96 × 10−27), myocardial infarction (MI) (Rg = 0.226, p = 1.08 × 10−17), and heart failure (HF) (Rg = 0.276, p = 8.43 × 10−20). Cross-trait meta-analysis and transcriptome-wide association analysis of smoking status identified 210 loci (32 novel loci) and 354 gene–tissue pairs jointly associated with T2D, 63 loci (12 novel loci) and 37 gene–tissue pairs with CAD, 38 loci (6 novel loci) and 17 gene–tissue pairs with MI, and 28 loci (3 novel loci) and one gene–tissue pair with HF. The shared loci were enriched in the exo-/endocrine, cardiovascular, nervous, digestive, and genital systems. Furthermore, we observed that smoking status was causally related to a higher risk of T2D (β = 0.385, p = 3.31 × 10−3), CAD (β = 0.670, p = 7.86 × 10−11), MI (β = 0.725, p = 2.32 × 10−9), and HF (β = 0.520, p = 1.53 × 10−6).ConclusionsOur findings provide strong evidence on shared genetic etiology and causal associations between smoking status and T2D, CAD, MI, and HF, underscoring the potential shared biological mechanisms underlying the link between smoking and T2D and CVDs. This work opens up a new way of more effective and timely prevention of smoking-related T2D and CVDs.

Distinct metabolic features of genetic liability to type 2 diabetes and coronary artery disease: a reverse Mendelian randomization study

“…(68) We also did not find consistent evidence that either T2D or CAD liability increases smoking or alcohol behaviours. Although increased smoking and drinking are risk factors for both T2D and CAD,(69,70) the lack of signal seen in our study suggests that they are more distal features of disease liability. This provides further evidence that the reverse-MR approach is useful for revealing more proximal factors such as metabolites that are directly involved in the disease process and highlights the importance of combining evidence from MR study designs in different directions to reveal the full scope of factors contributing to disease development.…”

Untargeted metabolomics unravel serum metabolic alterations in smokers with hypertension

“…Overwhelming evidences regarding the consequences of smoking have shown that cigarette smoking powerfully enhanced the risks of all-cause mortality, cardiovascular mortality and major adverse cardiovascular events (Chi et al, 2022;Thiravetyan and Vathesatogkit, 2022). Tobacco smoking and even second-hand exposure has been demonstrated to be associated with cardiovascular risk as well as the development of hypertension (HTN) (Dikalov et al, 2019;Bernabe-Ortiz and Carrillo-Larco, 2021).…”

The Global Burden of Type 2 Diabetes Attributable to Tobacco: A Secondary Analysis From the Global Burden of Disease Study 2019

“…According to the GBD 2019, smoking is the third leading risk factor for T2D burden worldwide, with 9.9% of the T2D burden attributable to smoking (4). The biological mechanism may involve oxidative stress, inflammatory markers, and glucose metabolism irregularities (5,6). The 2014 Surgeon General's Report, for the first time, inferred causal association between smoking and T2D, as well as the potential dose-response relationship (7).…”