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

Jinzhu Jia,Tao Huang,Yanna Chi,Xinpei Wang

doi:10.3389/fendo.2022.809445

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.

Highlights

Despite concerted efforts to combat the global tobacco epidemic, tobacco smoking remains the leading preventable cause of morbidity and mortality [1]
Two recent large-scale genome-wide association studies (GWASs) on tobacco use revealed that smoking initiation was genetically positively correlated with type 2 diabetes (T2D), coronary artery disease (CAD), myocardial infarction (MI), and heart failure (HF) and that cigarettes per day and smoking cessation were genetically positively correlated with CAD
We found that the shared genes of smoking status with T2D, CAD, MI, and HF were all most strongly enriched in the adrenal gland (Figure 5)

Summary

Introduction

Despite concerted efforts to combat the global tobacco epidemic, tobacco smoking remains the leading preventable cause of morbidity and mortality [1]. Smoking has multiple well-known adverse health effects [2, 3], and its association with type 2 diabetes (T2D) and cardiovascular diseases (CVDs) has been a major public health concern. Considerable studies, both prospective cohort studies among different population groups [4–6] and metaanalyses [7–10], have provided compelling evidence of the important role of smoking in increasing the risk of T2D and CVDs. Approximately 30%~40% of the increased risk of T2D [2] and 20%~30% of all CVD deaths [11, 12] compared to never smokers are attributed to smoking. Single-nucleotide polymorphisms (SNPs) in some genes have been reported to have effects on both smoking and T2D or CVDs [22–24]

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Results

Conclusion