Bidirectional Relationship Between Type 2 Diabetes Mellitus and Coronary Artery Disease: Prospective Cohort Study and Genetic Analyses
Introduction
Type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) are leading causes of death worldwide. These two cardiometabolic conditions often coexist, and their relationship has been extensively studied. T2DM is considered a putative causal risk factor for CAD, with a meta-analysis of prospective studies involving nearly 700,000 individuals confirming a doubled risk of CAD among T2DM patients compared to those without T2DM. Genome-wide association studies (GWAS) have identified a strong overall genetic correlation between T2DM and CAD, suggesting a shared genetic basis. Additionally, multiple pleiotropic loci have been reported to independently affect both diseases. Mendelian randomization (MR) studies have consistently identified a causal association between genetically determined T2DM and CAD.
However, several gaps remain in understanding the intrinsic link between T2DM and CAD. Previous studies have used GWAS data from populations of admixed ancestry or small sample sizes, limiting statistical power. Additionally, reverse causation—the effect of genetically determined CAD on subsequent T2DM—has not been thoroughly assessed. Overweight status and obesity, as reflected by body mass index (BMI), contribute to both conditions but have not been adequately considered in previous genetic studies. Furthermore, limited functional annotation has been performed to relate statistical evidence with biological pathways. This study aims to comprehensively investigate the phenotypic and genetic relationships between T2DM and CAD, leveraging large-scale observational and genetic data.
Methods
Ethical Approval and Data Sources
Ethical approval for the study was granted by the National Health Service North West Multi-Centre Research Ethics Committee. The study utilized data from the United Kingdom Biobank (UKB), a large prospective cohort study involving approximately 500,000 individuals aged 40–69 years at baseline. The UKB data included 472,050 participants of white descent. Diagnoses of T2DM and CAD were defined according to the International Classification of Diseases, Tenth Revision (ICD-10) and ICD-9 codes.
GWAS summary statistics were obtained from the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium, the largest GWAS of T2DM in people of European ancestry, and the CARDIoGRAMplusC4D consortium, the largest GWAS of CAD. Additional GWAS data from multiancestry individuals were also included to increase the generalizability and robustness of the findings.
Statistical Analysis
Observational Analysis
The baseline characteristics of the UKB participants were presented as means or medians for continuous variables and frequencies for categorical variables. The association between T2DM and the risk of subsequent CAD was assessed using Cox proportional-hazards regression models, with adjustments for age, sex, assessment center, and principal components. Similar analyses were conducted to assess the association between CAD and the risk of subsequent T2DM.
Global and Local Genetic Correlation Analyses
Genetic correlation between T2DM and CAD was calculated using linkage-disequilibrium (LD) score regression software. Local genetic correlation was estimated using r-HESS software, which partitions the whole genome into 1703 LD-independent regions. Cross-trait meta-analysis was performed using Cross-Phenotype Association software (CPASSOC) to identify pleiotropic loci affecting both traits.
Functional Annotation and Tissue Enrichment Analysis
SNPs were mapped to genes using Ensembl Variant Effect Predictor. Tissue enrichment analysis was conducted based on 54 tissue types available in the Genotype-Tissue Expression (GTEx) project.
Univariable MR Analysis
Bidirectional two-sample MR was performed using TwoSampleMR software to make causal inferences. Sensitivity analyses, including MR-Egger regression and the weighted-median method, were conducted to test the robustness of the results.
Multivariable MR and Mediation Analysis
Multivariable MR was performed to estimate the independent causal effects between T2DM and CAD after adjusting for BMI. Mediation analysis was conducted to assess the mediation effect of systolic blood pressure (SBP) and intake of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (C10AA).
Results
Phenotypic Association
The analysis of the risk of incident CAD associated with T2DM followed participants for 5,303,441 person-years, during which 3,323 T2DM patients and 26,380 T2DM-free individuals developed CAD. After adjusting for age, sex, assessment center, and principal components, T2DM patients showed a significantly increased risk of CAD (HR = 2.70, 95% CI: 2.60–2.81). The effect was attenuated after further adjustment for BMI but remained statistically significant (HR = 2.28, 95% CI: 2.19–2.37). The effect stabilized to 2.12 (95% CI: 2.01–2.24) in the full model.
In the analysis of the risk of incident T2DM associated with CAD, participants were followed for 5,368,323 person-years, during which 3,810 CAD patients and 17,608 CAD-free individuals developed T2DM. After adjusting for age, sex, assessment center, and principal components, CAD patients showed a significantly increased risk of T2DM (HR = 2.44, 95% CI: 2.35–2.53), which was weakened after adjusting for BMI (HR = 1.99, 95% CI: 1.92–2.06) and further attenuated to 1.72 (95% CI: 1.63–1.81) in the full model.
Global and Local Genetic Correlations
A strong positive overall genetic correlation was observed between T2DM and CAD (rg = 0.39, P = 1.43 × 10^-75). When the effect of BMI was removed, the estimate of genetic correlation was attenuated but remained statistically significant (T2DMadjBMI–CAD: rg = 0.31, P = 1.20 × 10^-36). Partitioning the whole genome into 1703 LD-independent regions identified five genomic regions with significant local genetic correlation. Of these, four remained significant for T2DMadjBMI and CAD when the effect of BMI was removed. An additional genomic region (6p21.33) showed a significant local signal specific to T2DMadjBMI and CAD.
Cross-Trait Meta-Analysis
Cross-trait meta-analysis identified a total of 107 independent significant pleiotropic SNPs. Five novel SNPs shared between T2DM and CAD were found, and a novel locus (rs4762753) was identified for T2DMadjBMI and CAD. This SNP was located near phosphodiesterase 3A (PDE3A) and found to be associated with the nitric oxide (NO)–cyclic guanosine monophosphate (cGMP) signaling pathway.
Functional Annotation and Tissue Enrichment Analysis
Tissue enrichment analysis suggested enrichment for the expression of genes shared by T2DM and CAD in several tissues, including the liver, skeletal muscle, brain frontal cortex, and pancreas. Suggestive enrichments for the expression of genes shared by T2DMadjBMI and CAD were observed in the brain frontal cortex, pancreas, and liver.
Univariable MR Analysis
In the bidirectional two-sample MR analysis, genetically determined T2DM significantly increased the risk of CAD (OR = 1.13, 95% CI: 1.11–1.16). Conversely, genetically determined CAD was also associated with an increased risk of T2DM (OR = 1.12, 95% CI: 1.07–1.18). This bidirectional causal relationship was further supported by sensitivity analysis and was not affected by directional pleiotropy.
Multivariable MR and Mediation Analysis
After adjusting for BMI, the effect of T2DM on CAD (OR = 1.17, 95% CI: 1.14–1.20) and the effect of CAD on T2DM (OR = 1.23, 95% CI: 1.17–1.30) remained consistent in both direction and magnitude. The proportion mediated by SBP and intake of C10AA was estimated as 54.1% (95% CI: 24.9%–83.4%) in the total effect of T2DM on CAD and 90.4% (95% CI: 29.3%–151.5%) in the total effect of CAD on T2DM.
Discussion
This study confirmed a bidirectional relationship between T2DM and CAD through observational and genetic analyses. The findings suggest that T2DM and CAD are inherently linked through biological pleiotropy and common origins. The strong positive genetic correlation observed was largely independent of BMI, indicating a shared genetic basis that is partly driven by, but also independent of, BMI. The identification of six novel pleiotropic loci and the bidirectional causal relationship further support the intrinsic link between T2DM and CAD.
The mediating role of SBP and intake of C10AA in the causal relationship between T2DM and CAD provides important insights into the biological mechanisms underlying this relationship. The findings highlight the potential cardiovascular benefits for T2DM patients with active interventions targeting common risk factors, especially blood pressure. The identification of specific pleiotropic variants and pathways regulating common pathological elements may help discover therapeutic targets for the prevention and treatment of cardiometabolic comorbidities.
The study has several limitations, including the restriction of primary findings to populations with European ancestry and the inclusion of participants from several studies in both the T2DM GWAS and CAD GWAS. However, the replication of causal associations using multiethnic T2DM data indicates the generalizability to other populations. The considerable weak-instrument bias in the two-sample MR was not expected due to the high F-statistic of the instrumental variables.
In summary, this study provides comprehensive genetic insight into the observed associations underlying T2DM and CAD, advancing our understanding of the complicated relationship between these two common cardiometabolic diseases. The findings have important implications for the prevention and treatment of T2DM and CAD, highlighting the need for integrated care targeting both conditions.
doi.org/10.1097/CM9.0000000000002894
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