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Exploring the causal pathway from body mass index to coronary heart disease: a network Mendelian randomization study
Xun Hu1, Xiao-Dong Zhuang1, Wei-Yi Mei1
1Cardiology Department, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, PR China.
Insights
Higher body mass index (BMI) increases coronary heart disease (CHD) risk, partly through glycated hemoglobin (HbA1c) and triglycerides (TG). These factors, along with other lipids, act as key mediators in this association.
Area of Science:
- Genetics
- Cardiovascular Disease Epidemiology
- Metabolic Health
Background:
- Obesity, indicated by body mass index (BMI), is a known risk factor for coronary heart disease (CHD).
- The precise mediating pathways from BMI to CHD, particularly involving metabolic factors like glycated hemoglobin (HbA1c) and lipids, require further elucidation.
- Network Mendelian randomization (MR) offers a robust framework to investigate these causal relationships using genetic data.
Purpose of the Study:
- To determine the causal effect of body mass index (BMI) on coronary heart disease (CHD) using a network Mendelian randomization (MR) approach.
- To investigate whether glycated hemoglobin (HbA1c) and key lipid parameters (total cholesterol, LDL, HDL, triglycerides) act as causal mediators in the pathway from BMI to CHD.
Main Methods:
- Employed a network MR framework utilizing summary-level genome-wide association study (GWAS) data.
- Instrumental variables for exposure (BMI) and mediators (HbA1c, lipids) were derived from large-scale consortia (GIANT, CARDIoGRAMplusC4D, Global Lipids Genetics, MAGIC).
- Multiple MR methods, including inverse-variance-weighted, MR Egger, and weighted-median approaches, were used for robust causal inference.
Main Results:
- A significant causal association was found between higher BMI and increased odds of CHD (OR per 1 SD increase in BMI: 1.562).
- BMI showed positive causal associations with HbA1c and triglycerides (TG), and a negative association with HDL cholesterol.
- HbA1c, total cholesterol (TC), LDL, and TG were causally associated with increased CHD risk, while HDL was not.
Conclusions:
- Elevated BMI significantly increases the risk of coronary heart disease (CHD).
- This increased risk is partially mediated by metabolic factors, specifically glycated hemoglobin (HbA1c) and lipid parameters.
- HbA1c and triglycerides (TG) appear to be the primary mediators linking higher BMI to increased CHD risk.
Background:
We applied a network Mendelian randomization (MR) framework to determine the causal association between body mass index (BMI) and coronary heart disease (CHD) and explored whether glycated hemoglobin (HbA1c) and lipid parameters (total cholesterol, TC; low-density lipoprotein cholesterol, LDL; high-density lipoprotein cholesterol, HDL; triglycerides, TG) serve as causal mediators from BMI to CHD by integrating summary-level genome-wide association study data.
Methods:
Network MR analysis, an approach using genetic variants as the instrumental variables for both the exposure and mediator to infer causality was performed. Summary statistics from the GIANT consortium were used (n = 152,893) for BMI, CARDIoGRAMplusC4D consortium data were used (n = 184,305) for CHD, Global Lipids Genetics Consortium data were used (n = 108,363) for TC, LDL, HDL and TG, and MAGIC consortia data were used (n = 108,363) for HbA1c.
Results:
The inverse-variance-weighted-method estimate indicated that the odds ratio (95% confidence interval) for CHD was 1.562 (1.391-1.753) per 1 standard deviation (kg/m2) increase in BMI. Results were consistent in MR Egger method and weighted-median methods. MR estimate indicated that BMI was positively associated with HbA1c and TG, and negatively associated with HDL, but was not associated with TC or LDL. Moreover, HbA1c, TC, LDL, and TG were positively associated with CHD, yet there was no causal association between HDL and CHD. HbA1c was positively associated with TC, LDL, and HDL, but was not associated with TG.
Conclusions:
Higher BMI conferred an increased risk of CHD, which was partially mediated by HbA1c and lipid parameters. HbA1c and TG might be the main mediators in the link from BMI to CHD.
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