Investigating the causal effect of Dickkopf-1 on coronary artery disease and ischemic stroke: a Mendelian
Peng-Fei Zheng1,2,3, Jing-Jing Rong1,2,3, Zhao-Fen Zheng1,2,3
1Cardiology Department, Hunan Provincial People’s Hospital, Furong, Changsha 410000, Hunan, China.
Insights
Elevated Dickkopf-related protein 1 (DKK1) genetically increases the risk of coronary artery disease (CAD) and ischemic stroke (IS). This suggests DKK1 is a potential therapeutic target for preventing these cardiovascular conditions.
Area of Science:
- Cardiovascular Genetics
- Molecular Biology
- Epidemiology
Background:
- Elevated plasma Dickkopf-related protein 1 (DKK1) levels correlate with atherosclerosis.
- The causal role of DKK1 in coronary artery disease (CAD) and ischemic stroke (IS) requires elucidation.
Purpose of the Study:
- To investigate the causal association between genetic liability to DKK1 and the risk of CAD and IS.
- To explore DKK1 as a potential therapeutic target for cardiovascular diseases.
Main Methods:
- Utilized a two-sample Mendelian randomization (MR) approach.
- Employed summary statistics from large-scale genome-wide association studies (GWAS) and the FinnGen biobank.
- Applied eight MR methods to assess causality and detect pleiotropy.
Main Results:
- Genetic liability to DKK1 was significantly associated with an increased risk of CAD (OR: 1.087, P=0.006).
- Genetic liability to DKK1 was also associated with an increased risk of IS (OR: 1.096, P=0.039).
- Established a causal link between DKK1 genetic predisposition and higher risks of CAD and IS.
Conclusions:
- DKK1 plays a causal role in the development of CAD and IS.
- DKK1 represents a promising therapeutic target for the prevention and treatment of CAD and IS.
- Further research into DKK1 modulation could impact cardiovascular disease management.
Abstract:
Epidemiological investigations have indicated a correlation between elevated plasma levels of Dickkopf-related protein 1 (DKK1) and the presence of atherosclerosis. However, the exact causal relationship of DKK1 with the development of coronary artery disease (CAD) and ischemic stroke (IS) remains unclear. To address this gap, our study aimed to explore their causal association using a two-sample Mendelian randomization (MR) approach. We obtained summary statistics from genome-wide association studies (GWAS) meta-analyses conducted by Folkersen et al. and Nikpay et al., which included data from 21,758 individuals for DKK1 and 42,096 cases of CAD. Additionally, we obtained data from the FinnGen biobank analysis round 5, which included 10,551 cases of IS. Eight MR methods were employed to estimate causal effects and detect directional pleiotropy. Our findings demonstrated that genetic liability to DKK1 was associated with increased risks of CAD (odds ratio [OR]: 1.087; 95% confidence interval [CI]: 1.024-1.154; P = 0.006) and IS (OR: 1.096; 95% CI: 1.004-1.195; P = 0.039). These results establish a causal link between genetic liability to DKK1 and elevated risks of CAD and IS. Consequently, DKK1 may represent a promising therapeutic target for the prevention and treatment of CAD and IS.
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