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Circulating α-Klotho Levels in Relation to Cardiovascular Diseases: A Mendelian Randomization Study
Xingang Sun1, Lu Chen1, Yuxian He1
1Department of Cardiology and Atrial Fibrillation Center of The First Affiliated Hospital of Zhejiang University, Hangzhou, China.
Insights
Genetically predicted higher levels of circulating alpha-Klotho show a protective effect against atrial fibrillation (AF). However, this study found no causal link between alpha-Klotho and coronary artery disease (CAD) or stroke risk.
Area of Science:
- Genetics
- Cardiovascular Medicine
- Biomarkers
Background:
- Circulating α-Klotho's protective role in cardiovascular diseases (CVD) is suggested but lacks causal evidence.
- Investigating the causal relationship between genetically predicted α-Klotho and major CVDs is crucial.
Purpose of the Study:
- To determine if genetically predicted circulating α-Klotho levels are causally associated with the risk of coronary artery disease (CAD), atrial fibrillation (AF), heart failure (HF), and stroke.
- To elucidate the causal link between α-Klotho and ischemic stroke (IS) and its subtypes.
Main Methods:
- A two-sample Mendelian randomization (MR) study utilized 5 single-nucleotide polymorphisms for genetically predicted α-Klotho.
- Fixed-effects inverse-variance weighted (IVW) and meta-analysis combined estimates from multiple data sources.
- Sensitivity analyses included simple median, weighted median, MR-Egger, and MR-pleiotropy residual sum and outlier (MR-PRESSO).
Main Results:
- A suggestive inverse causal association was found between α-Klotho and CAD (OR, 0.97; P=0.044).
- A significant inverse association was observed between α-Klotho and AF (OR, 0.96; P=0.005).
- No causal associations were detected for HF, any stroke, IS, or IS subtypes.
Conclusions:
- Genetically predicted circulating α-Klotho has a protective effect on preventing atrial fibrillation (AF) risk.
- No significant causal association was found between genetically predicted α-Klotho levels and the risk of CAD, HF, stroke, IS, or IS subtypes.
Background:
Several studies have reported a protective role of circulating α-Klotho on cardiovascular diseases (CVD); however, the causality remains unclear. We aim to elucidate whether genetically predicted circulating α-Klotho levels were causally associated with the risk of coronary artery disease (CAD), atrial fibrillation (AF), heart failure (HF), stroke, ischemic stroke (IS), and IS subtypes.
Methods:
A two-sample Mendelian randomization (MR) study was designed, with 5 single-nucleotide polymorphisms associated with circulating α-Klotho levels utilized as instrumental variables. MR estimates on each CVD outcome derived from the fixed-effects inverse-variance weighted (IVW) approach in different data sources were combined by the fixed-effects meta-analysis approach, complemented by several sensitivity analyses including the simple median, the weighed median, MR-Egger regression, and MR-pleiotropy residual sum and outlier.
Results:
In the meta-analysis combining different data sources, suggestive inverse causal association of circulating α-Klotho concentrations with CAD [Odds ratio (OR), 0.97; 95% confidence interval (CI), 0.94, 1.00; P = 0.044] and significant inverse association of circulating α-Klotho concentrations with AF (OR, 0.96; 95% CI, 0.93, 0.99; P = 0.005) was observed. However, there was no causal association of α-Klotho with HF, any stroke, IS, or IS subtypes neither in different data sources nor in the meta-analysis. Complementary sensitivity analyses showed consistent and robust results in general.
Conclusion:
Evidence was found for a protective effect of circulating α-Klotho on the prevention of AF risk. However, no significant causal association between genetically predicted circulating α-Klotho levels and risk of CAD, HF, stroke, IS, or IS subtypes was found.
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