Abstract
BackgroundSeveral 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.MethodsA 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.ResultsIn 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.ConclusionEvidence 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.
Highlights
Several studies have reported a protective role of circulating a-Klotho on cardiovascular diseases (CVD); the causality remains unclear
We observed suggestive inverse associations of circulating a-Klotho levels with the risk of coronary artery disease (CAD) in the CARDIoGRAMplusC4D (OR, 0.96; 95% confidence intervals (CIs), 0.92, 1.00; P = 0.037; Figure 2) and atrial fibrillation (AF) in the genome-wide association study (GWAS) meta-analysis by Nielsen et al (OR, 0.96; 95% CI, 0.93, 0.99; P = 0.019; Figure 2)
The associations for CAD and AF were not replicated in the FinnGen consortium, the suggestive and significant associations for CAD and AF persisted in the meta-analysis combining different data sources (CAD: odds ratios (ORs), 0.97; 95% CI, 0.94, 1.00; P = 0.044; AF: OR, 0.96; 95% CI, 0.93, 0.99; P = 0.005; Figure 2)
Summary
We aim to elucidate whether genetically predicted circulating a-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
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