Circulating α-Klotho Levels in Relation to Cardiovascular Diseases: A Mendelian Randomization Study

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.