Cardiac Troponin I and Risk of Stroke: A Mendelian Randomization Study

Abstract

Purpose: Cardiac troponin I (cTnI) is a well-established biomarker for stroke prediction, especially in patients with heart diseases. However, the causal effect of circulating cTnI on stroke remains unclear.

Methods: We employed Mendelian Randomization (MR) analysis to determine the associations between genetically predicted circulating cTnI levels and stroke and its subtypes. Summary-level data for exposure and outcomes were generated from different genome-wide association studies. Single-nucleotide polymorphisms (SNPs) associated with circulating cTnI at genome-wide significance level (P < 5 × 10^-8) were employed as instrumental variables (IVs). We used fixed-effect inverse-variance weighted (IVW) as the main method for pooling MR estimates. Sensitivity analyses and multivariable MR analyses were carried out to assess the robustness of the results.

Results: Using the fixed-effects IVW method, we found that genetically elevated plasma cTnI levels may have a causal effect on the risk of cardioembolic stroke (CES) (odds ratio (OR), 1.58; 95% confidence interval (CI), 1.17-2.13; P = 0.003). Additional analyses including multiplicative random-effects (mre) IVW, weighted median, MR-Egger and MR-PRESSO yielded similar results, but with broader CIs that span 1.0. The total effect of cTnI on CES was attenuated by adjusting for the effect of atrial fibrillation (OR,1.26; 95% CI, 0.76-2.11; P = 0.371) and smoking (OR,1.53; 95% CI, 0.87-2.66; P = 0.137). In addition, we found no causal effect of cTnI on the risk of any stroke and other stroke subtypes, including any ischemic stroke, large artery stroke, cardioembolic stroke, small vessel stroke, and intracerebral hemorrhage. These results were consistent across sensitivity analyses.

Conclusion: This study provides little evidence that increased serum cTnI levels lead to a higher risk of stroke.

Keywords: Mendelian randomization; cardiac troponin I; causation; genome-wide association studies; stroke.

Figure 1

Schematic diagram showing the assumptions of Mendelian randomization analysis.

Figure 2

Associations of genetic predicted cTnI levels with stroke and its subtypes. A proxy SNP (rs8039472) was used to replace SNP (rs8024538) (pairwise r² = 0.92) in all the datasets. *No outliers detected. ^†MR-PRESSO outlier detected: rs12331618.