Bidirectional mendelian randomzation study of TET2-clonal haematopoiesis of indeterminate potential-mutations with hs-CRP in patients with STEMI
X X Zhao, R Z Chen, J N Li, L H Xue, N Li, L Song, H B Yan, H J ZhaoAbstract
Introduction
Clonal haematopoiesis of indeterminate potential (CHIP), driven by age-related somatic mutations in hematopoietic stem cells, has emerged as a novel modulator of cardiovascular risk.
Objectives
This study investigates the prognostic interplay between TET2-CHIP mutations, systemic inflammation quantified by high-sensitivity C-reactive protein (hs-CRP) by bidirectional Mendelian randomization (MR) to elucidate causal relationships among ST-segment elevation myocardial infarction (STEMI) patients.
Patients and methods
A bidirectional Mendelian randomization study was performed using genetic instruments for TET2-CHIP from the UK Biobank (2,041 cases; 173,918 controls) and hs-CRP data from the European Bioinformatics Institute consortium (353,466 cases and 34,594,039 controls) to assess causality.
Results
Bidirectional MR studies indicated that the increased value of hs-CRP improves the propensity for CHIP.265 single-nucleotide polymorphisms (SNPs) with P < 10−8 were pruned as 10 Mb apart and in linkage disequilibrium with each SNP exhibiting an F-statistic exceeding the threshold of 10 (p＜5*10-8, r2＜0.001, window size=1000kb). Inverse variance weighted estimates suggested that hs-CRP had a risk causal relationship effect on TET2-CHIP mutations (odds ratio = 1.0024, 95% confidence interval: 1.0005-1.0043, P = 0.0153) . MR-Egger (Q = 215.2087, Q value = 0.2817；IVW，Q = 215.871, Q value = 0.2876) and MR-PRESSO (p value=0.564) intercept did not identify any pleiotropic SNPs. We found no evidence supporting significant horizontal pleiotropy (Egger intercept = 0.00004, P = 0.4291) . Forest plot has shown the beta estimates and 95% confidence intervals of MR. No significant heterogeneity of instrumental variables or horizontal pleiotropy was found. The findings of scatter plots indicated that the trajectories of various algorithms exhibit an overall upward trend, suggesting that the risk of TET2-CHIP mutations escalates with increasing concentrations of hs-CRP. The positive potential causal effect of TET2-CHIP on hs-CRP was not shown in the conventional two-sample MR approach [inverse variance weighted method; Estimate = 0.6296, 95% CI: 0.3262–1.2154, P = 0.1680]. According to the results of reverse MR analysis, no significant causal effect of CHIP was found on hs-CRP. We next evaluated the relationship of PCSK9 with the occurrence of CHIP acquired genome-wide singleton single nucleotide polymorphism. However, MR analyses did not supported a causal relationship between PCSK9 and increased somatic mutations in two-sample MR study.
Conclusion
Mendelian randomization establishes a unidirectional causal relationship where genetically determined hs-CRP elevation predisposes to TET2-CHIP acquisition. These findings align with emerging paradigms of somatic mutation-driven inflammation while providing novel insights into risk stratification and therapeutic targeting in post-MI populations.Mendelian randomization of CRP on CHIPScatter plots