# WITHDRAWN: The effect of ischemia on expression quantitative trait loci (eQTL) in human myocardium and insights into myocardial injury etiology

## TL;DR

This study explores how ischemia affects gene expression in human heart tissue and identifies genes linked to myocardial injury.

## Contribution

The study identifies novel eQTLs with potential causal effects on myocardial injury biomarkers and links them to cell-specific expression patterns.

## Key findings

- Cis-eQTLs were replicated in both internal and external cohorts with no major changes post-ischemia.
- Ten eQTLs with potential causal effects on troponin were identified, including TYW1 and TMEM80, which were differentially expressed in human and mouse data.
- CFAP161, a gene with causal effect on troponin, showed higher expression in endothelial cells post-ischemia and shared regulatory loci with myocardial infarction.

## Abstract

To understand the pathological processes of myocardial ischemia in humans, we performed RNA sequencing of the left ventricle (LV) tissue samples in 118 patients undergoing aortic valve replacement surgery at baseline and after cold cardioplegic arrest/ischemia, single-cell RNA sequencing was additionally performed in four patients. We characterized the genetic basis of interindividual variation in the transcriptome of human LV in baseline and post-ischemia conditions by the identification of local expression quantitative trait loci (cis-eQTL). We also conducted a genome-wide association study in an independent cohort of 2,371 patients undergoing coronary artery bypass graft surgery to assess the association between genetic variants and myocardial injury. We integrated the results with the eQTL data and identified the causal genes of myocardial injury. Finally, using mouse ischemic data, we assessed the similarity with human LV transcription in genes differentially expressed at the two conditions.

The cis-eQTL were replicated with high rates in both internal and external cohorts. We did not observe any dramatic change in the impact of cis-eQTL on gene expressions in baseline condition compared to post-ischemia condition. We identified 10 eQTLs with putative causal effect on troponin as a biomarker of myocardial injury (p-value < 0.005), such as TYW1, USP49, FLG, TMEM80, and GBAP1, which were differentially expressed in human data (p-value < 8E-3) whereas TYW1 and TMEM80 were also differentially expressed in mouse data (p-value < 0.01). We observed the higher expression of most causal genes in cardiac myocytes at post-ischemia condition, however, CFAP161 with a causal effect on troponin (p-value = 0.002) had a higher expression in endothelial cells. CFAP161 and two other causal genes MRAS and ICA1L (p-value < 0.02) shared regulatory loci with myocardial infarction using external data. The findings in this study provide insights into eQTL changes due to ischemia-induced during bypass surgery, a major clinical problem. Since this type of ischemia shares commonalities with MI, the findings may provide insights into the pathological processes of myocardial ischemia and offer potential clinical applications.