Fig. 1. Description of the study design.

First, we performed whole exome sequencing of 168 patients and 51 out of them had MACE end point. After quality filtering, a total of 127,834 variants were subjected to single variant association analysis and 6268 variants showed nominal association (P < 0.05). Gene-based association analyses identified 408 genes associated with MACE (P < 0.05). As validation, the 6MB targeted region including 6268 top SNPs and 408 top genes was further analyzed in additional 1703 patients through multivariable Cox regression analysis. A total of 177 SNPs and 82 genes were replicated in validation datasets. Finally, we performed meta-analysis of the two-stage associations and identified eight genetic variants contributed to MACE (P < 7.98 × 10⁻⁶ = 0.05/6268). Then, we performed functional analysis on the eight significant SNPs or genes; further, we developed the first superior classifier for predicting MACE.