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Abstract
BackgroundAcute myocardial infarction (AMI), characterized by an event of myocardial necrosis, is a common cardiac emergency worldwide. However, the genetic mechanisms of AMI remain largely elusive.MethodsA genome-wide association study dataset of AMI was obtained from the CARDIoGRAMplusC4D project. A transcriptome-wide association study (TWAS) was conducted using the FUSION tool with gene expression references of the left ventricle and whole blood. Significant genes detected by TWAS were subjected to Gene Ontology (GO) enrichment analysis. Then the TWAS results of AMI were integrated with mRNA expression profiling to identify common genes and biological processes. Finally, the identified common genes were validated by RT-qPCR analysis.ResultsTWAS identified 1,050 genes for the left ventricle and 1,079 genes for whole blood. Upon comparison with the mRNA expression profile, 4 common genes were detected, including HP (PTWAS = 1.22 × 10–3, PGEO = 4.98 × 10–2); CAMP (PTWAS = 2.48 × 10–2, PGEO = 2.36 × 10–5); TNFAIP6 (PTWAS = 1.90 × 10–2, PGEO = 3.46 × 10–2); and ARG1 (PTWAS = 8.35 × 10–3, PGEO = 4.93 × 10–2). Functional enrichment analysis of the genes identified by TWAS detected multiple AMI-associated biological processes, including autophagy of mitochondrion (GO: 0000422) and mitochondrion disassembly (GO: 0061726).ConclusionThis integrative study of TWAS and mRNA expression profiling identified multiple candidate genes and biological processes for AMI. Our results may provide a fundamental clue for understanding the genetic mechanisms of AMI.
Highlights
Acute myocardial infarction (AMI), defined by an event of myocardial necrosis caused by the rupture of an atherosclerotic plaque, has become the leading cause of death and disability worldwide (Murray et al, 2015)
Genome-wide association studies (GWAS) have successfully identified great numbers of loci, only a small proportion of phenotypic variance explains coronary artery disease or AMI (Deloukas et al, 2013). This is probably because significant single nucleotide polymorphisms (SNPs) identified by GWAS are mainly enriched in non-coding regulatory regions
Multiple studies have indicated that Transcriptome-wide association study (TWAS) exhibited good performance in identifying novel genes of complex cardiovascular diseases, such as atrial fibrillation (Zhang et al, 2019) and calcific aortic valve stenosis (Thériault et al, 2018)
Summary
Acute myocardial infarction (AMI), defined by an event of myocardial necrosis caused by the rupture of an atherosclerotic plaque, has become the leading cause of death and disability worldwide (Murray et al, 2015). Genome-wide association studies (GWAS) have identified several genetic loci that confer susceptibility to AMI, such as CDKN2A/2B, CELSR2-PSRC1-SORT1, CXCL12, ABO, LDLR, and APOA5 (Qi et al, 2011; Do et al, 2015; Nikpay et al, 2015). GWAS have successfully identified great numbers of loci, only a small proportion (approximately 10.6%) of phenotypic variance explains coronary artery disease or AMI (Deloukas et al, 2013). This is probably because significant single nucleotide polymorphisms (SNPs) identified by GWAS are mainly enriched in non-coding regulatory regions.
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