Discovery of circadian rhythm-related hub genes in acute myocardial infarction: A two-sample Mendelian randomization study

Circadian rhythms have been reported in a variety of physiological processes that may influence cardiovascular disease, while little is known about the effects of circadian rhythm-related genes (CRRGs) on acute myocardial infarction (AMI). The genome-wide association study (GWAS) data of AMI (ukb-a-533) and expression quantitative trait loci (eQTL) data of CRRGs were downloaded from the integrative epidemiology unit Open GWAS database. The relationship between the CRRGs and AMI was assessed by the two-sample Mendelian randomization (TSMR) analysis. The hub genes that could directly affect AMI were identified based on the inverse variance weighted (IVW) algorithms. Subsequently, the TSMR results were evaluated via sensitivity analyses and MR-Steiger filtering. Then, the expression in immune cells and tissues was predicted from the Human Protein Atlas and Genotype-Tissue Expression databases. Finally, the molecular regulatory networks were generated based on the hub genes. In TSMR results, NR1H3 (IVW: odds ratio (OR) = 1.0009, 95% confidence interval (CI) = 1.0005-1.0013), SREBF1 (IVW: OR = 1.0015, 95% CI = 1.0007-1.0022), SIRT1 (IVW: OR = 1.0007, 95% CI = 1.0001-1.0013), and HIF1A (IVW: OR = 1.0022, 95% CI = 1.0004-1.0039) were risk factors for AMI patients, while NCOA1 (IVW: OR = 0.9984, 95% CI = 0.9969-0.9998) was a protective factor for AMI patients (P < .05). Importantly, the 5 hub genes could affect AMI occurrence in one direction. The expression levels of HIF1A, NCOA1, and SREBF1 were highest in neutrophils than the other immune cells. Also, HIF1A and SREBF1 had higher expression in the heart (left ventricle and atrial appendage) and artery (aorta, tibial, and coronary). Moreover, the transcription factor, NFKB1, might regulate the hub genes except for NCOA1. Generally, 4 risk genes (NR1H3, SREBF1, SIRT1, and HIF1A) and 1 protective gene (NCOA1) associated with circadian rhythm for AMI patients were identified, providing new insights into the diagnosis and treatment of AMI.