Acute myocardial infarction, 90 Cardiovascular proteins and Paroxysmal ventricular tachycardia: a Mendelian randomization study

BackgroundPrevious studies have shown that acute myocardial infarction (AMI) may be associated with paroxysmal ventricular tachycardia (PVT). However, the causal effect between AMI and PVT, and whether cardiovascular proteins act as a mediator remain unclear. MethodsThe genetic data of AMI, 90 Cardiovascular proteins (CVPs) and PVT were obtained from large-scale genome-wide association studies (GWAS). The Mendelian randomization analysis was applied to evaluate the casual association among the AMI, CVPs and PVT. The inverse variance weighting casual effect was regarded as main statistical method. We further investigated whether CVPs take a mediating role in the pathway from AMI to PVT. ResultsThere were three positive, including ESM-1 (OR 1.139, 95%CI 1.034-1.255, P-FDR=0.014), GAL (OR 1.105,95%CI 1.025-1.191, P-FDR=0.015) and PRL (OR 1.084, 95%CI 1.004-1.170, P-FDR=0.038), and four negative, including FAS (OR 0.928, 95%CI 0.885-0.974, P-FDR=0.009), LEP (OR 0.938, 95%CI 0.891-0.987, P-FDR=0.018), TNF-R1 (OR 0.930, 95%CI 0.883-0.979, P-FDR=0.014) and TNF-R2 (OR 0.928, 95%CI 0.883-0.974, P-FDR=0.009), casual effects between genetic liability of AMI on CVPs. We identified two positive, including IL-27 (OR 1.371, 95%CI 1.010-1.861, P-FDR=0.045) and MMP-12 (OR 1.330, 95%CI 1.035-1.709, P-FDR=0.045), and two negative, including LEP (OR 0.614, 95%CI 0.384-0.981, P-FDR=0.045) and TF (OR 0.714, 95%CI 0.514-0.992, P-FDR=0.045), casual effects between genetic liability of CVPs on PVT. In addition, the AMI played a positive casual effect on PVT (OR 1.736, 95%CI 1.300-2.318, P-FDR<0.001) mediating by LEP with 5.71%. ConclusionsThe AMI was casually correlated to PVT, and LEP acted as a mediator in the pathway from AMI to PVT. Key MessagesO_ST_ABSWhat is already known on this topic?C_ST_ABSPrevious retrospective and prospective clinical studies have suggested that attention should be paid to the risk of subsequent malignant ventricular arrhythmias, including ventricular tachycardia and ventricular fibrillation, in patients with acute myocardial infarction. What this study adds?We used Mendelian randomization to demonstrate the genetic relationship between acute myocardial infarction and paroxysmal ventricular tachycardia, and found that leptin mediated the occurrence of paroxysmal ventricular tachycardia in clinical patients with acute myocardial infarction for the first time. In addition, we also found a large number of cardiovascular proteins closely genetically related to acute myocardial infarction or paroxysmal ventricular tachycardia, How this study might affect research, practice or policy?Our research provides a new insight which means that appropriate serological detection or intervention for patients with acute myocardial infarction can predict or prevent the occurrence of secondary malignant ventricular arrhythmias and reduce the mortality of patients with acute myocardial infarction in the future. Also, the cardiovascular proteins detected by Mendelian randomization analysis are helpful for the diagnosis and prevention of the two. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=108 SRC="FIGDIR/small/24314334v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@1796215org.highwire.dtl.DTLVardef@166f34org.highwire.dtl.DTLVardef@dece5aorg.highwire.dtl.DTLVardef@1bda137_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract.C_FLOATNO C_FIG We carefully analyzed the causal relationship among AMI, 90 CVPs and PVT in the complicated MR analysis. We found three positive (ESM-1, GAL and PRL) and four negative casual effects (FAS, LEP, TNF-R1 and TNF-R2) between genetic liability of AMI on CVPs. There were two positive (IL-27 and MMP-12) and two negative (LEP and TF) casual effects between genetic liability of CVPs on PVT. The AMI played a positive casual effect on PVT mediating by LEP with 5.71%. We identified two positive (Dkk-1 and PDGF_subunit_B) and two negative (RAGE and SPON1) casual effects between genetic liability of CVPs on AMI, and thee positive (IL-1ra, MCP-1 and TIE2) casual effects between genetic liability of CVPs on PVT. AMI, acute myocardial infarction; PVT, paroxysmal ventricular tachycardia; CVPs, cardiovascular proteins; AGRP, agouti-related protein; ESM-1, endocan; FAS, tumor necrosis factor receptor superfamily member 6; GAL, galactose-alpha-1,3-galactose; LEP, leptin; PRL, placental growth factor; TNF-R1, tumor necrosis factor receptor 1; TNF-R2, tumor necrosis factor receptor 2; IL-27, interleukin-27; MMP-12, matrix metalloproteinase-12; TF, tissue factor; Dkk-1, dickkopf-related protein 1; PDGF_subunit_B, platelet-derived growth factor subunit B; RAGE, receptor for advanced glycosylation end products; SCF,stem cell factor; SPON1, spondin-1; IL-1ra, interleukin-1 receptor antagonist protein; MCP-1, monocyte chemotactic protein 1; TIE2, angiopoietin-1 receptor.