New genetic variants associated with major adverse cardiovascular events in patients with acute coronary syndromes and treated with clopidogrel and aspirin

Liu, Xiaomin; Xu, Hanshi; Xu, Huaiqian; Geng, Qingshan; Mak, Wai-Ho; Ling, Fei; Su, Zheng; Yang, Fang; Zhang, Tao; Chen, Jiyan; Yang, Huanming; Wang, Jian; Zhang, Xiuqing; Xu, Xun; Jia, Huijue; Zhang, Zhiwei; Xiao, Lan; Zhong, Shilong

doi:10.1038/s41397-021-00245-5

Cited by 9 publications

(5 citation statements)

References 41 publications

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“…Therefore, MYOM2 may be important for hypertrophic cardiomyopathy and Tetralogy of Fallot [28]. MYOM2 is downregulated in both animal models and patients with phenotypes related to major adverse cardiovascular events [29]. The inhibitory function of another miR-483-5p gene target revealed by our analysis is TIMP2, a key determinant of post-MI myocardial remodeling; TIMP2 replenishment in diseased myocardium could provide a potential therapy in reducing or preventing disease progression [30].…”

Section: Discussionmentioning

confidence: 78%

“…In the present study, we specify the candidate target genes for mir-483-5p in heart tissue, among them PLA2G5, GRK2, MYOM2, TIMP2, ADAMTS2 and HGSNAT. Indeed, regulation of many of these genes related to cardiovascular diseases and correlated with MI in previously published reports [26][27][28][29][30][31] (Scheme 2). For instance, elevated plasma sPLA2-IIA (encoded by the PLA2G5 gene) predicts coronary heart disease risk [26] and is involved in inflammation.…”

Section: Discussionmentioning

confidence: 85%

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Characterization of Systemic and Culprit-Coronary Artery miR-483-5p Expression in Chronic CAD and Acute Myocardial Infarction Male Patients

Володько

Volinsky

Yarkoni

et al. 2023

IJMS

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Coronary artery disease (CAD) is the leading cause of mortality worldwide. In chronic and myocardial infarction (MI) states, aberrant levels of circulating microRNAs compromise gene expression and pathophysiology. We aimed to compare microRNA expression in chronic-CAD and acute-MI male patients in peripheral blood vasculature versus coronary arteries proximal to a culprit area. Blood from chronic-CAD, acute-MI with/out ST segment elevation (STEMI/NSTEMI, respectively), and control patients lacking previous CAD or having patent coronary arteries was collected during coronary catheterization from peripheral arteries and from proximal culprit coronary arteries aimed for the interventions. Random coronary arterial blood was collected from controls; RNA extraction, miRNA library preparation and Next Generation Sequencing followed. High concentrations of microRNA-483-5p (miR-483-5p) were noted as ‘coronary arterial gradient’ in culprit acute-MI versus chronic-CAD (p = 0.035) which were similar to controls versus chronic-CAD (p < 0.001). Meanwhile, peripheral miR-483-5p was downregulated in acute-MI and chronic-CAD, compared with controls (1.1 ± 2.2 vs. 2.6 ± 3.3, respectively, p < 0.005). A receiver operating characteristic curve analysis for miR483-5p association with chronic CAD demonstrated an area under the curve of 0.722 (p < 0.001) with 79% sensitivity and 70% specificity. Using in silico gene analysis, we detected miR-483-5p cardiac gene targets, responsible for inflammation (PLA2G5), oxidative stress (NUDT8, GRK2), apoptosis (DNAAF10), fibrosis (IQSEC2, ZMYM6, MYOM2), angiogenesis (HGSNAT, TIMP2) and wound healing (ADAMTS2). High miR-483-5p ‘coronary arterial gradient’ in acute-MI, unnoticed in chronic-CAD, suggests important local mechanisms for miR483-5p in CAD in response to local myocardial ischemia. MiR-483-5p may have an important role as a gene modulator for pathologic and tissue repair states, is a suggestive biomarker, and is a potential therapeutic target for acute and chronic cardiovascular disease.

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Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 85%

Characterization of Systemic and Culprit-Coronary Artery miR-483-5p Expression in Chronic CAD and Acute Myocardial Infarction Male Patients

Володько

Volinsky

Yarkoni

et al. 2023

IJMS

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“…In addition, MYOM2 was also defined as a pleiotropic gene of CAD and T2DM by MTAR ( P MTAR-O

), with 11 novel pleiotropic SNPs discovered in the vicinity of this gene. Previous GWASs have found that other SNPs (rs755900673 and rs17064642) at this gene were associated with T2DM and adverse cardiovascular events, and the novel pleiotropic SNPs we identified provide more evidence for the shared mechanism between these two diseases [ 41 , 42 ]. MYOM2 encodes a major component of the vertebrate myofibrillar M band, and hypomethylated CpG sites of MYOM2 have previously been reported to be associated with atherosclerosis-related phenotypes [ 43 ].…”

Section: Discussionmentioning

confidence: 79%

Shared Genetic Architectures between Coronary Artery Disease and Type 2 Diabetes Mellitus in East Asian and European Populations

Li,

Zhou,

et al. 2024

Biomedicines

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Coronary artery disease (CAD) is a common comorbidity of type 2 diabetes mellitus (T2DM). However, the pathophysiology connecting these two phenotypes remains to be further understood. Combined analysis in multi-ethnic populations can help contribute to deepening our understanding of biological mechanisms caused by shared genetic loci. We applied genetic correlation analysis and then performed conditional and joint association analyses in Chinese, Japanese, and European populations to identify the genetic variants jointly associated with CAD and T2DM. Next, the associations between genes and the two traits were also explored. Finally, fine-mapping and functional enrichment analysis were employed to identify the potential causal variants and pathways. Genetic correlation results indicated significant genetic overlap between CAD and T2DM in the three populations. Over 10,000 shared signals were identified, and 587 were shared by East Asian and European populations. Fifty-six novel shared genes were found to have significant effects on both CAD and T2DM. Most loci were fine-mapped to plausible causal variant sets. Several similarities and differences of the involved genes in GO terms and KEGG pathways were revealed across East Asian and European populations. These findings highlight the importance of immunoregulation, neuroregulation, heart development, and the regulation of glucose metabolism in shared etiological mechanisms between CAD and T2DM.

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“…We identified 50 of these genetic variants significantly associated with the severity of CVDs (e.g., ACS, CAD, and/or PAD). These variants ( Table 3 ) were associated with inflammatory pathways, cholesterol transport, and regulation and signaling cascades in previous GWASs [ 38 , 50 , 51 ]. Although most of these CVD-linked variants occur within intronic regions, they can either enhance or reduce gene expressions [ 52 ].…”

Section: Discussionmentioning

confidence: 95%

“…Reports of numerous SNPs associated with CVDs can be found in the available literature [ 38 , 50 , 51 ]. We identified 50 of these genetic variants significantly associated with the severity of CVDs (e.g., ACS, CAD, and/or PAD).…”

Section: Discussionmentioning

confidence: 99%

Non-Random Enrichment of Single-Nucleotide Polymorphisms Associated with Clopidogrel Resistance within Risk Loci Linked to the Severity of Underlying Cardiovascular Diseases: The Role of Admixture

Monero-Paredes,

Feliu-Maldonado,

Carrasquillo-Carrion

et al. 2023

Genes

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Cardiovascular disease (CVD) is one of the leading causes of death in Puerto Rico, where clopidogrel is commonly prescribed to prevent ischemic events. Genetic contributors to both a poor clopidogrel response and the severity of CVD have been identified mainly in Europeans. However, the non-random enrichment of single-nucleotide polymorphisms (SNPs) associated with clopidogrel resistance within risk loci linked to underlying CVDs, and the role of admixture, have yet to be tested. This study aimed to assess the possible interaction between genetic biomarkers linked to CVDs and those associated with clopidogrel resistance among admixed Caribbean Hispanics. We identified 50 SNPs significantly associated with CVDs in previous genome-wide association studies (GWASs). These SNPs were combined with another ten SNPs related to clopidogrel resistance in Caribbean Hispanics. We developed Python scripts to determine whether SNPs related to CVDs are in close proximity to those associated with the clopidogrel response. The average and individual local ancestry (LAI) within each locus were inferred, and 60 random SNPs with their corresponding LAIs were generated for enrichment estimation purposes. Our results showed no CVD-linked SNPs in close proximity to those associated with the clopidogrel response among Caribbean Hispanics. Consequently, no genetic loci with a dual predictive role for the risk of CVD severity and clopidogrel resistance were found in this population. Native American ancestry was the most enriched within the risk loci linked to CVDs in this population. The non-random enrichment of disease susceptibility loci with drug-response SNPs is a new frontier in Precision Medicine that needs further attention.

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New genetic variants associated with major adverse cardiovascular events in patients with acute coronary syndromes and treated with clopidogrel and aspirin

Cited by 9 publications

References 41 publications

Characterization of Systemic and Culprit-Coronary Artery miR-483-5p Expression in Chronic CAD and Acute Myocardial Infarction Male Patients

Characterization of Systemic and Culprit-Coronary Artery miR-483-5p Expression in Chronic CAD and Acute Myocardial Infarction Male Patients

Shared Genetic Architectures between Coronary Artery Disease and Type 2 Diabetes Mellitus in East Asian and European Populations

Non-Random Enrichment of Single-Nucleotide Polymorphisms Associated with Clopidogrel Resistance within Risk Loci Linked to the Severity of Underlying Cardiovascular Diseases: The Role of Admixture

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