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Influence of microRNA-related polymorphisms on clinical outcomes in coronary artery disease.

ABSTRACT: Genetic variants in pre-microRNA (miRNA) genes or the 3'UTR of miRNA target genes could influence miRNA-mediated regulation of gene expression and thus contribute to the susceptibility and prognosis of human diseases. This study aimed to investigate the effect of 6 miRNA-related polymorphisms (miR-149 rs71428439, miR-146a rs2910164, miR-499 rs3746444, miR-423 rs6505162, miR-4513 rs2168518, and FABP2 rs11724758) on prognosis in 1004 patients with angiographic coronary artery disease (CAD). We found that miR-4513 rs2168518 was associated with blood pressure, triglycerides, total cholesterol, and fasting glucose levels, and risk of diabetes mellitus. miR-499 rs3746444 and miR-423 rs6505162 were associated with blood pressure and HDL levels, respectively. Both miR-4513 rs2168518 and miR-499 rs3746444 had significant impact on even-free survival. Furthermore, miR-4513 rs2168518 was associated with higher morality in CAD patients. In conclusion, miR-4513 rs2168518 and miR-499 rs3746444 might be potential biomarkers for the clinical prognosis of CAD.

SUBMITTER: Li Q

PROVIDER: S-EPMC4399102 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Influence of microRNA-related polymorphisms on clinical outcomes in coronary artery disease.

Li Qianzhen Q Chen Liangwan L Chen Daozhong D Wu Xijie X Chen Meifang M

American journal of translational research 20150215 2

Genetic variants in pre-microRNA (miRNA) genes or the 3'UTR of miRNA target genes could influence miRNA-mediated regulation of gene expression and thus contribute to the susceptibility and prognosis of human diseases. This study aimed to investigate the effect of 6 miRNA-related polymorphisms (miR-149 rs71428439, miR-146a rs2910164, miR-499 rs3746444, miR-423 rs6505162, miR-4513 rs2168518, and FABP2 rs11724758) on prognosis in 1004 patients with angiographic coronary artery disease (CAD). We fou ...[more]

PMID: 25901206

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Project description:Background Dual antiplatelet therapy based on aspirin and P2Y12 receptor antagonists such as clopidogrel is currently the primary treatment for coronary artery disease (CAD). However, a percentage of patients exhibit clopidogrel resistance, in which genetic factors play vital roles. This study aimed to investigate the roles of GAS5 (growth arrest-specific 5) and its rs55829688 polymorphism in clopidogrel response in patients with CAD. Methods and Results A total of 444 patients with CAD receiving dual antiplatelet therapy from 2017 to 2018 were enrolled to evaluate the effect of GAS5 single nucleotide polymorphism rs55829688 on platelet reactivity index. Platelets from 37 patients of these patients were purified with microbeads to detect GAS5 and microRNA-223-3p (miR-223-3p) expression. Platelet-rich plasma was isolated from another 17 healthy volunteers and 46 newly diagnosed patients with CAD to detect GAS5 and miR-223-3p expression. A dual-luciferase reporter assay was performed to explore the interaction between miR-223-3p and GAS5 or P2Y12 3'-UTR in (human embryonic kidney 293 cell line that expresses a mutant version of the SV40 large T antigen) HEK 293T and (megakaryoblastic cell line derived in 1983 from the bone marrow of a chronic myeloid leukemia patient with megakaryoblastic crisis) MEG-01 cells. Loss-of-function and gain-of-function experiments were performed to reveal the regulation of GAS5 toward P2Y12 via miR-223-3p in MEG-01 cells. We observed that rs55829688 CC homozygotes showed significantly decreased platelet reactivity index than TT homozygotes in CYP2C19 poor metabolizers. Platelet GAS5 expression correlated positively with both platelet reactivity index and P2Y12 mRNA expressions, whereas platelet miR-223-3p expression negatively correlated with platelet reactivity index. Meanwhile, a negative correlation between GAS5 and miR-223-3p expressions was observed in platelets. MiR-223-3p mimic reduced while the miR-223-3p inhibitor increased the expression of GAS5 and P2Y12 in MEG-01 cells. Knockdown of GAS5 by siRNA increased miR-223-3p expression and decreased P2Y12 expression, which could be reversed by the miR-223-3p inhibitor. Meanwhile, overexpression of GAS5 reduced miR-223-3p expression and increased P2Y12 expression, which could be reversed by miR-223-3p mimic. Conclusions GAS5 rs55829688 polymorphism might affect clopidogrel response in patients with CAD with the CYP2C19 poor metabolizer genotypes, and GAS5 regulates P2Y12 expression and clopidogrel response by acting as a competitive endogenous RNA for miR-223-3p.

Dataset Information

Influence of microRNA-related polymorphisms on clinical outcomes in coronary artery disease.

Publications

Influence of microRNA-related polymorphisms on clinical outcomes in coronary artery disease.

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