Coding SNPs in hsa-miR-1343-3p and hsa-miR-6783-3p target sites of CYP2C19 modulates clopidogrel response in individuals with cardiovascular diseases

Sharma, Anu Radha and Vohra, Manik and Shukla, Vaibhav and Guddattu, Vasudeva and Razak, Abdul UK and Shetty, Ranjan K and Umakanth, Shashikiran and Satyamoorthy, K and Rai, Padmalatha S (2020) Coding SNPs in hsa-miR-1343-3p and hsa-miR-6783-3p target sites of CYP2C19 modulates clopidogrel response in individuals with cardiovascular diseases. Life Sciences, 245. pp. 1-9. ISSN 0024-3205

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Abstract

Aims: To investigate the impact of microRNA target SNPs (mirSNPs) and their interaction with miRNAs on important drug-metabolizing enzymes, transporters and target genes for prediction of clopidogrel drug response in cardiovascular disease individuals. Main methods: A prospective cross-sectional study was conducted on 292 individuals undergoing clopidogrel drug therapy. All the enrolled participants were administered 300 mg loading dose followed by 75 mg dose of maintenance therapy. Platelet aggregations were measured before administration of the loading dose and 2 h post fifth day dose of clopidogrel maintenance therapy. Clopidogrel carboxylic acid metabolite from plasma and urine were analyzed post maintenance therapy using the RP-HPLC method. Genotyping of mirSNP's shortlisted through in silico analysis was performed by tetra ARMS PCR and validated by Sanger DNA sequencing. The levels of selected miRNAs were estimated by the TaqMan-PCR assay. Functional validation of mirSNPs was performed in HepG2 cells after transfecting with the selected gene and miRNA mimics. Protein expressions were analyzed by western blot. Key findings: 23% of enrolled individuals showed resistance to clopidogrel therapy. Out of 13 mirSNP's analyzed, CYP2C19 rs4244285 was associated with clopidogrel drug resistance and clopidogrel carboxylic acid metabolite in urine and plasma. hsa-miR-1343-3p and hsa-miR-6783-3p levels were significantly high in individuals with CYP2C19 rs4244285 mutant genotype and these miRNAs down-regulated the protein expression of CYP2C19. Significance: We demonstrated the role of coding mirSNP (rs4244285) in the regulation of the CYP2C19 gene through miRNAs and its implications to clopidogrel drug response prediction in the Indian population.

Item Type: Article
Uncontrolled Keywords: Clopidogrel ; miRNA pharmacogenomics ; Pharmacoepigenetics ; mirSNPs ; miRNAs ; Drug response.
Subjects: Medicine > KMC Manipal > Cardiology
Departments at MU > Statistics
Life Sciences > MLSC Manipal
Medicine > KMC Manipal > Medicine
Depositing User: KMC Library
Date Deposited: 25 Jun 2020 08:59
Last Modified: 25 Jun 2020 08:59
URI: http://eprints.manipal.edu/id/eprint/155201

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