Details

Autor(en) / Beteiligte

• Sharma, Anu Radha
• Vohra, Manik
• Shukla, Vaibhav
• Guddattu, Vasudeva
• Razak UK, Abdul
• Shetty, Ranjan
• Umakanth, Shashikiran
• Satyamoorthy, Kapaettu
• Rai, Padmalatha S.

Titel

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

Ist Teil von

• Life sciences (1973), 2020-03, Vol.245, p.117364-8, Article 117364

Ort / Verlag

Netherlands: Elsevier Inc

Erscheinungsjahr

2020

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. 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. 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. 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. •Clopidogrel resistance was observed in 23% of enrolled individuals.•CYP2C19 rs4244285 was associated with clopidogrel drug resistance.•CYP2C19 rs4244285 showed association to clopidogrel carboxylic acid metabolite in urine and plasma.•miR-1343-3p and miR-6783-3p were up-regulated in individuals with CYP2C19 rs4244285 AA genotype.•miR-1343-3p and miR-6783-3p down-regulated the protein expression of CYP2C19.