Association between polymorphisms in microRNA seed region and warfarin stable dose

Abstract

BackgroundThe optimal dose of anticoagulant warfarin varies among patients to achieve the target international normalised ratio. Although genetic variations related to warfarin pharmacokinetics and vitamin K cycle are important factors associated with warfarin dose requirements, these variations do not completely explain the large interindividual variability observed in the most populations, suggesting that additional factors may contribute to this variability. microRNAs have recently been introduced as regulators of drug function genes, and therefore, may be involved in drug responses. In this study, we aimed to evaluate the possible association between variants in the seed region of microRNAs, which target the genes involved in the action of warfarin and warfarin dose requirement.Methods526 samples were collected from Iranian patients. Four selected polymorphisms in the seed region of microRNAs (rs2910164, rs66683138, rs12416605 and rs35770269 in miR-146a, miR-3622a, miR-938 and miR-449c, respectively) were genotyped by PCR-restriction fragment length polymorphism method.Resultsrs2910164 C/G in the seed region of miR-146a was associated with warfarin dose requirement (p<0.001); the patients with GG genotype had the higher mean dose of warfarin (40.6 mg/week, compared with 33.9 and 31.8 mg/week for GC and CC genotypes, respectively). The association of other polymorphisms with warfarin dose requirement was not statistically significant.Conclusionrs2910164 C/G in the seed region of miR-146a is associated with warfarin maintenance dose, likely by disrupting interaction between miR-146a and ATP-binding cassette subfamily B member 1 gene, ABCB1. Therefore, this polymorphism may possibly be a potential factor for assessment of warfarin dose requirements.

Plasma miRNA profiles associated with stable warfarin dosage in Chinese patients

“…Roles of miRNAs in drug toxicity, safety assessment ( Marrone, Beland & Pogribny, 2015 ), and regulation of drug metabolism and disposition ( Yu, 2009 ) have been described. Previous studies have reported several miRNAs polymorphisms related to warfarin dose, and warfarin itself can also affect miRNAs expression ( Ciccacci et al, 2015 ; Rad, Mazaheri & Firozabadi, 2018 ; Hosseindokht et al, 2020 ; Jia et al., 2015 ). These studies suggest that miRNAs may have great value as new biomarkers and therapeutic targets.…”

“…These studies suggested that miRNAs may affect warfarin treatment by regulating VKORC1, which needs further verification. In recent years, many pieces of researches indicated that miRNAs polymorphisms ( Ciccacci et al, 2015 ; Hosseindokht et al, 2020 ), and SNPs in miRNAs binding sites ( Hosseindokht et al, 2019 ) could also affect the expression of warfarin target genes and further influence drug response. On the other hand, Rad, Mazaheri & Firozabadi (2018) and Jia et al.…”