Genetic variation in the 3′-UTR of CYP1A2, CYP2B6, CYP2D6, CYP3A4, NR1I2, and UGT2B7: potential effects on regulation by microRNA and pharmacogenomics relevance

Abstract

Introduction: Pharmacogenomics research has concentrated on variation in genes coding for drug metabolizing enzymes, transporters and nuclear receptors. However, variation affecting microRNA could also play a role in drug response. This project set out to investigate potential microRNA target sites in 11 genes and the extent of variation in the 3′-UTR of six selected genes; CYP1A2, CYP2B6, CYP2D6, CYP3A4, NR1I2, and UGT2B7.Methods: Fifteen microRNA target prediction algorithms were used to identify microRNAs predicted to regulate 11 genes. The 3′-UTR of the 6 genes which topped the list of potential microRNA targets was sequenced in 30 black South Africans. In addition, genetic variants within these genes were investigated for interference with mRNA-microRNA interactions. Potential effects of observed variants were determined using in silico prediction tools.Results: The 11 genes coding for DMEs, transporters and nuclear receptors were predicted to be targets of microRNAs with CYP2B6, NR1I2 (PXR), CYP3A4, and CYP1A2, interacting with the most microRNAs. The majority of identified genetic variants were predicted to interfere with microRNA regulation. For example, the variant, rs1054190C in NR1I2 was predicted to result in the presence of a binding site for the microRNA miR-1250-5p, while the variant rs1054191G was predicted to result in the absence of a recognition site for miR-371b-3p, miR-4258 and miR-4707-3p. Fifteen of the seventeen, novel variants occurred within microRNA target sequences.Conclusion: The 3′-UTR harbors variation that is likely to influence regulation of specific genes by microRNA. In silico prediction followed by functional validation could aid in decoding the contribution of variation in the 3′-UTR, to some unexplained heritability that affects drug response. Understanding the specific role of each microRNA may lead to identification of markers for targeted therapy and therefore improve personalized drug treatment.

Identification and validation of the microRNA response elements in the 3′-untranslated region of the UDP glucuronosyltransferase ( UGT ) 2B7 and 2B15 genes by a functional genomics approach

“…We next sought to determine whether the common SNP rs3100 c.1761 C/T [27] present in the UGT2B15 3’-UTR had an effect on binding of any of the candidate UGT2B15 -regulating miRNAs. Interestingly, in silico analysis using the bioinformatics program miRanda determined that the rs3100 SNP was located within the predicted miR-376c-3p MRE (Fig.…”

“…This way we demonstrated that SNP rs10929303 C>T located in the common UGT1A 3’-UTR created a novel MRE for miR-21–3p. Reporter gene assays by another group showed that the UGT2B15 3’-UTR rs3100 c.1761C (reference) allele resulted in lower UGT2B15-dependent luciferase reporter activity compared with the (variant) c.1761T allele in liver, breast, colon, and prostate cancer cell lines [27]. Those authors suggested that this SNP might be located within a miRNA binding site that could influence UGT2B15 expression.…”

Effect of pregnane X receptor polymorphisms on tacrolimus blood concentrations and the resulting adverse reactions in kidney transplantation recipients

“…At present, international research on NR1I2 gene polymorphisms focuses only on African Americans and Caucasians, instead of Asians or Chinese. Moreover, NR1I2 mutations differ greatly between the races (Tsuchiya et al, 2004;Wang et al, 2007;Swart and Dandara, 2014). Uno et al (2003) first discovered the NR1I2 promoter region six-base pair deletion mutation (rs3842689, -/GAGAAG), which occurs in a potential liver nuclear factor (HNF-1) binding site.…”

The expression, induction and pharmacological activity of CYP1A2 are post-transcriptionally regulated by microRNA hsa-miR-132-5p

“…Similar to CYP1A1 and CYP1B1, CYP1A2 is primarily inducible through aromatic hydrocarbon receptor-mediated transactivation by ligand binding and nuclear translocation [8]. In addition, accumulating evidence indicates that CYP1A2 expression is influenced by genetic polymorphisms [9] and transcriptional factors [8,10]; recently it was been predicted that CYP1A2 may be subject to post-transcriptional regulation by microRNAs (miRNAs) [11]. …”

“…They usually bind to their target sequences within the 3′-untranslated regions (3′-UTR) of mRNA molecules, which facilitates mRNA degradation or translational repression [11–13]. Some miRNAs have been found to interact directly with CYP450 mRNA transcripts.…”