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Genetic variations significantly influence drug response through pharmacokinetics, receptor interactions, and biologic milieu modifications. Pharmacokinetic alterations impact drug metabolism and clearance, affecting efficacy and toxicity. Variants in drug-metabolizing enzymes, such as CYP2C9 and CYP2C19, alter drug activation and elimination. For example, CYP2C9 loss-of-function variants require lower warfarin doses to prevent excessive bleeding, while CYP2C19 variants reduce clopidogrel...
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Genetic polymorphisms in drug targets have emerged as critical determinants of interindividual variability in drug response and toxicity. Pharmacogenomic investigations increasingly focus on identifying these variations to personalize and optimize therapeutic interventions. A drug target may be a receptor, enzyme, or signaling protein involved in pharmacologic responses or disease-related pathways. While early pharmacogenetic studies focused primarily on drug metabolism, current research...
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Advances in genomics have profoundly influenced drug discovery by increasing both the speed and accuracy of pharmaceutical development. Pharmacogenomics, which examines how genetic variation influences drug response, facilitates the identification of novel therapeutic targets and enables patient stratification for personalized treatment. These strategies contribute to improved drug efficacy, minimized adverse effects, and more efficient clinical trial design.Mapping genetic differences...
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Altered Gene Expression Associated with microRNA Binding Site Polymorphisms.

Urmo Võsa1, Tõnu Esko2, Silva Kasela1

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Summary
This summary is machine-generated.

Genetic variations in microRNA response elements (MRE-SNPs) can alter gene expression by affecting miRNA binding. These MRE-SNPs are linked to complex traits, offering insights into genetic regulation.

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Area of Science:

  • Genetics and Genomics
  • Molecular Biology
  • Bioinformatics

Background:

  • Allele-specific gene expression, driven by genetic variation in regulatory regions, is crucial for complex trait development.
  • MicroRNAs (miRNAs) regulate gene expression by binding to target messenger RNAs, often within miRNA response elements (MREs).

Purpose of the Study:

  • To investigate how polymorphisms within MREs (MRE-SNPs) impact allele-specific gene expression by disrupting or creating miRNA binding sites.
  • To identify MRE-SNPs associated with complex traits and elucidate their potential causative mechanisms.

Main Methods:

  • Integrated public expression quantitative trait locus (eQTL) data with miRNA binding site predictions.
  • Utilized small RNA sequencing and Argonaute crosslinking immunoprecipitation (AGO-CLIP) datasets to validate miRNA binding efficiency modulation by genetic variants.
  • Analyzed MRE-SNPs in relation to known complex trait-associated genomic regions.

Main Results:

  • Identified specific genetic variants that modulate miRNA binding efficiency, thereby affecting allele-specific gene expression.
  • Discovered MRE-SNPs located within genomic regions linked to complex traits, suggesting a role in disease etiology.
  • Demonstrated that MRE-SNPs can alter gene expression by changing miRNA binding affinity.

Conclusions:

  • Polymorphisms in MREs can significantly influence allele-specific gene expression and contribute to the genetic basis of complex traits.
  • This study enhances the understanding of gene expression regulation by miRNAs and provides a framework for interpreting eQTL effects.
  • The findings offer potential mechanisms for how genetic variation impacts complex traits through miRNA-mediated gene regulation.