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Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
Identification of NR1I2 genetic variation using resequencing.
Cristi R King1, Ming Xiao, Jinsheng Yu
1Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.
European Journal of Clinical Pharmacology
|April 4, 2007
Summary
Genetic variations in the nuclear receptor NR1I2 (PXR) were analyzed across global populations. Specific NR1I2 polymorphisms correlate with altered expression of drug-metabolizing genes, suggesting clinical relevance.
Area of Science:
- Pharmacogenomics
- Molecular biology
- Human genetics
Background:
- The nuclear receptor NR1I2 (PXR/SXR) is crucial for regulating genes involved in drug metabolism and transport, primarily in the liver and intestines.
- NR1I2 activation by xenobiotics leads to heterodimerization with RXR, influencing downstream gene expression (e.g., ABCB1, CYP2C, CYP3A).
Purpose of the Study:
- To investigate the extent of genetic variation in the NR1I2 gene across diverse world populations.
- To identify novel polymorphisms and assess their association with gene expression.
Main Methods:
- Pooled resequencing was employed to identify NR1I2 variations in African, Asian, and European populations.
- PCR and Pyrosequencing validated findings, while real-time PCR quantified RNA expression of NR1I2, ABCB1, and CYP3A4.
Main Results:
- 36 single nucleotide polymorphisms (SNPs) in NR1I2 were identified, with 36% unique to the African population; 13 novel polymorphisms were discovered.
- The NR1I2 -566A > C polymorphism showed a significant association with ABCB1 and CYP3A4 RNA expression in colon tumors (P=0.04).
Conclusions:
- Genetic variations in NR1I2 contribute to altered function, potentially impacting drug metabolism and transport.
- These findings highlight the clinical significance of NR1I2 genetic diversity in personalized medicine.
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