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Functional polymorphisms in carboxylesterase1A2 (CES1A2) gene involves specific protein 1 (Sp1) binding sites
Mika Yoshimura1, Tomomi Kimura, Miho Ishii
1Department of Molecular Epidemiology, Medical Research Institute, Tokyo Medical Dental University, 2-3-10 Kanda-surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
Biochemical and Biophysical Research Communications
|March 11, 2008
Summary
Genetic variations in the Carboxylesterase 1 (CES1) promoter influence drug metabolism. A specific haplotype with Sp1 binding sites shows higher activity, impacting prodrug activation and ACE inhibitor response.
Area of Science:
- Pharmacogenetics
- Molecular Biology
- Drug Metabolism
Background:
- Carboxylesterase 1 (CES1) is crucial for activating prodrugs and impacts pharmacokinetics.
- A prior study linked the CES1A2 gene's -816A/C SNP to imidapril responsiveness.
Purpose of the Study:
- To identify functional polymorphisms in the CES1A2 promoter region.
- To investigate the impact of these variations on CES1 activity and drug response.
Main Methods:
- Re-sequencing of the CES1A2 promoter region in 100 Japanese hypertensive patients.
- Identification and linkage disequilibrium analysis of SNPs and insertion/deletion variants.
- In vitro assays to assess transcription and Sp1 binding activities of identified haplotypes.
Main Results:
- Ten SNPs and one I/D variant were identified in the CES1A2 promoter.
- Seven SNPs and one I/D formed a haplotype block with high linkage disequilibrium.
- A minor haplotype (22% frequency) with Sp1 binding sites exhibited higher in vitro transcription and Sp1 binding activity compared to the major haplotype.
- The -816A/C SNP was in high linkage disequilibrium with these functional haplotypes.
Conclusions:
- Variations in Sp1 binding sites within the CES1A2 promoter are functional.
- These promoter variations are potential candidates for pharmacogenetic studies involving CES1-activated drugs.
- The findings provide a molecular basis for the association between CES1A2 genotype and imidapril efficacy.
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