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Pharmacogenetics of Drug Metabolizing Enzymes Involved in Cardiovascular Drug Treatment

Sanford, Jonathan Christian
http://rave.ohiolink.edu/etdc/view?acc_num=osu1405518187

Abstract Details

2014, Doctor of Philosophy, Ohio State University, Integrated Biomedical Science Graduate Program.
Regulatory variants, less well characterized than coding polymorphisms, have the potential to serve as clinically relevant biomarkers for determining drug efficacy or toxicity. This study focuses on the identification of functional regulatory single nucleotide polymorphisms (SNPs) in the candidate genes cytochrome P450 2C19 (CYP2C19), carboxylesterase 1A1 (CES1A1) and angiotensin-I converting enzyme (ACE), which are involved in the metabolism of many cardiovascular drugs. Using allelic mRNA ratios (an indicator of functional regulatory variants), classic molecular genetics and next-generation sequencing technologies, I demonstrate that cis-acting regulatory polymorphisms in these genes are present and may have utility as pharmacogenetic biomarkers. The drug metabolizing enzyme cytochrome P450 2C19 plays a major role in activation of clopidogrel (Plavix). Ultra-rapid metabolizer phenotype status has been associated with enhanced transcription caused by promoter allele CYP2C19*17. Here, I characterize the effect of CYP2C19*17 on gene expression in human liver. CYP2C19*17 heterozygotes and homozygotes show an increase in total CYP2C19 mRNA expression of 1.8-fold (p=0.028) and 2.9-fold (p=0.006), respectively compared to homozygous reference allele livers. Allelic mRNA ratios of ~1.8 fold (SD±0.6, p<0.005), also significantly associate with CYP2C19*17. Potential novel regulatory variants were identified in an individual of African descent whose allelic mRNA ratio (~2-fold) is not accounted for by CYP2C19*17. This indicates that additional regulatory SNPs may affect CYP2C19 expression in non-Caucasian populations. Carboxylesterase 1A1 metabolizes clopidogrel, ACE inhibitors and many other compounds. Coding polymorphisms have been shown to affect carboxylesterase 1A1 function and decrease clopidogrel efficacy. The previously described CES1A1VAR, a highly linked block of 11 SNPs in the 5' region of carboxylesterase 1A1, shows a strong association with allelic mRNA ratios (~1.35-fold). CES1A1VAR carriers also show a decrease in total gene expression of 2.65-fold (P = 0.003), and a 1.33-fold decrease in protein quantity (P= 0.008). Additional study of the carboxylesterase gene locus has identified a 5 SNP linkage block in the 5' UTR (termed CES1A1SVAR). Utility as a biomarker for these variants will require further study. Previously, our group had shown angiotensin converting enzyme-1 (a target of ACE inhibitors) harbors enhancer SNPs prevalent in African populations with function in heart tissue. Performed here, a survey of other tissues indicates that enhancer SNP function is limited to the heart. Further, allelic mRNA analysis provides evidence of regulatory variants in Caucasian liver tissue (~2-fold), putamen (~1.7-fold, Hispanic and African descent) and adipose (RNA-sequencing, ~1.35-fold). These targeted studies demonstrate the impact genetic variability can have on gene expression. CES1A1VAR in particular has potential as a pharmacogenetic biomarker, especially in predicting clopidogrel response. CYP2C19 and ACE studies also indicate that these genes harbor functional variants active in certain tissues or present in certain populations. These enzymes affect the metabolism of numerous drugs (cardiovascular or otherwise) making pharmacogenetic characterization crucial to effective prediction of drug efficacy or toxicity.
Wolfgang Sadee, Dr.rer.nat (Advisor)
Mitch Phelps, PhD (Committee Member)
Amanda Toland, PhD (Committee Member)
Daren Knoell, PharmD (Committee Member)
153 p.
Genetics; Molecular Biology; Pharmacology
pharmacogenetics; genetics; cytochrome; drug metabolism; angiotensin; carboxylesterase; CYP2C19; ACE; CES1; cardiovascular; allele; polymorphism; SNP; clopidogrel

Recommended Citations

Citations

  • Sanford, J. C. (2014). Pharmacogenetics of Drug Metabolizing Enzymes Involved in Cardiovascular Drug Treatment [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1405518187

    APA Style (7th edition)

  • Sanford, Jonathan. Pharmacogenetics of Drug Metabolizing Enzymes Involved in Cardiovascular Drug Treatment. 2014. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1405518187.

    MLA Style (8th edition)

  • Sanford, Jonathan. "Pharmacogenetics of Drug Metabolizing Enzymes Involved in Cardiovascular Drug Treatment." Doctoral dissertation, Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1405518187

    Chicago Manual of Style (17th edition)

osu1405518187
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This open access ETD is published by The Ohio State University and OhioLINK.