# The Impact of Carboxylesterase 1 ( CES1 ) in Personalized Antiplalet Therapy

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2021 · $309,000

## Abstract

PROJECT SUMMARY
 Medical management of coronary artery disease patients is most commonly achieved through dual
antiplatelet therapy with aspirin and clopidogrel in order to reduce rates of recurrent atherothrombotic events.
While clopidogrel is generally effective, substantial inter-individual variation in platelet response to this
medication has been documented and patients who have altered clopidogrel response have increased risk of
experiencing a cardiovascular event and would likely benefit from alternative treatment strategies. Previous
investigations have shown that clopidogrel response is highly heritable; however, apart from CYP2C19*2,
identification of genetic factors that are reproducibly associated with clopidogrel response has been limited.
We have previously shown that a missense loss-of-function single nucleotide polymorphism (SNP) in exon 4 of
carboxylesterase 1 (CES1) results in a catalytic site glycine (G)-to-glutamic acid (E) amino acid substitution at
position 143 (G143E) and substantially impacts response to clopidogrel. Importantly, CES1 is the primary
enzyme responsible for metabolizing the clopidogrel prodrug, its intermediate metabolite (2-oxo-clopidogrel),
and the final bioactive thiol metabolite into biologically inactive carboxylic acid derivatives. Therefore, genetic
variation affecting CES1 expression and/or activity is likely to be a critical determinant of clopidogrel efficacy.
However, no investigation to date has characterized the impact of genetic variation in CES1 on clopidogrel
response. In this proposal, our overall hypothesis is that comprehensive characterization of CES1 will unveil
novel variants that significantly impact variable clopidogrel response and that use of an alternative P2Y12
receptor inhibitor (i.e. ticagrelor) will reverse the effect of these variants on on-treatment platelet function. We
will test this hypothesis by leveraging existing exome and whole genome sequencing data in 5,000 individuals
to bioinformatically prioritize genetic variation in CES1 and then assess the impact of these variants on
clopidogrel efficacy in participants of the Pharmacogenomics of Anti-Platelet Intervention Study (N = 566) and
International Clopidogrel Pharmacogenomics Consortium (N = 5,819). We will extend these findings by
performing a prospective, randomized crossover study of clopidogrel (75 mg per day for 7 days) and ticagrelor
(90 mg twice daily for 7 days) in healthy individuals by CES1 genotype (G143E and the most significantly
associated variant identified in Specific Aim 1, 30 individuals per genotype group) in order to assess the
interaction of genotype and drug choice on on-treatment agonist-stimulated platelet aggregation. These
studies will contribute to our knowledge regarding the genetic underpinnings underlying clopidogrel resistance
and will assess the impact of alternative antiplatelet therapy in individuals who are genetically predisposed to
altered clopidogrel response. Understanding drug re...

## Key facts

- **NIH application ID:** 10191007
- **Project number:** 5R01HL137922-05
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** JOSHUA PATRICK LEWIS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $309,000
- **Award type:** 5
- **Project period:** 2017-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10191007

## Citation

> US National Institutes of Health, RePORTER application 10191007, The Impact of Carboxylesterase 1 ( CES1 ) in Personalized Antiplalet Therapy (5R01HL137922-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10191007. Licensed CC0.

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