@article{9e323fe774d04883bca3659246f67d21,
title = "Next-Generation Sequencing of CYP2C19 in Stent Thrombosis: Implications for Clopidogrel Pharmacogenomics",
abstract = "Purpose: Describe CYP2C19 sequencing results in the largest series of clopidogrel-treated cases with stent thrombosis (ST), the closest clinical phenotype to clopidogrel resistance. Evaluate the impact of CYP2C19 genetic variation detected by next-generation sequencing (NGS) with comprehensive annotation and functional studies. Methods: Seventy ST cases on clopidogrel identified from the PLATO trial (n = 58) and Mayo Clinic biorepository (n = 12) were matched 1:1 with controls for age, race, sex, diabetes mellitus, presentation, and stent type. NGS was performed to cover the entire CYP2C19 gene. Assessment of exonic variants involved measuring in vitro protein expression levels. Intronic variants were evaluated for potential splicing motif variations. Results: Poor metabolizers (n = 4) and rare CYP2C19*8, CYP2C19*15, and CYP2C19*11 alleles were identified only in ST cases. CYP2C19*17 heterozygote carriers were observed more frequently in cases (n = 29) than controls (n = 18). Functional studies of CYP2C19 exonic variants (n = 11) revealed 3 cases and only 1 control carrying a deleterious variant as determined by in vitro protein expression studies. Greater intronic variation unique to ST cases (n = 169) compared with controls (n = 84) was observed with predictions revealing 13 allele candidates that may lead to a potential disruption of splicing and a loss-of-function effect of CYP2C19 in ST cases. Conclusion: NGS detected CYP2C19 poor metabolizers and paradoxically greater number of so-called rapid metabolizers in ST cases. Rare deleterious exonic variation occurs in 4%, and potentially disruptive intronic alleles occur in 16% of ST cases. Additional studies are required to evaluate the role of these variants in platelet aggregation and clopidogrel metabolism.",
keywords = "CYP2C19, Intronic, Pharmacogenomics, Stent thrombosis, Translational medicine",
author = "Morales-Rosado, {Joel A.} and Kashish Goel and Lingxin Zhang and Axel {\AA}kerblom and Saurabh Baheti and Black, {John L.} and Niclas Eriksson and Lars Wallentin and Stefan James and Storey, {Robert F.} and Goodman, {Shaun G.} and Jenkins, {Gregory D.} and Eckloff, {Bruce W.} and Bielinski, {Suzette J.} and Hugues Sicotte and Stephen Johnson and Roger, {Veronique L.} and Liewei Wang and Richard Weinshilboum and Klee, {Eric W.} and Rihal, {Charanjit S.} and Pereira, {Naveen L.}",
note = "Funding Information: This study was supported by NIH/NHLBI grant U01 HL128606 to N.L.P. PLATO study was funded by AstraZeneca. Funding Information: Shaun Goodman is supported by the Heart & Stroke Foundation of Ontario/University of Toronto Polo Chair and receives research grant support and speaker/consulting honoraria from AstraZeneca, Bayer, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, and Sanofi. Lars Wallentin received research grants, consulting fee, lecture fee, and travel support from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, and Pfizer; institutional research grant, consulting fee, lecture fee, travel support, and honoraria from GlaxoSmithKline; institutional research grant from Roche Diagnostics, Merck & Co; and consulting fees from Abbott. Axel {\AA}kerblom received consulting, lecture fees, and institutional research grant from AstraZeneca. Niclas Eriksson received institutional research grant from AstraZeneca. Robert F. Storey has received research grants and personal fees from AstraZeneca, GlyCardial Diagnostics and Thromboserin, and consulting/lecture fees from Amgen, Bayer, Bristol Myers Squibb/Pfizer, Haemonetics and Portola. Richard Weinshilboum and Liewei Wang are cofounders of and stockholders in OneOme LLC, a pharmacogenomic decision support company. John L. Black and the Mayo Clinic have licensed intellectual property to AssureX Health (Myriad) and received royalties. He is also a co-founder of OneOme LLC and, with Mayo Clinic, has intellectual property to the company and owns stock in the company. The remaining 13 authors, Joel A. Morales-Rosado, Kashish Goel, Lingxin Zhang, Saurabh Baheti, Stefan James, Gregory D. Jenkins, Suzette J. Bielinski, Hugues Sicotte, Stephen Johnson, Veronique L. Roger, Eric W. Klee, Charanjit S. Rihal, and Naveen L. Pereira, do not have a conflict of interest. Publisher Copyright: {\textcopyright} 2020, Springer Science+Business Media, LLC, part of Springer Nature.",
year = "2021",
month = jun,
doi = "10.1007/s10557-020-06988-w",
language = "English (US)",
volume = "35",
pages = "549--559",
journal = "Cardiovascular Drugs and Therapy",
issn = "0920-3206",
publisher = "Kluwer Academic Publishers",
number = "3",
}