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Novel Cyp2C19 Genetic Variants associated with Stent Thrombosis: a Next Generation Sequencing Study
Mayo Clinic, Rochester, MN, USA.
Mayo Clinic, Rochester, MN, USA.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
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2018 (engelsk)Inngår i: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 71, nr 11, s. 1205-1205Artikkel i tidsskrift, Meeting abstract (Annet vitenskapelig) Published
Abstract [en]

Background

Commonly tested Loss-of-function (LOF) alleles in CYP2C19 are present in 30-40% of patients who experience stent thrombosis. The objective of this study was to identify novel genetic variants in CYP2C19 gene associated with stent thrombosis.

Methods

We included 70 patients with definite stent thrombosis while on clopidogrel who had stored DNA samples in our institutional (n=12) or PLATO trial (n=70) biorepository. Cases were matched 1:1 with controls for age, race, sex, diabetes, type of stent, and presentation. All controls were on clopidogrel and free of recurrent events. Clinical Pharmacogenetics (PGx) Implementation Consortium (CPIC) guidelines were used to determine the list of known PGx variants and dbSNP version 142 was used to assess novel variants. Whole exome sequencing was performed using the protocol for Agilent's SureSelect Human All Exon v5 + UTRs 75 MB kit and additional custom primers were designed to cover the entire CYP2C19 gene.

Results

Mean age was 63 ± 12 years, and 71% were male. We identified a total of 456 single nucleotide variants (SNV) in the CYP2C19 gene (cases: 376; controls: 288), of which 5 were synonymous, 6 non-synonymous, 46 indels and 449 intronic SNVs. There were 168 vs. 80 novel CYP2C19 variants and 10 vs. 5 indels in cases vs. controls, respectively. Four SNVs (3 missense and 1 synonymous) were present only in cases, whereas 3 SNVs (1 misssense, 1 synonymous and 1 intron) were unique to controls. There were no detectable differences in the frequency of LOF CYP2C19*2 allele (cases 34% vs. controls 31%) or other CPIC annotated PGx variants in cases and controls. After excluding the known PGx variants, there were 10 indels (all intronic) out of which 7 were novel in cases and were not present in controls.

Conclusion

We describe several novel genetic variants in the CYP2C19 gene in patients treated with clopidogrel after coronary stenting. We identified 168 novel SNVs and 10 novel indels in the CYP2C19 gene of patients with stent thrombosis. Four SNVs and 9 indels were unique to cases. Functional validation of these CYP2C19 genetic variants may provide important insights of CYP2C19 and the pathophysiology of stent thrombosis in clopidogrel treated patients.

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ELSEVIER SCIENCE INC , 2018. Vol. 71, nr 11, s. 1205-1205
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Identifikatorer
URN: urn:nbn:se:uu:diva-357331DOI: 10.1016/S0735-1097(18)31746-7ISI: 000429659702455OAI: oai:DiVA.org:uu-357331DiVA, id: diva2:1239383
Konferanse
67th Annual Scientific Session and Expo of the American-College-of-Cardiology (ACC), MAR 10-12, 2018, Orlando, FL
Tilgjengelig fra: 2018-08-16 Laget: 2018-08-16 Sist oppdatert: 2018-08-16bibliografisk kontrollert

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