Effects of genetic variation in protease activated receptor 4 after an acute coronary syndrome: Analysis from the TRACER trial

Pierluigi Tricoci, Megan Neely, Michael J. Whitley, Leonard C. Edelstein, Lukas M. Simon, Chad Shaw, Paolo Fortina, David J. Moliterno, Paul W. Armstrong, Phil Aylward, Harvey White, Frans Van de Werf, Lisa K. Jennings, Lars Wallentin, Claes Held, Robert A. Harrington, Kenneth W. Mahaffey, Paul F. Bray

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Variation in platelet response to thrombin may affect the safety and efficacy of PAR antagonism. The Thr120 variant of the common single nucleotide polymorphism (SNP) rs773902 in the protease-activated receptor (PAR) 4 gene is associated with higher platelet aggregation compared to the Ala120 variant. We investigated the relationship between the rs773902 SNP with major bleeding and ischemic events, safety, and efficacy of PAR1 inhibition in 6177 NSTE ACS patients in the TRACER trial. There was a lower rate of GUSTO moderate/severe bleeding in patients with the Thr120 variant. The difference was driven by a lower rate in the smaller homozygous group (recessive model, HR 0.13 [0.02–0.92] P = 0.042). No significant differences were observed in the ischemic outcomes. The excess in bleeding observed with PAR1 inhibition was attenuated in patients with the Thr120 variant, but the interactions were not statistically significant. In summary, lower major bleeding rates were observed in the overall TRACER cohort with the hyperreactive PAR4 Thr120 variant. The increase in bleeding with vorapaxar was attenuated with the Thr120 variant, but we could not demonstrate an interaction with PAR1 inhibition. These findings warrant further exploration, including those of African ancestry where the A allele (Thr120) frequency is ~65%.

LanguageEnglish
Pages37-43
Number of pages7
JournalBlood Cells, Molecules, and Diseases
Volume72
DOIs
Publication statusPublished - 1 Sep 2018

Keywords

  • Bleeding
  • PAR1
  • PAR4
  • Pharmacogenetics
  • Platelets

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Hematology
  • Cell Biology

Cite this

Tricoci, Pierluigi ; Neely, Megan ; Whitley, Michael J. ; Edelstein, Leonard C. ; Simon, Lukas M. ; Shaw, Chad ; Fortina, Paolo ; Moliterno, David J. ; Armstrong, Paul W. ; Aylward, Phil ; White, Harvey ; Van de Werf, Frans ; Jennings, Lisa K. ; Wallentin, Lars ; Held, Claes ; Harrington, Robert A. ; Mahaffey, Kenneth W. ; Bray, Paul F. / Effects of genetic variation in protease activated receptor 4 after an acute coronary syndrome : Analysis from the TRACER trial. In: Blood Cells, Molecules, and Diseases. 2018 ; Vol. 72. pp. 37-43.
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abstract = "Variation in platelet response to thrombin may affect the safety and efficacy of PAR antagonism. The Thr120 variant of the common single nucleotide polymorphism (SNP) rs773902 in the protease-activated receptor (PAR) 4 gene is associated with higher platelet aggregation compared to the Ala120 variant. We investigated the relationship between the rs773902 SNP with major bleeding and ischemic events, safety, and efficacy of PAR1 inhibition in 6177 NSTE ACS patients in the TRACER trial. There was a lower rate of GUSTO moderate/severe bleeding in patients with the Thr120 variant. The difference was driven by a lower rate in the smaller homozygous group (recessive model, HR 0.13 [0.02–0.92] P = 0.042). No significant differences were observed in the ischemic outcomes. The excess in bleeding observed with PAR1 inhibition was attenuated in patients with the Thr120 variant, but the interactions were not statistically significant. In summary, lower major bleeding rates were observed in the overall TRACER cohort with the hyperreactive PAR4 Thr120 variant. The increase in bleeding with vorapaxar was attenuated with the Thr120 variant, but we could not demonstrate an interaction with PAR1 inhibition. These findings warrant further exploration, including those of African ancestry where the A allele (Thr120) frequency is ~65{\%}.",
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Tricoci, P, Neely, M, Whitley, MJ, Edelstein, LC, Simon, LM, Shaw, C, Fortina, P, Moliterno, DJ, Armstrong, PW, Aylward, P, White, H, Van de Werf, F, Jennings, LK, Wallentin, L, Held, C, Harrington, RA, Mahaffey, KW & Bray, PF 2018, 'Effects of genetic variation in protease activated receptor 4 after an acute coronary syndrome: Analysis from the TRACER trial', Blood Cells, Molecules, and Diseases, vol. 72, pp. 37-43. https://doi.org/10.1016/j.bcmd.2018.07.004

Effects of genetic variation in protease activated receptor 4 after an acute coronary syndrome : Analysis from the TRACER trial. / Tricoci, Pierluigi; Neely, Megan; Whitley, Michael J.; Edelstein, Leonard C.; Simon, Lukas M.; Shaw, Chad; Fortina, Paolo; Moliterno, David J.; Armstrong, Paul W.; Aylward, Phil; White, Harvey; Van de Werf, Frans; Jennings, Lisa K.; Wallentin, Lars; Held, Claes; Harrington, Robert A.; Mahaffey, Kenneth W.; Bray, Paul F.

In: Blood Cells, Molecules, and Diseases, Vol. 72, 01.09.2018, p. 37-43.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Effects of genetic variation in protease activated receptor 4 after an acute coronary syndrome

T2 - Blood Cells, Molecules, and Diseases

AU - Tricoci, Pierluigi

AU - Neely, Megan

AU - Whitley, Michael J.

AU - Edelstein, Leonard C.

AU - Simon, Lukas M.

AU - Shaw, Chad

AU - Fortina, Paolo

AU - Moliterno, David J.

AU - Armstrong, Paul W.

AU - Aylward, Phil

AU - White, Harvey

AU - Van de Werf, Frans

AU - Jennings, Lisa K.

AU - Wallentin, Lars

AU - Held, Claes

AU - Harrington, Robert A.

AU - Mahaffey, Kenneth W.

AU - Bray, Paul F.

PY - 2018/9/1

Y1 - 2018/9/1

N2 - Variation in platelet response to thrombin may affect the safety and efficacy of PAR antagonism. The Thr120 variant of the common single nucleotide polymorphism (SNP) rs773902 in the protease-activated receptor (PAR) 4 gene is associated with higher platelet aggregation compared to the Ala120 variant. We investigated the relationship between the rs773902 SNP with major bleeding and ischemic events, safety, and efficacy of PAR1 inhibition in 6177 NSTE ACS patients in the TRACER trial. There was a lower rate of GUSTO moderate/severe bleeding in patients with the Thr120 variant. The difference was driven by a lower rate in the smaller homozygous group (recessive model, HR 0.13 [0.02–0.92] P = 0.042). No significant differences were observed in the ischemic outcomes. The excess in bleeding observed with PAR1 inhibition was attenuated in patients with the Thr120 variant, but the interactions were not statistically significant. In summary, lower major bleeding rates were observed in the overall TRACER cohort with the hyperreactive PAR4 Thr120 variant. The increase in bleeding with vorapaxar was attenuated with the Thr120 variant, but we could not demonstrate an interaction with PAR1 inhibition. These findings warrant further exploration, including those of African ancestry where the A allele (Thr120) frequency is ~65%.

AB - Variation in platelet response to thrombin may affect the safety and efficacy of PAR antagonism. The Thr120 variant of the common single nucleotide polymorphism (SNP) rs773902 in the protease-activated receptor (PAR) 4 gene is associated with higher platelet aggregation compared to the Ala120 variant. We investigated the relationship between the rs773902 SNP with major bleeding and ischemic events, safety, and efficacy of PAR1 inhibition in 6177 NSTE ACS patients in the TRACER trial. There was a lower rate of GUSTO moderate/severe bleeding in patients with the Thr120 variant. The difference was driven by a lower rate in the smaller homozygous group (recessive model, HR 0.13 [0.02–0.92] P = 0.042). No significant differences were observed in the ischemic outcomes. The excess in bleeding observed with PAR1 inhibition was attenuated in patients with the Thr120 variant, but the interactions were not statistically significant. In summary, lower major bleeding rates were observed in the overall TRACER cohort with the hyperreactive PAR4 Thr120 variant. The increase in bleeding with vorapaxar was attenuated with the Thr120 variant, but we could not demonstrate an interaction with PAR1 inhibition. These findings warrant further exploration, including those of African ancestry where the A allele (Thr120) frequency is ~65%.

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