OC 03.4 - A Common, Racially Diverse Protease Activated Receptor 4 Functional Variant Impacts Ischemic Stroke Outcomes: Evidence for a Pharmacogenetic Effect

Saturday, June 24, 2023

13:45 – 14:00 ET

Room: 710B

Session Available As: On-Demand

Presenting Author(s)

Frederik Denorme, PhD (he/him/his)

Research Assistant Professor
University of Utah
Salt Lake City, Utah, United States

Co-Author(s)

NA

Nicole D. Armstrong

Instructor
University of Alabama at Birmingham
Birmingham, Alabama, United States
MS

Michelle Stoller

Research Associate
University of Utah
Salt Lake City, Utah, United States
Irina Portier, PhD

Postdoc
University of Utah
Salt Lake City, Utah, United States
JR

John PBJ Rustad

Technician
University of Utah
Salt Lake City, Utah, United States
MC

Mark J J. Cody

Research Associate
University of Utah
Salt Lake City, Utah, United States
RT

Rikki M Tanner

Researcher
University of Alabama at Birmingham
Birmingham, Alabama, United States
MN

Marvin T. Nieman

Associate Professor
Case Western Reserve University
Cleveland, Ohio, United States
Steven E McKenzie, MD, PhD

Professor
Thomas Jefferson University
Philadelphia, Pennsylvania, United States
CY

Christian C C. Yost

Professor
University of Utah
Salt Lake City, Utah, United States
LL

Leslie Lange

Professor
University of Colorado
Aurora, Colorado, United States
Mary Cushman, MD, MSc (she/her/hers)

Professor
Department of Medicine, Larner College of Medicine at the University of Vermont, USA
Colchester, Vermont, United States
MI

Marguerite M Irvin

Professor
University of Alabama at Birmingham
Birmingham, Alabama, United States
PB

Paul F Bray

Professor
University of Utah
Salt Lake City, Utah, United States
Robert A. Campbell, PhD

Professor
University of Utah, Salt Lake City, UT, USA; Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA
Salt Lake City, Utah, United States

Background: Black individuals have a higher incidence of ischemic stroke (IS) than White individuals. The platelet receptor PAR4 harbors a functional dimorphism: rs773902 A/G (encoding Thr120/Ala120), and the A allele is associated with greater ex vivo platelet aggregation. The A allele frequency is 0.6 in Black individuals and 0.2 in White subjects. It is unknown whether the A allele contributes to racial differences in IS.

Aims: To test the effect of the PAR4 rs773902 variant on IS.

Methods: A Black subject-only analysis of 487 IS cases and 7,133 controls was performed in a prospective cohort, examining if the A allele was a risk for incident IS and outcomes. Models were adjusted for age, sex, the first 5 genetic principal components, smoking, hypertension and diabetes. Furthermore, we generated the first humanized PAR4 (hPAR4) mouse strains expressing either hPAR4 Thr120 or Ala120.

Results: The A allele was a risk factor for incident IS (HR 1.24; CI 1.04-1.53, p=0.046) and worse IS outcomes (HR 2.04; CI 1.10-3.79, p=0.025). In a murine stroke model, hPAR4 Thr120 mice had worse stroke outcomes compared to hPAR4 Ala120 mice (60% increase, p=0.001). This phenotype was mediated, in part, by enhanced platelet activation (p=0.002), platelet-neutrophil interactions (p=0.014), and neutrophil extracellular traps (p=0.001). We next evaluated the efficacy of standard anti-platelet drugs on stroke outcomes in both mouse strains. Interestingly, ticagrelor pretreatment improved stroke outcomes in hPAR4 Ala120 mice (50% decrease, p=0.007), but was ineffective in hPAR4 Thr120 mice, even when ticagrelor was combined with aspirin. Importantly, blocking platelet-neutrophil interactions downstream of PAR4 with an anti-P-selectin antibody improved stroke outcomes in hPAR4 Thr120 mice (55% decrease, p=0.004).

Conclusion(s): These results support a causal role for PAR4 Thr120 in IS that may explain part of the racial disparity in stroke. Our findings further suggest different anti-platelet therapies may be needed for patients expressing PAR4 Thr120.

Learning Objectives:

Upon completion, participant will be able to understand the effect of rs773902 on platelet function.
Upon completion, participant will be able to describe the impact of rs773902 on ischemic stroke.
Upon completion, participant will be able to better understand racial disparities in clinical trials for stroke.