The rs10509646 SNP in the HHEX gene was associated with higher on-treatment platelet reactivity on clopidogrel in TIA/ischaemic stroke patients (P=0.0003 for PFA-100 closure times).
Observational (n=94)
Yes
Do CYP2C19 and other genotypes influence on-treatment platelet reactivity status in TIA/ischaemic stroke patients on clopidogrel?
Up to 33% of TIA/stroke patients predicted to be poor-intermediate CYP2C19 metabolizers still achieve adequate P2Y12-inhibition on clopidogrel, and novel SNPs like HHEX may also influence platelet reactivity.
p-value: p=0.0003
Abstract Background and aims Patients with CYP2C19 loss-of-function (LOF) Single Nucleotide Polymorphisms (SNPs) may be more likely to exhibit ‘Clopidogrel-High on-Treatment Platelet Reactivity’ (HTPR). Few studies concurrently assessed the influence of CYP2C19/other pharmacogenetic factors on Clopidogrel-HTPR status and outcomes in cerebrovascular disease (CVD) patients. Methods In the prospective Optimal Antiplatelet Therapy in TIA and Ischaemic Stroke-International pilot-observational study, 94 TIA-ischaemic stroke patients underwent centralised pharmacogenetics analysis to classify them as predicted CYP2C19 ‘Poor-Intermediate’, ‘Normal’ or ‘Rapid-Ultrarapid’ Clopidogrel Metabolisers. Analyses for candidate SNPs in RAD18, ASIC2 3/21 (14%) did not exhibit Clopidogrel-HTPR on any of the 3 platforms. There was an association between rs10509646 SNP in the HHEX gene on chromosome 10 (pilot GWAS data) and on-treatment platelet reactivity, with shorter median PFA-100 closure times (P=0.0003), and higher mean P2Y12-Reactivity Units on VerifyNow (P=0.005) with homozygous ‘non-wild type’ vs. homozygous ‘wild type (normal)’ HHEX genotypes. Conclusions Almost 1/3 of our CVD population have CYP2C19 LOF SNPs, and up to 33% of these predicted Poor-Intermediate Metabolisers have adequate P2Y12-inhibition on Clopidogrel. Novel SNPs may influence Clopidogrel-HTPR status in CVD patients in Ireland. Conflict of interest No conflict of interest. Prof McCabe's research work is supported by grant funding from several charities and organisations, including the Meath Foundation; The Adelaide Health Foundation; an Enterprise Ireland Innovation Partnership Programme grant with Acquis BI Technology, Ltd.; the VNRF; and in-kind contributions from Werfen, Spain; Sysmex Ireland-UK; Sinnowa, China; Genomadix Inc., Canada and Acquis BI Technology Ltd. *denotes co-first authorship between DS and IN. These data are presented on behalf of the OATS-I Study Research Group, the following members also qualify for authorship on this abstract: Collins DR (4, 14), Ryan DJ (4, 14), McCarthy AJ (1, 3, 4 ), Murphy SM (1, 3), Egan B (15), O’Donnell MJ (16), de Borst GJ (17), Zgaga L (18), Walsh C (18, 19), Kelleher JD (20, 21), Macey C (22), Hennessy M (23, 24): (14) Age-Related Health Care Department, (15) Department of Vascular Surgery, TUH/AMNCH; (16) College of Medicine, Nursing and Health, University of Galway / University Hospital Galway, Galway, Ireland; (17) University Medical Centre Utrecht, Utrecht, Netherlands; (18) Department of Public Health and Primary Care, (19) Department of Biostatistics, (20) Department of Computer Sciences, (21) ADAPT SFI centre, Trinity College Dublin (TCD), Dublin, Ireland; (22) Irish Heart Foundation, Dublin, Ireland; (23) Wellcome-HRB Clinical Research Facility, St James's Hospital, Dublin, Ireland; (24) School of Medicine, Trinity College Dublin, Ireland
Smith et al. (Fri,) conducted a observational in TIA and Ischaemic Stroke (n=94). Clopidogrel was evaluated on On-treatment platelet reactivity (PFA-100 closure times and VerifyNow P2Y12-Reactivity Units) (p=0.0003). The rs10509646 SNP in the HHEX gene was associated with higher on-treatment platelet reactivity on clopidogrel in TIA/ischaemic stroke patients (P=0.0003 for PFA-100 closure times).