ICPC publishes GWAS analysis on platelet reactivity and cardiovascular response in patients treated with clopidogrel

The GWAS analysis on platelet reactivity and cardiovascular outcome for clopidogrel, the third paper by the International Clopidogrel Pharmacogenomics Consortium (ICPC), has just been published in journal Clinical Pharmacology & Therapeutics.

Clopidogrel is an antiplatelet agent widely used in patients with acute coronary syndrome, percutaneous coronary intervention, or ischemic stroke. Individual responses to clopidogrel show substantial variability, and poor response is often associated with adverse cardiovascular outcomes. Genetic variants in CYP2C19 play an important role in response to clopidogrel. However, loss of function variants in CYP2C19 only account for a small percentage of the overall variation in platelet reactivity, suggesting that novel genetic variants for clopidogrel response remain to be discovered.

The International Clopidogrel Pharmacogenomics Consortium (ICPC) was established to identify genetic factors influencing clopidogrel efficacy and cardiovascular outcomes, using both genome-wide and candidate gene approaches. It comprises 17 study sites from 13 countries that contributed clinical and genetic data for a total of 8,929 patients treated with clopidogrel. Investigators from ICPC performed a GWAS on data from 2,750 individuals of European ancestry. The GWAS analysis showed that CYP2C19*2 is still the strongest genetic determinant of on-clopidogrel platelet reactivity, and no SNP reached genome wide significance for major adverse cardiovascular events (MACE) endpoints. However, in subgroup analyses for patients with coronary artery disease, percutaneous coronary intervention, and acute coronary syndrome, mutations in SCOS5P1, CDC42BPA and CTRAC1 showed genome-wide significance with MACE or stent thrombosis outcomes. This study represents the largest GWAS performed to date for clopidogrel response.

In addition to the GWAS analysis, the ICPC previously published the design paper and results from the candidate gene study, which developed a pharmacogenomic polygenic response score (PgxRS) - based on 31 candidate gene polymorphisms and assessed in 3,391 clopidogrel treated patients from the ICPC.  Several variants in CYP2C19, CES1, CYP2C9, CYP2B6 and PEAR1 were identified to have significantly influenced on-clopidogrel platelet reactivity. Patients who carried increasing number of risk alleles that lead to high platelet reactivity were significantly more likely to experience adverse cardiovascular events than patients who carried alleles that lead to better platelet inhibition.

For more information, please refer to the following publications by ICPC:

1. Genome-wide association study of platelet reactivity and cardiovascular response in patients treated with clopidogrel: a study by the International Clopidogrel Pharmacogenomics Consortium (ICPC). Clin Pharmacol Ther. 2020 May 30. doi: 10.1002/cpt.1911. PMID: 32472697
2. Pharmacogenomic Polygenic Response Score Predicts Ischemic Events and Cardiovascular Mortality in Clopidogrel-Treated Patients. Eur Heart J Cardiovasc Pharmacother. 2019 Sep 3:pvz045. doi:10.1093/ehjcvp/pvz045. PMID: 31504375.
3. Genome-wide and candidate gene approaches of clopidogrel efficacy using pharmacodynamic and clinical end points-Rationale and design of the International Clopidogrel Pharmacogenomics Consortium (ICPC). Am Heart J. 2018 Apr;198:152-159. doi: 10.1016/j.ahj.2017.12.010. PMID: 29653637

European Union awards €15 million to U-PGx consortium

The European Union H2020 programme has awarded a €15 million grant to the Ubiquitous Pharmacogenomics (U-PGx) consortium for an international pharmacogenomics research and implementation project.

The aim of the U-PGx consortium is to make actionable pharmacogenomic data and effective treatment optimization accessible to every European citizen. The objective of the research and implementation project is to map genetic profiles of 8,000 patients, and then implement stratified prescribing of drugs in these patients based on the Dutch Pharmacogenetics Working Group guidelines. The cost-effectiveness and clinical-effectiveness of this approach will then be evaluated. Educational activities are also planned to assist in the training and education of health care professionals and patients regarding pharmacogenomics.

U-PGx will host its 1st annual consortium meeting in Athens, Greece in September 2016; Teri Klein, co-principal investigator of PharmGKB and the Clinical Pharmacogenetics Implementation Consortium (CPIC), will be in attendance. Dr. Russ Altman, co-principal investigator of PharmGKB, is on the advisory board for U-PGx.

Visit the U-PGx website

GWAS on SSRI treatment outcome in patients with depression: ISPC cohort and meta-analysis

The treatment response to selective serotonin reuptake inhibitors (SSRIs), a major class of antidepressant drugs, varies considerably between patients. The International SSRI PharmacogenomicsConsortium (ISPC) was established with the primary goal of identifying genetic variations that may contribute to SSRI treatment outcome in patients with depressive disorder.

  The ISPC includes eight research groups that contributed clinical and genetic data. A genome-wide association study of 4-week treatment outcomes, measured using the 17-item Hamilton Rating Scale for Depression (HRSD-17), was performed using data from 865 subjects from seven sites and the results are published in the journal Translational Psychiatry.

  Although many top association signals in the ISPC analysis for the primary outcomes percent change in HRSD-17 score and response map to interesting candidate genes (see Table 2 in the article), none were significant at the genome-wide level. The associations did not replicate using data from the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics Study (PGRN-AMPS) and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. 

Top association results in the meta-analysis of response based on data from the ISPC, PGRN-AMPS and STAR*D cohorts included SNPs in the HPRTP4 (hypoxanthine phosphoribosyltransferase pseudogene 4) /VSTM5 (V-set and transmembrane domain containing 5) region, which approached genome-wide significance (p=5.03E-08), and SNPs 5’ upstream of the neuregulin-1 gene, NRG1 (p=1.20E-06).

CYP2D6 genotype and tamoxifen response: meta-analysis of heterogeneous population

Tamoxifen treatment results in substantial inter-individual variability of outcome, possibly due to genetic variability in CYP2D6.  The clinical usefulness of CYP2D6 genotyping for prediction of tamoxifen outcome has not been established because of conflicting reports.   This controversy is well illustrated by secondary analyses from 3 large adjuvant tamoxifen trials (ATAC, BIG 1-98, and ABCSG 8), which came to different conclusions regarding the association between CYP2D6 genotype variants.  The International Tamoxifen Pharmacogenomics Consortium (ITPC) was established to aggregate the worldwide experience regarding CYP2D6 and the clinical outcomes of tamoxifen as adjuvant therapy for breast cancer. It comprises twelve research projects from nine countries and three continents that contributed clinical and genetic data for a total of 4,973 breast cancer patients treated with tamoxifen. Investigators from ITPC performed a meta-analysis on data from 4,973 tamoxifen treated patients and the result was just released in Journal Clinical Pharmacology and Therapeutics. The meta-analysis showed that “CYP2D6 poor metabolizer status was associated with poorer Invasive Disease-Free Survival (IDFS: HR=1.25; 95% CI 1.06, 1.47; P=0.009)” in patients meeting strict criterion. “However, CYP2D6 was not statistically significant when tamoxifen duration, menopausal status, and annual follow-up were not specified (Criterion 2, n=2443; 49%; P=0.25) nor when no exclusions were applied (Criterion 3, n=4935; 99%; P=0.38)”. This study demonstrates the complexity of performing a retrospective biomarker study. The lack of effect in the entire heterogeneous population highlights the need for prospective studies to fully establish the value of CYP2D6 genotyping in tamoxifen therapy.

The data used in the meta-analysis are available for download on the PharmGKB.

 --Blog post written by Li Gong

Novel SNP in CYP2C cluster associated with warfarin dose in African Americans

The International Warfarin Pharmacogenetics Consortium (IWPC),  which involves investigators from eight institutions including Stanford University, has identified a SNP that is associated with warfarin dose requirement in the African American population. As described in Lancet, rs12777823, located in the CYP2C cluster, shows an effect in African Americans that is independent from those of CYP2C9*2 and CYP2C9*3.  In this first investigation of warfarin dose requirements in African Americans, this new association reached genome-wide significance in a GWAS and was also found to be significant in a replication cohort.  Individuals heterozygous for the rs12777823 A allele need a dose reduction of 6·92 mg/week and those homozygous for this allele need reduction in dose of 9·34 mg/week.

The data used in these studies are available on the PharmGKB.