The Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study: Variation in Platelet Response to Clopidogrel and Aspirin

Abstract

Clopidogrel and aspirin are commonly prescribed anti-platelet medications indicated for patients who have experienced, or are at risk for, ischemic cardiovascular events. The Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study was designed to characterize determinants of clopidogrel and dual anti-platelet therapy (DAPT) response in a healthy cohort of Old Order Amish from Lancaster, PA. Following a loading dose, clopidogrel was taken once a day for 7 days. One hour after the last dose of clopidogrel, 325 mg of aspirin was given. Ex vivo platelet aggregometry was performed at baseline, post-clopidogrel, and post-DAPT. Platelet aggregation measurements were significantly lower after both interventions for all agonists tested (p <0.05), although there was large inter-individual variation in the magnitude of anti-platelet response. Female sex and older age were associated with higher platelet aggregation at all three time-points. Change in aggregation was correlated among the various agonists at each time point. Heritability (h2) of change in platelet aggregation was significant for most traits at all time-points (range h2=0.14–0.57). Utilization of a standardized, short-term intervention provided a powerful approach to investigate sources of variation in platelet aggregation response due to drug therapy. Further, this short-term intervention approach may provide a useful paradigm for pharmacogenomics studies.

Familial Hypercholesterolemia and Type 2 Diabetes in the Old Order Amish

“…For samples with both exome sequence and chip genotype data ( n = 2,695), the concordance rate for the R3527Q variant was 99.85%. All study subjects had participated in at least one of the community-based studies our group had carried out in this population over the past 20 years as part of our Amish Complex Disease Research Program (9–13). Among these were 640 subjects heterozygous ( n = 625) or homozygous ( n = 15) for APOB R3527Q, corresponding to an allele frequency of 6% and carrier frequency of 12%, consistent with what we have previously reported (7).…”

From Genotype to Phenotype: Nonsense Variants in SLC13A1 Are Associated with Decreased Serum Sulfate and Increased Serum Aminotransferases

“…All known Amish carriers of the rare SLC13A1 SNVs, R12X, W48X, and R237C, for whom fasting, serum aliquots were available, were selected for sulfate measurement. Such subjects consisted of participants from the Amish Pharmacogenomics of Antiplatelet Intervention (PAPI) Study ( Shuldiner et al 2009 ; Bozzi et al 2015 ), the Amish Heredity and Phenotype Intervention (HAPI) Heart Study ( Mitchell et al 2008 ), the Amish Family Calcification Study (AFCS) ( Post et al 2007 ), the Amish Family Longevity Study (AFLS) ( Mitchell et al 2001 ; Sorkin et al 2005 ), and the Amish Wellness Study (AWS) (Supplemental Material, File S1 ). All other subjects consisted of randomly selected participants of the Amish PAPI ( Shuldiner et al 2009 ; Bozzi et al 2015 ) or HAPI Heart ( Mitchell et al 2008 ) studies for whom fasting serum aliquots were available.…”

Genome-wide analysis of clopidogrel active metabolite levels identifies novel variants that influence antiplatelet response

“…Amish individuals from Lancaster, Pennsylvania were recruited into the PAPI Study between 2006 and 2012 [3, 9]. Participants were over age 20, generally healthy, and agreed to discontinue the use of medications, supplements, and vitamins at least one week prior to study initiation.…”

“…Follow-up platelet aggregation and clopidogrel metabolite measurements were obtained 1 hour following the last clopidogrel dose. Exclusion criteria and additional information regarding recruitment and design of the PAPI Study have been previously described [3, 9]. The protocol was approved by the University of Maryland, Baltimore Institutional Review Board.…”