No abstract

Platelet function mediates both beneficial and harmful effects on human health, but few genes are known to contribute to variability in the process. We tested association of 2.5 million SNPs with platelet aggregation responses to 3 agonists (ADP, epinephrine and collagen) in two European-ancestry cohorts (N ≤ 2,753 in the Framingham Heart Study, N ≤ Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Women experienced the same or greater decreases in platelet reactivity after aspirin therapy, retaining modestly more platelet reactivity compared with men. However, most women achieved total suppression of aggregation in the direct COX-1 pathway, the putative mechanism for aspirin's cardioprotection.

Background-Cardiac troponin I (cTnI) is a highly sensitive and specific marker for myocardial injury that predicts outcomes in patients with acute coronary syndromes. Cardiovascular complications are the leading cause of morbidity and mortality in patients who have undergone vascular surgery. However, postoperative surveillance with cardiac enzymes is not routinely performed in these patients. We evaluated the association between postoperative cTnI levels and 6-month mortality and perioperative myocardial infarction (MI) after vascular surgery. Methods and Results-Two hundred twenty-nine patients having aortic or infrainguinal vascular surgery or lower extremity amputation were included in this study. Blood samples were analyzed for cTnI immediately after surgery and the mornings of postoperative days 1, 2, and 3. An elevated cTnI was defined as serum concentrations Ͼ1.5 ng/mL in any of the 4 samples. Twenty-eight patients (12%) had postoperative cTnI Ͼ1.5ng/mL, which was associated with a 6-fold increased risk of 6-month mortality (adjusted OR, 5.9; 95% CI, 1.6 to 22.4) and a 27-fold increased risk of MI (OR, 27.1; 95% CI, 5.2 to 142.7). Furthermore, we observed a dose-response relation between cTnI concentration and mortality. Patients with cTnI Ͼ3.0 ng/mL had a significantly greater risk of death compared with patients with levels Յ0.35 ng/mL (OR, 4.9; 95% CI, 1.3 to 19.0). Conclusions-Routine postoperative surveillance for cTnI is useful for identifying patients who have undergone vascular surgery who have an increased risk for short-term mortality and perioperative MI. Further research is needed to determine whether intervention in these patients can improve outcome.

Y, et al. (2019) Use of >100,000 NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium whole genome sequences improves imputation quality and detection of rare variant associations in admixed African and Hispanic/Latino populations. PLoS Genet 15(12): e1008500.

Genetic variation is thought to contribute to variability in platelet function; however, the specific variants and mechanisms that contribute to altered platelet function are poorly defined. With the use of a combination of fine mapping and sequencing of the platelet endothelial aggregation receptor 1 (PEAR1) gene we identified a common variant (rs12041331) in intron 1 that accounts for < 15% of total phenotypic variation in platelet function. Association findings were robust in 1241 persons of European ancestry (P ‫؍‬ 2.22 ؋ 10 ؊8 ) and were replicated down to the variant and nucleotide level in 835 persons of African ancestry (P ‫؍‬ 2.31 ؋ 10 ؊27 ) and in an independent sample of 2755 persons of European descent (P ‫؍‬ 1.64 ؋ 10 ؊5 ). Sequencing confirmed that variation at rs12041331 accounted most strongly (P ‫؍‬ 2.07 ؋ 10 ؊6 ) for the relation between the PEAR1 gene and platelet function phenotype. A doseresponse relation between the number of G alleles at rs12041331 and expression of PEAR1 protein in human platelets was confirmed by Western blotting and ELISA. Similarly, the G allele was associated with greater protein expression in a luciferase reporter assay. These experiments identify the precise genetic variant in PEAR1 associated with altered platelet function and provide a plausible biologic mechanism to explain the association between variation in the PEAR1 gene and platelet function phenotype. (Blood. 2011;118(12):3367-3375)

Background Aspirin or dual antiplatelet therapy (DAPT) with aspirin and clopidogrel is standard therapy for patients at increased risk for cardiovascular events. However, the genetic determinants of variable response to aspirin (alone and in combination with clopidogrel) are not known. Methods and Results We measured ex-vivo platelet aggregation before and after DAPT in individuals (n=565) from the Pharmacogenomics of Antiplatelet Intervention (PAPI) Study and conducted a genome-wide association study (GWAS) of drug response. Significant findings were extended by examining genotype and cardiovascular outcomes in two independent aspirin-treated cohorts: 227 percutaneous coronary intervention (PCI) patients, and 1,000 patients of the International VErapamil SR/trandolapril Study (INVEST) GENEtic Substudy (INVEST-GENES). GWAS revealed a strong association between single nucleotide polymorphisms on chromosome 1q23 and post-DAPT platelet aggregation. Further genotyping revealed rs12041331 in the platelet endothelial aggregation receptor-1 (PEAR1) gene to be most strongly associated with DAPT response (P=7.66×10−9). In Caucasian and African American patients undergoing PCI, A-allele carriers of rs12041331 were more likely to experience a cardiovascular event or death compared to GG homozygotes (hazard ratio = 2.62, 95%CI 0.96-7.10, P=0.059 and hazard ratio = 3.97, 95%CI 1.10-14.31, P=0.035 respectively). In aspirin-treated INVEST-GENES patients, rs12041331 A-allele carriers had significantly increased risk of myocardial infarction compared to GG homozygotes (OR=2.03, 95%CI 1.01-4.09, P=0.048). Conclusions Common genetic variation in PEAR1 may be a determinant of platelet response and cardiovascular events in patients on aspirin, alone and in combination with clopidogrel. Clinical Trial Registration Information clinicaltrials.gov; Identifiers: NCT00799396 and NCT00370045

Nitric oxide (NO) regulates platelet activation by cGMP-dependent mechanisms and by mechanisms that are not completely defined. Platelet activation includes exocytosis of platelet granules, releasing mediators that regulate interactions between platelets, leukocytes, and endothelial cells. Exocytosis is mediated in part by N-ethylmaleimide-sensitive factor (NSF), an ATPase that disassembles complexes of soluble NSF attachment protein receptors. We now demonstrate that NO inhibits exocytosis of dense granules, lysosomal granules, and ␣-granules from human platelets by Snitrosylation of NSF. Platelets lacking endothelial NO synthase show increased rolling on venules, increased thrombosis in arterioles, and increased exocytosis in vivo. Regulation of exocytosis is thus a mechanism by which NO regulates thrombosis.␣-granules ͉ nitric oxide N itric oxide (NO) plays a major role in vascular homeostasis, regulating vascular tone, leukocyte trafficking, and platelet adhesion and aggregation (1-4). NO regulates thrombosis in part by inhibition of platelet adhesion and aggregation (2, 5, 6). One well described pathway by which NO regulates platelet activation is mediated by guanylate cyclase (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). NO activates guanylate cyclase in platelets, leading to an increase in cGMP (25)(26)(27). Targets of cGMP in platelets include cGMP-regulated phosphodiesterases (PDEs) PDE2 and PDE5, cGMP-dependent protein kinase type I␤, and perhaps cAMP-dependent protein kinases as well (28). The cGMP pathway mediates many of the effects of NO on platelet activation, such as inhibition of platelet aggregation. Thus, cGMP is a major mediator of NO signal transduction in platelets.NO also regulates platelets by cGMP-independent pathways. For example, certain NO donors inhibit platelet aggregation in a cGMP-independent manner (12,(29)(30)(31). Furthermore, NO activates platelet ADP-ribosyltransferase in a cGMP-independent manner (32). Finally, NO inhibits Ca 2ϩ mobilization in platelets independent of cGMP (33). Thus, NO inhibits platelet activation by both cGMP-dependent and less well characterized cGMPindependent pathways.Exocytosis of platelet granules is an important process by which platelets mediate thrombosis and vascular inflammation. The three types of platelet granules: dense granules, ␣-granules, and lysosomal granules, contain molecules that are released into the blood or are translocated to the platelet surface after exocytosis. Dense granules, the first to be released upon activation, contain small molecules such as serotonin, ATP and ADP, which are involved in platelet recruitment and activation. Contents of the ␣-granule include von Willebrand factor, P-selectin, and ␤-thromboglobulin, which promote platelet adherence, aggregation, and rolling on vessel walls. Lysosomal granules are the last to be released and contain degradative enzymes (34,35).Platelet granule exocytosis is mediated by a set of proteins that regulate vesicle trafficking (35)(36)(37)(38). Soluble N-...