Variation of PEAR1 DNA methylation influences platelet and leukocyte function

Abstract

BackgroundPlatelet-endothelial aggregation receptor 1 (PEAR-1) is a transmembrane receptor involved in platelet activation and megakaryopoiesis whose expression is driven by DNA methylation. PEAR1 variants were associated with differential platelet response to activation and cardiovascular outcomes. We aimed at investigating the link between PEAR1 methylation and platelet and leukocyte function markers in a family-based population.ResultsWe measured PEAR1 methylation in 605 Moli-family participants with available blood counts, plasma P-selectin and C-reactive protein, whole blood platelet P-selectin, and platelet-leukocyte mixed conjugate measurements. We performed principal component analysis (PCA) to identify groups of highly correlated CpG sites. We used linear mixed regression models (using age, gender, BMI, smoking, alcohol drinking, being a proband for family recruitment, being a member of myocardial infarction (MI) family as fixed effects, and family as a random effect) to evaluate associations between PEAR1 methylation and phenotypes. PEAR1 methylation Factor2, characterized by the previously identified megakaryocyte-specific CpG sites, was inversely associated with platelet-monocyte conjugates, P-selectin, and WBC counts, while positively associated with the platelet distribution width (PDW) and with leukocyte CD11b and L-selectin. Moreover, PEAR1 Factor2 methylation was negatively associated with INFLAscore, a low-grade inflammation score. The latter was partially mediated by the PEAR1 methylation effect on platelet variables. PEAR1 methylation association with WBC measurements and INFLAscore was confirmed in the independent cohort FLEMENGHO.ConclusionsWe report a significant link between epigenetic signatures in a platelet functional gene and inflammation-dependent platelet function variability measured in two independent cohorts.

Development of a poor-prognostic-mutations derived immune prognostic model for acute myeloid leukemia

“…It sustains αIIbβ3 activation in aggregating platelets and attenuates megakaryopoiesis by controlling the degree of Akt phosphorylation 37 , 38 . Moreover, methylation-controlled PEAR1 expression can activate platelets and have an impact on inflammation 39 – 41 . Both in vitro and in vivo studies in endothelial cells showed an inverse correlation between PEAR1 expression and vascular assembly, which implies that PEAR1 modifies neo-angiogenesis 42 .…”

Genetic Variation in PEAR1, Cardiovascular Outcomes and Effects of Aspirin in a Healthy Elderly Population

“…21 The modifying effect of the rs12041331-A genotype on association with cardiovascular and bleeding events and aspirin treatment was analyzed using an interaction term in a multivariable Cox regression model. these processes has been platelet aggregation; however, other proposed functions of this receptor include maintenance of endothelial cell function, 13,25 megakaryopoiesis and thrombopoiesis, 7 neoangiogenesis, 26 leukocyte function, 17 and neuronal phagocytosis. 27,28 These and other publications have prompted numerous genetic studies attempting to correlate PEAR1 polymorphisms with related phenotypes and diseases.…”

“…Since its identification in 2005, multiple investigations have been published highlighting the role of PEAR1 in several important biological processes 5 . The most extensively studied of these processes has been platelet aggregation; however, other proposed functions of this receptor include maintenance of endothelial cell function, 13,25 megakaryopoiesis and thrombopoiesis, 7 neoangiogenesis, 26 leukocyte function, 17 and neuronal phagocytosis 27,28 . These and other publications have prompted numerous genetic studies attempting to correlate PEAR1 polymorphisms with related phenotypes and diseases.…”

“…Genetic variants in the PEAR1 gene have been associated with platelet aggregation 8,9 and in response to antiplatelet agents, including aspirin, 10–12 clopidogrel, 13 ticagrelor, 14 and prasugrel 15 . Most notably, an intronic variant rs12041331 in the PEAR1 gene is among the strongest genetic modifiers of platelet aggregation, particularly in those treated with aspirin, and results in allele‐specific differences in H3K4Me1 methylation leading to differential gene and protein expression 11,16,17 . Despite the evidence demonstrating the influence of PEAR1 rs12041331 on agonist‐stimulated platelet aggregation in aspirin‐treated patients, the impact of this variant on thrombotic and bleeding events remains unclear.…”

Impact of Platelet Endothelial Aggregation Receptor-1 Genotypes on Long-Term Cerebrovascular Outcomes in Patients With Minor Stroke or Transient Ischemic Attack

“…Studies have shown that genetic variants in the PEAR1 gene were not only associated with platelet aggregation ( 8 , 9 ) but also the response to antiplatelet agents including aspirin ( 10 ) and clopidogrel ( 11 ). Rs12041331 is an intronic variant that is supposed to modify PEAR1 expression in the protein level via a different allele-specific DNA methylation and has been found to be correlated with platelet aggregation ( 12 , 13 ). Although there has been evidence that PEAR1 rs12041331 has an effect on agonist-stimulated platelet aggregation in aspirin-treated patients ( 14 ), it is still controversial whether this genetic polymorphism in PEAR1 is associated with clinical outcomes.…”