Platelet Endothelial Aggregation Receptor Research Articles

Molecular characterization of positively selected genes contributing aquatic adaptation in marine mammals.

Marine mammals, which have evolved independently into three distinct lineages, share common physiological features that contribute to their adaptation to the marine environment. To identify positively selected genes (PSGs) for adaptation to the marine environment using available genomic data from three taxonomic orders: cetaceans, pinnipeds, and sirenians. Based on the genomes within each group of Artiodactyla, Carnivora and Afrotheria, we performed selection analysis using the branch-site model in CODEML. Based on the branch-site model, 460, 614, and 359 PSGs were predicted for the cetaceans, pinnipeds, and sirenians, respectively. Functional enrichment analysis indicated that genes associated with hemostasis were positively selected across all lineages of marine mammals. We observed positive selection signals for the hemostasis and coagulation-related genes plasminogen activator, urokinase (PLAU), multimerin 1 (MMRN1), gamma-glutamyl carboxylase (GGCX), and platelet endothelial aggregation receptor 1 (PEAR1). Additionally, we found out that the sodium voltage-gated channel alpha subunit 9 (SCN9A), serine/arginine repetitive matrix 4 (SRRM4), and Ki-ras-induced actin-interacting protein (KRAP) are under positive selection pressure and are associated with cognition, neurite outgrowth, and IP3-mediated Ca2 + release, respectively. This study will contribute to our understanding of the adaptive evolution of marine mammals by providing information on a group of candidate genes that are predicted to influence adaptation to aquatic environments, as well as their functional characteristics.

Effect of PEAR1, PTGS1 gene polymorphisms on the recurrence of aspirin-treated patients with ischemic stroke in the Han population of China: A 4-year follow-up study.

Platelet endothelial aggregation receptor 1 (PEAR1) and prostaglandin endoperoxide synthase 1 (PTGS1) polymorphisms can affect laboratory aspirin resistance. However, the impact of genetic polymorphisms on the recurrence of ischemic stroke (IS) patients treated with aspirin is not fully understood. This study aimed to examine the relationship between gene polymorphisms of PEAR1 and PTGS1 and IS recurrence in patients treated with aspirin. Peripheral blood samples were collected from 174 patients with nonrecurrent IS and 34 with recurrent IS after aspirin treatment. Follow-up was performed on all patients. PEAR1 rs12041331 and PTGS1 rs10306114 polymorphisms were determined using the PCR fluorescence probe method. And the correlations of them with the clinical characteristics were examined by multivariable logistic regression analysis. The distribution frequencies of PEAR1 rs12041331 and PTGS1 rs10306114 genotypes were in Hardy-Weinberg equilibrium, and there was no significant difference in the distribution of PEAR1 rs12041331 polymorphism. Compared to the nonrecurrent group, the AA genotype of the PTGS1 polymorphism was more frequent in the recurrent group (59.77% vs 35.29%, P = .003), and the A allele also showed a higher frequency than the G allele in the recurrent group (P = .001). Multivariable logistic regression analysis showed that smoking (OR = 5.228, 95% CI: 1.938-14.102, P = .001), coronary heart disease (OR = 4.754, 95% CI: 1.498-15.089, P = .008), and the polymorphism at PTGS1(A>G) AA/AG + GG (OR = 2.955, 95% CI: 1.320-6.616, P = .008) were independently associated with IS recurrence in Chinese patients. Our findings suggested that PTGS rs10306114 polymorphisms should receive more attention in the use of aspirin in patients with IS.

Genetic Polymorphisms of GP1BA, PEAR1, and PAI-1 May Be Associated with Serum sIgE and Blood Eosinophil Levels in Chinese Patients with Allergic Diseases.

It has been suggested that genetic factors may be substantially linked to allergy disorders. This study aims to investigate the relationship between the serum specific Immunoglobulin E [sIgE], blood eosinophil, and the polymorphisms of glycoprotein Ib alpha gene [GP1BA] rs6065, platelet endothelial aggregation receptor 1 gene [PEAR1] rs12041331, and plasminogen activator inhibitor 1 gene [PAI-1] rs1799762. From the Peking Union Medical College Hospital, this study enrolled 60 healthy participants and 283 participants with allergic diseases. TaqMan-minor groove binder [MGB] quantitative polymerase chain reaction [qPCR] was used to examine the gene polymorphisms in each group. The TaqMan-MGB qPCR results were completely consistent with the DNA sequencing results, according to other studies in this medical center [Kappa =1, p <0.001]. The GP1BA rs6065, PEAR1 rs12041331, and PAI-1 rs1799762 polymorphisms did not show different distribution between allergy patients and healthy individuals. Concerning allergy patients, the CT [n=33] genotype of GP1BA rs6065 had higher blood eosinophil level than the CC [n=250] genotype [0.59, IQR 0.32-0.72 vs 0.31, IQR 0.15-0.61, *109/L, p =0.005]. The serum sIgE of AA [n=46] genotype of PEAR1 rs12041331 was lower [median 3.7, interquartile quartiles [IQR] 0.2-16.8, kU/L] than the GA [n=136] and GG [n=101] genotypes [GA median 16.3, IQR 3.1-46.3, kU/L, p = 0.002; GG median 12.9, IQR 3.0-46.9, kU/L, p =0.003]. The GA genotypes of PEAR1 rs12041331were with higher blood eosinophil levels [median 0.42, IQR 0.17-0.74 *109/L] than the AA genotype [median 0.25, IQR 0.15-0.41*109/L, p =0.012]. The sIgE of the 5G5G [n=44] genotype of PAI-1 rs1799762 was lower [median 5.0, IQR 0.1-22.8, kU/L] than the 4G5G [n=144] [median 17.3, IQR 3.7-46.0, kU/L, p = 0.012]. The GP1BA rs6065, PEAR1 rs12041331, and PAI-1 rs1799762 polymorphisms may be associated with the genetic susceptibility of serum sIgE or blood eosinophil in Chinese allergic disease patients.

Trivalent nanobody-based ligands mediate powerful activation of GPVI, CLEC-2, and PEAR1 in human platelets whereas FcγRIIA requires a tetravalent ligand

BackgroundClustering of the receptors glycoprotein receptor VI (GPVI), C-type lectin-like receptor 2 (CLEC-2), low-affinity immunoglobulin γ Fc region receptor II-a (FcγRIIA), and platelet endothelial aggregation receptor 1 (PEAR1) leads to powerful activation of platelets through phosphorylation of tyrosine in their cytosolic tails and initiation of downstream signaling cascades. GPVI, CLEC-2, and FcγRIIA signal through YxxL motifs that activate Syk. PEAR1 signals through a YxxM motif that activates phosphoinositide 3-kinase. Current ligands for these receptors have an undefined valency and show significant batch variation and, for some, uncertain specificity. ObjectivesWe have raised nanobodies against each of these receptors and multimerized them to identify the minimum number of epitopes to achieve robust activation of human platelets. MethodsDivalent and trivalent nanobodies were generated using a flexible glycine-serine linker. Tetravalent nanobodies utilize a mouse Fc domain (IgG2a, which does not bind to FcγRIIA) to dimerize the divalent nanobody. Ligand affinity measurements were determined by surface plasmon resonance. Platelet aggregation, adenosine triphosphate secretion, and protein phosphorylation were analyzed using standardized methods. ResultsMultimerization of the nanobodies led to a stepwise increase in affinity with divalent and higher-order nanobody oligomers having sub-nanomolar affinity. The trivalent nanobodies to GPVI, CLEC-2, and PEAR1 stimulated powerful and robust platelet aggregation, secretion, and protein phosphorylation at low nanomolar concentrations. A tetravalent nanobody was required to activate FcγRIIA with the concentration-response relationship showing a greater variability and reduced sensitivity compared with the other nanobody-based ligands, despite a sub-nanomolar binding affinity. ConclusionThe multivalent nanobodies represent a series of standardized, potent agonists for platelet glycoprotein receptors. They have applications as research tools and in clinical assays.

Using the PEAR1 Polymorphisms Rs12041331 and Rs2768759 as Potential Predictive Markers of 90-Day Bleeding Events in the Context of Minor Strokes and Transient Ischemic Attack.

In this study, we explored the relationship between the platelet endothelial aggregation receptor 1 (PEAR1) polymorphisms, platelet reactivity, and clinical outcomes in patients with minor stroke or transient ischemic attack (TIA). Randomized controlled trial subgroups were assessed, wherein patients received dual antiplatelet therapy for at least 21 days. Platelet reactivity was measured at different time intervals. Genotypes were categorized as wild-type, mutant heterozygous, and mutant homozygous. Clinical outcomes were evaluated after 90 days. The rs12041331 polymorphism predominantly influenced adenosine diphosphate channel platelet activity, with the AA genotype displaying significantly lower residual platelet activity to the P2Y12 response unit (p < 0.01). This effect was more evident after 7 days of dual antiplatelet treatment (p = 0.016). Mutant A allele carriers had decreased rates of recurrent stroke and complex endpoint events but were more prone to bleeding (p = 0.015). The rs2768759 polymorphism majorly impacted arachidonic acid (AA) channel platelet activity, which was particularly noticeable in the C allele carriers. Our regression analysis demonstrated that rs12041331 AA + GA and rs2768759 CA predicted 90-day post-stroke bleeding. In conclusion, the PEAR1 polymorphisms rs12041331 and rs2768759 interfere with platelet aggregation and the performance of antiplatelet drugs. These genetic variations may contribute to bleeding events associated with minor stroke and TIA.

The 4G/5G polymorphism of plasminogen activator inhibitor type 1 is a predictor of allergic cough.

Background: It has been suggested that genetic factors may be substantially linked to allergy disorders. This study aims to investigate the relationship between the genetic susceptibility of Chinese patients with allergy disorders and the polymorphisms of plasminogen activator inhibitor 1 gene (PAI-1) rs1799762, cysteinyl leukotriene receptor 1 gene (CYSLTR1) rs320995, gasdermin B gene (GSDMB) rs7216389, glycoprotein IIIa gene (GPIIIa) rs5918, glycoprotein Ib alpha gene (GP1BA) rs6065, platelet endothelial aggregation receptor 1 gene (PEAR1) rs12041331, and tumor necrosis factor alpha gene (TNF-α) rs1800629. Methods: From the Peking Union Medical College Hospital, this study enrolled 60 healthy participants and 286 participants with allergic diseases. TaqMan-minor groove binder (MGB) quantitative polymerase chain reaction (qPCR) was used to examine the gene polymorphisms in each group. Results: The TaqMan-MGB qPCR results were completely consistent with the DNA sequencing results, according to other studies in this medical center (Kappa = 1, p < .001). Only the distribution of PAI-1 rs1799762 was different between patients with allergic cough and healthy people (χ2 = 7.48, p = .0238). With regard to cough patients, the 4G4G and 5G5G genotypes were more frequent (allergic cough vs. healthy individuals: 4G4G 57.9% vs. 26.7%; 5G5G 20.0% vs. 13.3%), but the 4G5G genotype was more frequent in healthy people (allergic cough vs. healthy individuals: 45.7% vs. 60.0%). The CYSLTR1 rs320995, GSDMB rs7216389, GPIIIa rs5918, GP1BA rs6065, PEAR1 rs12041331, and TNF-α rs1800629 polymorphisms, however, did not show any of such relationships. Conclusion: The PAI-1 rs1799762 polymorphisms may be associated with the genetic susceptibility of Chinese allergic disease patients with cough performance.

Impact of platelet endothelial aggregation receptor 1 genotypes and DNA methylation on platelet reactivity in patients with recurrent ischemic stroke treated with clopidogrel.

The aim of this study is to investigate the role of genetic variation and DNA methylation of PEAR1 rs12041331 in high on-treatment platelet reactivity (HPR) and recurrent ischemic stroke (RIS). Genotype, methylation, and mRNA of PEAR1 rs12041331 were detected in patients with cerebral ischemia, for the analysis of the effect of PEAR1 rs12041331 on HPR and RIS. The major G allele of PEAR1 rs12041331 was associated with hypermethylation, which was associated with HPR. This link was not observed for RIS. The PEAR1 rs12041331 genetic polymorphism and DNA methylation may be among the genetic factors affecting HPR. The correlation between PEAR1 and RIS needs to be studied further.

PEAR1 is a potential regulator of early hematopoiesis of human pluripotent stem cells.

Hemogenic endothelial (HE) cells are specialized endothelial cells to give rise to hematopoietic stem/progenitor cellsduring hematopoietic development. The underlying mechanisms that regulate endothelial-to-hematopoietic transition (EHT) of human HE cells are not fully understand. Here, we identified platelet endothelial aggregation receptor-1 (PEAR1) as a novel regulator of early hematopoietic development in human pluripotent stem cells (hPSCs). We found that the expression of PEAP1 was elevated during hematopoietic development. A subpopulation of PEAR1+ cells overlapped with CD34+ CD144+ CD184+ CD73- arterial-type HE cells. Transcriptome analysis by RNA sequencing indicated that TAL1/SCL, GATA2, MYB, RUNX1 and other key transcription factors for hematopoietic development were mainly expressed in PEAR1+ cells, whereas the genes encoding for niche-related signals, such as fibronectin, vitronectin, bone morphogenetic proteinsand jagged1, were highly expressed in PEAR1- cells. The isolated PEAR1+ cells exhibited significantly greater EHT capacity on endothelial niche, compared with the PEAR1- cells. Colony-forming unit (CFU) assays demonstrated the multilineage hematopoietic potential of PEAR1+ -derived hematopoietic cells. Furthermore, PEAR1 knockout in hPSCs by CRISPR/Cas9 technology revealed that the hematopoietic differentiation was impaired, resulting in decreased EHT capacity, decreased expression of hematopoietic-related transcription factors, and increased expression of niche-related signals. In summary, this study revealed a novel role of PEAR1 in balancing intrinsic and extrinsic signals for early hematopoietic fate decision.

PEAR1 regulates expansion of activated fibroblasts and deposition of extracellular matrix in pulmonary fibrosis

Pulmonary fibrosis is a chronic interstitial lung disease that causes irreversible and progressive lung scarring and respiratory failure. Activation of fibroblasts plays a central role in the progression of pulmonary fibrosis. Here we show that platelet endothelial aggregation receptor 1 (PEAR1) in fibroblasts may serve as a target for pulmonary fibrosis therapy. Pear1 deficiency in aged mice spontaneously causes alveolar collagens accumulation. Mesenchyme-specific Pear1 deficiency aggravates bleomycin-induced pulmonary fibrosis, confirming that PEAR1 potentially modulates pulmonary fibrosis progression via regulation of mesenchymal cell function. Moreover, single cell and bulk tissue RNA-seq analysis of pulmonary fibroblast reveals the expansion of Activated-fibroblast cluster and enrichment of marker genes in extracellular matrix development in Pear1−/− fibrotic lungs. We further show that PEAR1 associates with Protein Phosphatase 1 to suppress fibrotic factors-induced intracellular signalling and fibroblast activation. Intratracheal aerosolization of monoclonal antibodies activating PEAR1 greatly ameliorates pulmonary fibrosis in both WT and Pear1-humanized mice, significantly improving their survival rate.

Association of colorectal cancer with genetic and epigenetic variation in PEAR1-A population-based cohort study.

Platelet Endothelial Aggregation Receptor 1 (PEAR1) modulates angiogenesis and platelet contact-induced activation, which play a role in the pathogenesis of colorectal cancer. We therefore tested the association of incident colorectal cancer and genetic and epigenetic variability in PEAR1 among 2532 randomly recruited participants enrolled in the family-based Flemish Study on Environment, Genes and Health Outcomes (51.2% women; mean age 44.8 years). All underwent genotyping of rs12566888 located in intron 1 of the PEAR1 gene; in 926 participants, methylation at 16 CpG sites in the PEAR1 promoter was also assessed. Over 18.1 years (median), 49 colorectal cancers occurred, all in different pedigrees. While accounting for clustering of risk factors within families and adjusting for sex, age, body mass index, the total-to-HDL cholesterol ratio, serum creatinine, plasma glucose, smoking and drinking, use of antiplatelet and nonsteroidal anti-inflammatory drug, the hazard ratio of colorectal cancer contrasting minor-allele (T) carriers vs. major-allele (GG) homozygotes was 2.17 (95% confidence interval, 1.18–3.99; P = 0.013). Bootstrapped analyses, from which we randomly excluded from two to nine cancer cases, provided confirmatory results. In participants with methylation data, we applied partial least square discriminant analysis (PLS-DA) and identified two methylation sites associated with higher colorectal cancer risk and two with lower risk. In-silico analysis suggested that methylation of the PEAR1 promoter at these four sites might affect binding of transcription factors p53, PAX5, and E2F-1, thereby modulating gene expression. In conclusion, our findings suggest that genetic and epigenetic variation in PEAR1 modulates the risk of colorectal cancer in white Flemish. To what extent, environmental factors as exemplified by our methylation data, interact with genetic predisposition and modulate penetrance of colorectal cancer risk is unknown.

Association of Genetic Variability in Selected Genes with Platelet Hyperaggregability and Arterial Thrombosis

Abstract Introduction: Inherited platelet hyperaggregability, so called “Sticky platelet syndrome” (SPS), is a prothrombotic platelet disorder. The syndrome contributes more often to arterial than venous thrombosis. The most common localization of arterial occlusion involves cerebral or coronary arteries. However, SPS may also lead to thrombosis in the atypical sites of the circulation. This qualitative platelet alteration causes platelet hyperaggregability after a very low concentration of platelet inducers – adenosine diphosphate (ADP) and/or epinephrine (EPI). The precise genetic background of the syndrome has not been defined. In the present study we aimed to determine the association between selected single nucleotide polymorphisms (SNPs) within genes for platelet endothelial aggregation receptor 1 (PEAR1) and murine retrovirus integration site 1 (MRVI1) and the risk for arterial thrombosis in patients with SPS. The products of these selected genes play an important role in platelet aggregation. Patients and methods: We examined 69 patients with SPS and a history of arterial thrombosis and 69 healthy blood donors who served as controls. SPS was confirmed by a light transmission aggregometry (LTA) according to the method and criteria described by Mammen and Bick. We assessed two SNPs within PEAR1 gene (rs12041331, rs1256888) and two SNPs within MRVI1 gene (rs1874445, rs7940646). Results: Selected PEAR1 and MRVI1 polymorphisms seem not to be a risk factor for the development of SPS as the syndrome with an arterial thrombosis phenotype. However, in the subgroup of SPS1 patients there was found a decreased frequency of the minor A allele of SNP rs12041331 in PEAR1 gene (borderline p value, p=0.061) that can be hypothesized as protective against arterial thrombosis. In the same SPS1 subgroup the haplotype TA in PEAR1 gene also showed a decreased frequency with a borderline insignificance (p=0.056). We can theorize also about its protective role in SPS1 patients. We did not confirm the protective effect of polymorphism (T/T of rs 12566888) in PEAR1 against arterial thrombosis in SPS patients and SPS subgroups. Conclusion: Our results support the idea that examined genetic variability of the selected SNPs in PEAR1 and MRVI1 genes is not associated with platelet hyperaggregability manifested as arterial thrombosis. The possible protective role of the minor A allele of SNP rs12041331 as well as a role of haplotype TA in PEAR1 gene related to the arterial thrombosis found in the subgroup of SPS1 patients needs to be verified in further research.

Platelet Endothelial Aggregation Receptor 1 Polymorphism Is Associated With Functional Outcome in Small-Artery Occlusion Stroke Patients Treated With Aspirin.

Background: The role of genetic polymorphisms is important in defining the patient's prognosis and outcomes in coronary artery disease. The present study aimed to explore the association between platelet endothelial aggregation receptor 1 (PEAR1) rs12041331 polymorphism and the outcomes in patients with acute ischemic stroke treated with aspirin or dual antiplatelet therapy (DAPT) with clopidogrel.Methods: A total of 868 ischemic stroke patients admitted to our hospital from January 1, 2016 to December 30, 2018 were retrospectively studied. The Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification defined stroke subtypes. These patients were treated with aspirin alone or DAPT. The genotype distribution of PEAR1 rs12041331 single-nucleotide polymorphism (AA, AC, and CC) between different TOAST subtypes and treatment groups was assessed, and the clinical impact of genetic variants on functional outcomes defined by the National Institutes of Health Stroke Scale, modified Rankin Scale, and Barthel Index was analyzed using univariate and multivariate logistic regression models.Results: Among the 868 stroke patients, the PEAR1 AA genotype was 16%, GA was 47%, and GG was 36%. Forty-four percent had aspirin alone, and 56% had DAPT. Overall, the distribution of PEAR single-nucleotide polymorphism was not significant among the two treatment groups or subtypes of TOAST. In contrast, in patients treated with aspirin alone, PEAR1 AA tended to be higher in the small-artery occlusion (SAO) subtype when compared with the no-lacunar subtype, including cardioembolism and large-artery atherosclerosis. PEAR1 AA genotype was significantly associated with favorable functional outcomes at day 7 and discharge only in SAO patients treated with aspirin alone compared with the GG genotype. Multivariate regression models further suggested that AA genotype was independently associated with favorable outcomes in this group after being adjusted for three common stroke risk factors such as age, hypertension history, and C-reactive protein level [odds ratio (OR) 0.23, 95% confidence interval (CI), 0.07–0.64, P = 0.02 for 7-day National Institutes of Health Stroke Scale; OR 0.2, 95% CI, 0.06–0.66, P = 0.03 for 7-day modified Rankin Scale, and OR 0.25, 95% CI, 0.08–0.72, P = 0.03 for 7-day Barthel Index, respectively].Conclusion: The impact of PEAR1 rs12041331 polymorphism on aspirin depends on the TOAST subtype. PEAR1 AA carrier with SAO stroke is most sensitive to aspirin therapy. PEAR1 AA is an independent factor for the short-term functional outcomes in SAO patients treated with aspirin alone.Clinical Registration Number: 1800019911.

Biomarkers for Antiplatelet Therapies in Acute Ischemic Stroke: A Clinical Review.

Stroke is one of the world's leading causes of disability and death. Antiplatelet agents are administered to acute ischemic stroke patients as secondary prevention. Clopidogrel involves biotransformation by cytochrome P450 (CYP) enzymes into an active metabolite, and single nucleotide polymorphisms (SNPs) can influence the efficacy of this biotransformation. Despite the therapeutic advantages of aspirin, there is significant inter-individual heterogeneity in response to this antiplatelet drug. In this clinical review, the recent advances in the biomarkers of antiplatelet agents in acute ischemic stroke are discussed. The studies reviewed herein highlight the clinical relevance of antiplatelet resistance, pharmacotherapy of antiplatelet agents predicting drug response, strategies for identifying aspirin resistance, pharmacogenetic variants of antiplatelet agents, miRNAs, and extracellular vesicles (EVs) as biomarkers toward the personalized approach in the management of acute ischemic stroke. The precise pathways contributing to antiplatelet resistance are not very well known but are presumably multi-factorial. It is essential to understand the clinical relevance of clopidogrel and aspirin-related single nucleotide polymorphism (SNPs) as potential predictive and prognostic biomarkers. Prasugrel is a next-generation antiplatelet agent that prevents ADP-platelet activation by binding irreversibly to P2Y12 receptor. There are sporadic reports of prasugrel resistance and polymorphisms in the Platelet endothelial aggregation receptor-1 (PEAR1) that may contribute to a change in the pharmacodynamics response. Ticagrelor, a direct-acting P2Y12-receptor antagonist, is easily absorbed and partly metabolized to major AR-C124910XX metabolite (ARC). Ticagrelor's primary active metabolite, ARC124910XX (ARC), is formed via the most abundant hepatic cytochrome P450 (CYP) enzyme, CYP3A4, and CYP3A5. The integration of specific biomarkers, genotype as well as phenotype-related data in antiplatelet therapy stratification in patients with acute ischemic stroke will be of great clinical significance and could be used as a guiding tool for more effective, personalized therapy.

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

Background: Platelet endothelial aggregation receptor-1 (PEAR1) rs12041331 has been reported to affect agonist-stimulated platelet aggregation, but it remains unclear whether this variant plays a role in recurrent stroke. Here we assess the clinical relevance of PEAR1 rs12041331 in acute minor ischemic stroke (AMIS) and transient ischemic attack (TIA) Chinese patients treated with dual antiplatelet therapy (DAPT).Methods: We recruited 273 consecutive minor stroke and TIA patients, and Cox proportional hazard regression was used to model the relationship between PEAR1 rs12041331 and thrombotic and bleeding events.Results: Genotyping for PEAR1 rs12041331 showed 49 (18.0%) AA homozygotes, 129 (47.3%) GA heterozygotes, and 95 (34.7%) GG homozygotes. No association was observed between PEAR1 rs12041331 genotype and stroke or composite clinical vascular event rates (ischemic stroke, hemorrhagic stroke, TIA, myocardial infarction, or vascular death) or bleeding events regardless if individuals carried one or two copies of the A allele. Our results suggested that rs12041331 genetic polymorphism was not an important contributor to clinical events in AMIS and TIA patients in the setting of secondary prevention.Conclusions: Our data do provide robust evidence that genetic variation in PEAR1 rs12041331 do not contribute to atherothrombotic or bleeding risk in minor stroke and TIA patients treated with DAPT.

Role of platelet endothelial aggregation receptor 1 polymorphisms in idiopathic thrombocytopenic purpura: Is there an association?

Background: Genetic risk factors are implicated in the etiology and pathogenesis of immune thrombocytopenic purpura (ITP). Platelet endothelial aggregation receptor 1 (PEAR1) plays an important role in regulating megakaryopoiesis and thrombopoiesis. rs12041331 and rs12566888 single-nucleotide polymorphisms of PEAR1 are associated with megakaryocyte differentiation and platelet function. Materials and Methods: To conduct this study, 68 peripheral blood samples of patients with ITP (56 acute and 12 chronic) were collected. The amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) was used to detection of rs12041331 and rs12566888 PEAR1 polymorphisms. Results: Statistically significant differences were not seen between rs12041331 and rs12566888 genotypes in acute and chronic groups (P = 0.778, P = 0.844). The frequency of rs12041331 AG/AA genotypes and the rs12566888 GT genotype was more in acute ITP patients; on the other hand, the rs12566888 TT genotype was more in the chronic group. The highest platelet counts and platelet distribution width (PDW) were related to the rs12041331 AG allele. GT and TT of rs12566888 had more PDW and platelet count, respectively. Mean platelet volume values between alleles of both the polymorphisms were constant and did not differ much. In general, no statistically significant differences were observed between genotypes of polymorphisms and platelet parameters. Conclusions: There was no association between rs12041331 and rs12566888 with platelet parameters in ITP patients and the severity of this disease. Further investigation with a larger size is recommended.

Is the endogenous ligand for PEAR1 a proteoglycan: clues from the sea

Platelet Endothelial Aggregation Receptor 1 (PEAR1) is an orphan receptor of unknown function which mediates powerful activation of platelets and endothelial cells in response to crosslinking by antibodies and sulfated polysaccharides belonging to the dextran and fucoidan families. PEAR1 is a single transmembrane protein composed of 15 epidermal growth factor-like repeat sequences and with a conserved binding motif, YXXM, which when phosphorylated binds to phosphoinositide 3-kinase (PI3K). The 13th of the repeats has a heparin-binding sequence that is the site of interaction with the sulfated fucoidans and the only known endogenous ligand FcεRIα. Crosslinking of PEAR1 drives Src family kinase phosphorylation of the cytosolic tail leading to binding and activation of PI3K. In this Opinion Article, we summarize the literature on PEAR1 expression, structure and signaling, and the search for further endogenous ligands. We highlight one article in which phosphorylation of a 150 kDa platelet protein by heparin-containing ligands has been reported and propose that PEAR1 is a receptor for one or more glycosaminoglycan-conjugated proteins (proteoglycans). The up-regulation of PEAR1 at sites of inflammation in the vasculature and its role in angiogenesis suggests a role in the interplay of inflammation, platelets, coagulation, and thromboinflammation. We speculate that this may explain the link between single nucleotide variants in PEAR1 and cardiovascular disease.

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

The platelet endothelial aggregation receptor-1 (PEAR1) rs12041331 variant has been identified as a genetic determinant of platelet aggregation in response to antiplatelet therapies, including aspirin. However, association with atherothrombotic cardiovascular events is less clear, with limited evidence from large trials. Here, we tested association of rs12041331 with cardiovascular events and aspirin use in a randomized trial population of healthy older individuals. We undertook post hoc analysis of 13,547 participants of the ASPirin in Reducing Events in the Elderly (ASPREE) trial, median age 74years. Participants had no previous diagnosis of atherothrombotic cardiovascular disease at enrollment, and were randomized to either 100mg daily low-dose aspirin or placebo for median 4.7years follow-up. We used Cox proportional hazard regression to model the relationship between rs12041331 and the ASPREE primary cardiovascular disease (CVD) end point, and composites of major adverse cardiovascular events (MACE) and ischemic stroke (STROKE); and bleeding events; major hemorrhage (MHEM) and intracranial bleeding (ICB). We performed whole-population analysis using additive and dominant inheritance models, then stratified by treatment group. Interaction effects between genotypes and treatment group were examined. We observed no statistically significant association (P<0.05) in the population, or by treatment group, between rs12041331 and cardiovascular or bleeding events in either model. We also found no significant interaction effects between rs12041331-A and treatment group, for CVD (P=0.65), MACE (P=0.32), STROKE (P=0.56), MHEM (P=0.59), or ICB (P=0.56). The genetic variant PEAR1 rs12041331 is not associated with cardiovascular events in response to low-dose aspirin in a healthy elderly population.

PEAR1 polymorphisms as a prognostic factor in hemostasis and cardiovascular diseases.

Platelet Endothelial Aggregation Receptor (PEAR1), as a platelet receptor, plays a vital role in hemostasis. This receptor, by its extracellular part, causes platelet adhesion and consequently initiates platelet aggregation. Dysfunction of PEAR1 can disrupt platelet aggregation in patients with cardiovascular diseases (CVDs). The content used in this paper has been taken from English language articles (2005-2020) retrieved from Pubmed database and Google scholar search engine using "Cardiovascular Disease", "PEAR1", "Polymorphism", and "Platelet Aggregation" keywords. Some PEAR1 polymorphisms can disrupt homeostasis and interfere with the function mechanism of cardiac drugs. Since polymorphisms in this gene affect platelet function and the platelet aggregation process, PEAR1 could be further studied in the future as an essential factor in controlling the treatment process of patients with cardiovascular diseases. PEAR1 polymorphisms through disruption of the platelet aggregation process can be a risk factor in patients with CVDs. Therefore, controlling patients through genetic testing and the evaluation of PEAR1 polymorphisms can help improve the treatment process of patients. According to the studies on the PEAR1 gene and the effect of different polymorphisms on some crucial issues in CVDs patients (changes in platelet activity), it is clear that if there is a significant relationship between polymorphisms and CVDs, they can be used as prognostic and diagnostic markers. This study aims to evaluate the prognosis and drug treatment of the PEAR1 gene in CVDs patients.

PEAR1 suppresses the proliferation of pulmonary microvascular endothelial cells via PI3K/AKT pathway in ALI model

BackgroundActivation of the proliferation of pulmonary microvascular endothelial cells (PMVECs) is a key step in the recovery of the integrity of endothelial monolayer, which helps to alleviate acute lung injury (ALI). Platelet endothelial aggregation receptor-1 (PEAR1), expressed on endothelial cells, was reported to inhibit the proliferation of vascular endothelial cells and angiogenesis. However, little is known about its role and mechanism in vascular endothelial disorders in ALI. ObjectiveThe aim of this study was to investigate the impact of PEAR1 on the proliferation of pulmonary microvascular endothelial cells in ALI. MethodsWe tested the expression level of PEAR1 in the lungs of WT mice in ALI model induced by intestinal IR. Primary human pulmonary microvascular endothelial cells (HPMECs) were stimulated by 1 mg/L LPS in vitro. We synthesized siPEAR1 and Flag-PEAR1 plasmid to verify the role of PEAR1 on regulating the proliferation of HPMECs under LPS condition and to explore related signaling pathways. ResultsThe expression level of PEAR1 significantly increased in ALI induced by intestinal IR. PEAR1 knockdown enhanced the proliferation level of HPMECs, which, however, was inhibited by PEAR1 overexpression. PEAR1 knockdown activated PI3K/AKT pathway both in steady state and under LPS condition. PI3K inhibitor, LY294002, reversed the increasing proliferation level and cell progression of HPMECs induced by PEAR1 knockdown after LPS challenge. ConclusionsPEAR1 acts as a negative regulator in the proliferation of HPMECs in ALI model via the PI3K/AKT pathway.

Impact of Platelet Endothelial Aggregation Receptor-1 Genotypes on Platelet Reactivity and Early Cardiovascular Outcomes in Patients Undergoing Percutaneous Coronary Intervention and Treated With Aspirin and Clopidogrel.

The genetic determinants of response to clopidogrel and aspirin are incompletely characterized. Recently, PEAR1 (platelet endothelial aggregation receptor-1) rs12041331 polymorphism has been shown to influence the platelet reactivity, but its impact on cardiovascular outcomes remains unclear in patients treated with antiplatelet agents. In this prospective cohort study, 2439 Chinese patients with acute coronary syndrome or stable coronary artery disease undergoing coronary stent implantation and receiving clopidogrel and aspirin were consecutively recruited. Their platelet reactivity was determined by light transmission aggregometry at 5 and 30 days after coronary intervention. Genotyping was performed using an improved multiplex ligation detection reaction technique. All patients completed a 30-day follow-up for clinical outcomes. Genotyping for PEAR1 showed 768 (38.3%) GG homozygotes, 941 (46.9%) GA heterozygotes, and 298 (14.8%) AA homozygotes. The 30-day incidence of major adverse cardiovascular events, the composite of cardiovascular death, nonfatal myocardial infarction, and ischemic stroke were significantly higher in AA homozygotes than in non-AA homozygotes (adjusted hazard ratio, 2.78; 95% CI, 1.13-6.82; P=0.026), irrespective of CYP2C19*2 loss-of-function polymorphism and known outcome predictors including age, sex, smoking, and diabetes mellitus. The ADP-induced platelet aggregation was significantly lower in AA homozygotes than that in GG homozygotes at both time points, although no significant difference was found for the arachidonic acid-induced platelet aggregation among the 3 groups. About 15% of Chinese patients undergoing coronary stent implantation were AA homozygotes for PEAR1 rs12041331. These patients had ≈3-fold increase in short-term major adverse cardiovascular events risk compared with non-AA homozygotes, and the adverse clinical outcome is unlikely to be mediated by suboptimal pharmacological response to aspirin or clopidogrel. URL: https://www.clinicaltrials.gov . Unique identifier: NCT01968499.