Pairing megakaryopoiesis methylation with PEAR1

Johnson, Andrew D.

doi:10.1182/blood-2016-06-723940

Cited by 10 publications

(8 citation statements)

References 9 publications

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“…In many cases, these non‐coding variants are even located in regions defined as ‘enhancers’, important players in gene regulation . One such example is represented by rs12041331 in PEAR1 , a CpG‐SNP, a variant that introduces a CpG site into the sequence, leading to epigenetic changes with functional consequences for gene expression in megakaryocytes , the PLT precursors. About 20% of the PLT count‐associated variants from the eight selected studies reported in Table are also CpG‐SNPs; however, further research is required to functionally characterize them and their possible implication in the PLT formation or depletion processes.…”

Section: Introductionmentioning

confidence: 99%

Learning by counting blood platelets in population studies: survey and perspective a long way after Bizzozero

Izzi

Bonaccio

Gaetano

et al. 2018

Journal of Thrombosis and Haemostasis

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Platelet count represents a useful tool in clinical practice to discriminate individuals at higher risk of bleeding. Less obvious is the role of platelet count variability within the normal range of distribution in shaping the individual's disease risk profile. Epidemiological studies have shown that platelet count in the adult general population is associated with a number of health outcomes related to hemostasis and thrombosis. However, recent studies are suggesting a possible role of this platelet index also as an independent risk factor. In this review of adult population studies, we will first focus on known genetic and non-genetic determinants of platelet number variability. Next, we will evaluate platelet count as a marker and/or a predictor of disease risk and its interaction with other risk factors. We will then discuss the role of platelet count variability within the normal distribution range as a contribution to disease and mortality risk. The possibility of considering platelet count as a simple, inexpensive indicator of increased risk of disease and death in general populations could open new opportunities to investigate novel platelet pathophysiological roles as well as therapeutic opportunities. Future studies should also consider platelet count, not only platelet function, as a modulator of disease and mortality risk.

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Section: Introductionmentioning

confidence: 99%

Learning by counting blood platelets in population studies: survey and perspective a long way after Bizzozero

Izzi

Bonaccio

Gaetano

et al. 2018

Journal of Thrombosis and Haemostasis

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“…PEAR-1 in platelets supports activation of the α IIb β 3 integrin [1] and influences MK precursor proliferation through control of the PI3K-PTEN pathway [32]. We have already shown that PEAR1 methylation controls PEAR1 expression during megakaryopoiesis [30, 46] and is lower in carriers of rs12041331, a CpG-SNP whose presence alters the methylation pattern of the PEAR1 intron1 region causing differential binding of nuclear proteins [30].…”

Section: Discussionmentioning

confidence: 99%

Variation of PEAR1 DNA methylation influences platelet and leukocyte function

et al. 2019

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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.

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“…PEAR1 protein through the PI3K/PTEN pathway and continued activation of platelet aggregation via αIIbβ3 could alter megakaryocytopoiesis (13,14). Genetic studies have shown, two intronic variants (rs12041331and rs12566888), are associated with platelet function/activation (15). Recently, researchers have investigated the effects of single nucleotide polymorphism (SNPs) in PEAR1 through in vitro megakaryocytes (MK) differentiation of HSCs and found that PEAR1 during MK differentiation affects both platelet aggregation and the number of mature platelets (15,16).…”

Section: Introductionmentioning

confidence: 99%

“…Genetic studies have shown, two intronic variants (rs12041331and rs12566888), are associated with platelet function/activation (15). Recently, researchers have investigated the effects of single nucleotide polymorphism (SNPs) in PEAR1 through in vitro megakaryocytes (MK) differentiation of HSCs and found that PEAR1 during MK differentiation affects both platelet aggregation and the number of mature platelets (15,16). Recently, the role of PEAR1 SNPs has been highlighted in disorders such as coronary artery disease (CADs), acute coronary syndromes (ACS), sticky platelet syndrome (SPS), cardiovascular diseases (CVDs), deep vein thrombosis (DVT), and Kawasaki disease (KD) that are all associated with platelet activation/dysfunction.…”

Section: Introductionmentioning

confidence: 99%

PEAR1 Genetic Variants in Essential Thrombocythemia: A New Study of The Prevalence and Association of PEAR1 Variants with Hematological Parameters and ET Mutations

Maleknia

Jalali

Kaydani

et al. 2021

Preprint

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Objective: Essential thrombocythemia (ET) is a type of myeloproliferative neoplasm characterized by the expansion of the megakaryocytic/platelet line. Given the undeniable role of genetic variations in the pathogenesis of ET, as well as the proven effects of PEAR1 SNPs on platelet function, the innovative purpose of this study is to investigate the prevalence of PEAR1 variants (rs12041331 and rs12566888) and their relationship to hematological parameters and ET-related mutations.Materials and Methods: We studied 105 ET patients and analyzed ET patients' mutational profiles, including JAK2 V617F mutation (detected by Allele-specific PCR), CALR, and MPL mutations (both through PCR amplification). Two SNPs of the PEAR1 gene were assessed through ARMS-PCR, and the Sanger method was used for the validation of ARMS-PCR amplification.Results: The prevalence of rs12041331 and rs12566888 in ET patients were 43.9% and 38.5%, respectively, and rs12041331 was significantly associated with increased platelet counts (P-Value: 0.02). A significant relationship was also found between the rs12041331 and CALR mutation (P-Value: 0.03). Platelet count was higher in CALR+ patients (934.45 ×10 9/L ± 265.35 SD) than in JAK2 + patients (790.11 ×10 9/L ± 265.35 SD). Conversely, other hematological parameters and thrombosis were higher in JAK2 + patients than the CALR + patients.Conclusions: Our findings reinforce the idea that rs12041331 and rs12566888 may be associated with ET, and rs12041331 is significantly associated with increased platelet count. Besides, the prevalence of ET-related mutations in patients with rs12041331 and rs12566888 was almost similar; however, only CALR mutation had a significant relationship with rs12041331.

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Pairing megakaryopoiesis methylation with PEAR1

Cited by 10 publications

References 9 publications

Learning by counting blood platelets in population studies: survey and perspective a long way after Bizzozero

Learning by counting blood platelets in population studies: survey and perspective a long way after Bizzozero

Variation of PEAR1 DNA methylation influences platelet and leukocyte function

PEAR1 Genetic Variants in Essential Thrombocythemia: A New Study of The Prevalence and Association of PEAR1 Variants with Hematological Parameters and ET Mutations

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