Dataset Information

Genetic Variation in the Platelet Endothelial Aggregation Receptor 1 Gene Results in Endothelial Dysfunction.

ABSTRACT: Platelet Endothelial Aggregation Receptor 1 (PEAR1) is a newly identified membrane protein reported to be involved in multiple vascular and thrombotic processes. While most studies to date have focused on the effects of this receptor in platelets, PEAR1 is located in multiple tissues including the endothelium, where it is most highly expressed. Our first objective was to evaluate the role of PEAR1 in endothelial function by examining flow-mediated dilation of the brachial artery in 641 participants from the Heredity and Phenotype Intervention Heart Study. Our second objective was to further define the impact of PEAR1 on cardiovascular disease computationally through meta-analysis of 75,000 microarrays, yielding insights regarding PEAR1 function, and predictions of phenotypes and diseases affected by PEAR1 dysregulation. Based on the results of this meta-analysis we examined whether genetic variation in PEAR1 influences endothelial function using an ex vivo assay of endothelial cell migration. We observed a significant association between rs12041331 and flow-mediated dilation in participants of the Heredity and Phenotype Intervention Heart Study (P = 0.02). Meta-analysis results revealed that PEAR1 expression is highly correlated with several genes (e.g. ANG2, ACVRL1, ENG) and phenotypes (e.g. endothelial cell migration, angiogenesis) that are integral to endothelial function. Functional validation of these results revealed that PEAR1 rs12041331 is significantly associated with endothelial migration (P = 0.04). Our results suggest for the first time that genetic variation of PEAR1 is a significant determinant of endothelial function through pathways implicated in cardiovascular disease.

SUBMITTER: Fisch AS

PROVIDER: S-EPMC4583223 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Genetic Variation in the Platelet Endothelial Aggregation Receptor 1 Gene Results in Endothelial Dysfunction.

Fisch Adam S AS Yerges-Armstrong Laura M LM Backman Joshua D JD Wang Hong H Donnelly Patrick P Ryan Kathleen A KA Parihar Ankita A Pavlovich Mary A MA Mitchell Braxton D BD O'Connell Jeffrey R JR Herzog William W Harman Christopher R CR Wren Jonathan D JD Lewis Joshua P JP

PloS one 20150925 9

Platelet Endothelial Aggregation Receptor 1 (PEAR1) is a newly identified membrane protein reported to be involved in multiple vascular and thrombotic processes. While most studies to date have focused on the effects of this receptor in platelets, PEAR1 is located in multiple tissues including the endothelium, where it is most highly expressed. Our first objective was to evaluate the role of PEAR1 in endothelial function by examining flow-mediated dilation of the brachial artery in 641 participa ...[more]

PMID: 26406321

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Project description:BACKGROUND- Aspirin or dual antiplatelet therapy with aspirin and clopidogrel is a standard therapy for patients who are 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 dual antiplatelet therapy in individuals (n=565) from the Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study and conducted a genome-wide association study of drug response. Significant findings were extended by examining genotype and cardiovascular outcomes in 2 independent aspirin-treated cohorts: 227 percutaneous coronary intervention patients and 1000 patients of the International Verapamil SR/Trandolapril Study (INVEST) Genetic Substudy (INVEST-GENES). Results from the genome-wide association study revealed a strong association between single-nucleotide polymorphisms on chromosome 1q23 and post-dual antiplatelet therapyplatelet aggregation. Further genotyping revealed rs12041331 in the platelet endothelial aggregation receptor-1 (PEAR1) gene to be most strongly associated with dual antiplatelet therapy response (P=7.66×10(-9)). In white and black patients undergoing percutaneous coronary intervention, A-allele carriers of rs12041331 were more likely to experience a cardiovascular event or death compared with GG homozygotes (hazard ratio, 2.62; 95% confidence interval, 0.96-7.10; P=0.059; and hazard ratio, 3.97; 95% confidence interval, 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 with GG homozygotes (odds ratio, 2.03; 95% confidence interval, 1.01-4.09; P=0.048). CONCLUSION- Common genetic variation in PEAR1 may be a determinant of platelet response and cardiovascular events in patients on aspirin alone or in combination with clopidogrel. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00799396 and NCT00370045.

Project description: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.

Project description:Previous genome-wide association studies (GWAS) have identified several variants associated with platelet function phenotypes; however, the proportion of variance explained by the identified variants is mostly small. Rare coding variants, particularly those with high potential for impact on protein structure/function, may have substantial impact on phenotype but are difficult to detect by GWAS. The main purpose of this study was to identify low frequency or rare variants associated with platelet function using genotype data from the Illumina HumanExome Bead Chip. Three family-based cohorts of European ancestry, including ~4,000 total subjects, comprised the discovery cohort and two independent cohorts, one of European and one of African American ancestry, were used for replication. Optical aggregometry in platelet-rich plasma was performed in all the discovery cohorts in response to adenosine diphosphate (ADP), epinephrine, and collagen. Meta-analyses were performed using both gene-based and single nucleotide variant association methods. The gene-based meta-analysis identified a significant association (P = 7.13 × 10-7) between rare genetic variants in ANKRD26 and ADP-induced platelet aggregation. One of the ANKRD26 SNVs - rs191015656, encoding a threonine to isoleucine substitution predicted to alter protein structure/function, was replicated in Europeans. Aggregation increases of ~20-50% were observed in heterozygotes in all cohorts. Novel genetic signals in ABCG1 and HCP5 were also associated with platelet aggregation to ADP in meta-analyses, although only results for HCP5 could be replicated. The SNV in HCP5 intersects epigenetic signatures in CD41+ megakaryocytes suggesting a new functional role in platelet biology for HCP5. This is the first study to use gene-based association methods from SNV array genotypes to identify rare variants related to platelet function. The molecular mechanisms and pathophysiological relevance for the identified genetic associations requires further study.

Dataset Information

Genetic Variation in the Platelet Endothelial Aggregation Receptor 1 Gene Results in Endothelial Dysfunction.

Publications

Genetic Variation in the Platelet Endothelial Aggregation Receptor 1 Gene Results in Endothelial Dysfunction.

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