Polymorphism in the protease‐activated receptor‐4 gene region associates with platelet activation and perioperative myocardial injury

Muehlschlegel, Jochen D.; Perry, Tjörvi E.; Liu, Kuang Yu; Fox, Amanda A.; Lichtner, Peter; Collard, Charles D.; Shernan, Stanton K.; Hartwig, John H.; Body, Simon C.; Hoffmeister, Karin M.

doi:10.1002/ajh.22244

Cited by 15 publications

(15 citation statements)

References 44 publications

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“…This SNP is in the CPAMD8 gene, ;18 kb downstream of F2RL3, but has no linkage to the F2RL3 SNPs we have described here. 32 The rs773902 genotype was strongly associated with PAR4-induced platelet aggregation and calcium release, but not with the platelet aggregation response to other agonists, further supporting a PAR4-specific effect. A second amino acid-changing variant was identified, but only in black subjects.…”

Section: Discussionmentioning

confidence: 91%

Common variants in the human platelet PAR4 thrombin receptor alter platelet function and differ by race

Edelstein¹,

Simon

Lindsay³

et al. 2014

Blood

110

131

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• White individuals have a high frequency of the common PAR4 gene (F2RL3) variant Ala120; blacks have a high frequency of Thr120.• PAR4 Thr120 induces greater signaling and is associated with greater platelet aggregation and reduced inhibition by a PAR4 antagonist.Human platelets express 2 thrombin receptors: protease-activated receptor (PAR)-1 and PAR4. Recently, we reported 3.7-fold increased PAR4-mediated aggregation kinetics in platelets from black subjects compared with white subjects. We now show that platelets from blacks (n 5 70) express 14% more PAR4 protein than those from whites (n 5 84), but this difference is not associated with platelet PAR4 function. Quantitative trait locus analysis identified 3 common single nucleotide polymorphisms in the PAR4 gene (F2RL3) associated with PAR4-induced platelet aggregation. Among these single nucleotide polymorphisms, rs773902 determines whether residue 120 in transmembrane domain 2 is an alanine (Ala) or threonine (Thr). Compared with the Ala120 variant, Thr120 was more common in black subjects than in white subjects (63% vs 19%), was associated with higher PAR4-induced human platelet aggregation and Ca 21 flux, and generated greater inositol 1,4,5-triphosphate in transfected cells. A second, less frequent F2RL3 variant, Phe296Val, was only observed in blacks and abolished the enhanced PAR4-induced platelet aggregation and 1,4,5-triphosphate generation associated with PAR4-Thr120. PAR4 genotype did not affect vorapaxar inhibition of platelet PAR1 function, but a strong pharmacogenetic effect was observed with the PAR4-specific antagonist YD-3 [1-benzyl-3(ethoxycarbonylphenyl)-indazole]. These findings may have an important pharmacogenetic effect on the development of new PAR antagonists. (Blood. 2014;124(23):3450-3458)

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Section: Discussionmentioning

confidence: 91%

Common variants in the human platelet PAR4 thrombin receptor alter platelet function and differ by race

Edelstein¹,

Simon

Lindsay³

et al. 2014

Blood

110

131

View full text Add to dashboard Cite

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“…Proteinase-activated receptor 4 has been implicated in cardiovascular pathophysiology, especially inflammation, 37 platelet function, 38 and possibly perioperative myocardial injury after bypass surgery. 39 Subsequently, a pronounced association of lower F2RL3 methylation with higher mortality (both cardiovascular and noncardiovascular) was demonstrated in a cohort of patients with stable coronary heart disease. 40 Altogether, remarkably little is known about epigenetic patterns associated with cardiovascular disease in people who smoke.…”

Section: Epigenetics Of Tobacco-associated Cardiovascular Diseasementioning

confidence: 99%

Current Genetics and Epigenetics of Smoking/Tobacco-Related Cardiovascular Disease

Breitling¹

2013

ATVB

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Abstract-Genetic and epigenetic factors are of great importance in cardiovascular biology and disease. Tobacco-smoking, one of the most important cardiovascular risk factors, is itself partially determined by genetic background and is associated with altered epigenetic patterns. This could render the genetics and epigenetics of smoking-related cardiovascular disease a textbook example of environmental epigenetics and modern approaches to multimodal data analysis. A pronounced association of smoking-related methylation patterns in the F2RL3 gene with prognosis in patients with stable coronary heart disease has recently been described. Nonetheless, surprisingly little concrete knowledge on the role of specific genetic variants and epigenetic modifications in the development of cardiovascular diseases in people who smoke has been accumulated. Beyond the current knowledge, the present review briefly outlines some chief challenges and priorities for moving forward in this field. variation in antioxidative resilience seems to have no clinical cardiovascular consequences by itself, but-in interaction with the excessive oxidative stress caused by smoking-it means that smoking-associated cardiovascular risks are much greater in ε4 carriers than in other subjects. 10 It has been realized that such gene-environment interactions could also interfere with the performance of lipid-lowering drugs, but the extent of this potentially far-reaching problem still needs to be clarified. 11Given the multitude of physiological phenomena involved in tobacco-smoking-related cardiovascular disease (ref. 12 for an informative overview), it is hardly surprising that similar interactions with smoking have been reported for sequence variants in candidate genes coding for proteins as diverse as lipoprotein lipase and interleukin-6, 10 prothrombotic mutations like factor II G20210A, 13 or transforming growth factor-β1.14 One study investigating an interaction of interleukin-18 polymorphisms with smoking regarding cardiovascular disease risk was exceptional for its laudable collaborative design emphasizing statistical power.15 Nonetheless, the level of evidence for the vast majority of currently suggested gene-smoking interactions ultimately remains very limited. The evolution of findings concerning an interaction between tobacco-smoking and variants in glutathione S-transferase genes with respect to cardiovascular disease risk-which started out as a seemingly plausible effect modification supported by multiple lines of evidence 8 and was further sugested later meta-analysis, 16 only to vanish with subsequent sample size escalation 17 -should be taken as a reminder of the danger of prematurely overinterpreting gene-smoking interactions or even higher order interactions (eg, gene-age-smoking). 18Thorough replication and follow-up studies need to become more of a norm in this statistically challenging field. A New Era of EpigeneticsStudies on epigenetic aspects of health and disease have exploded in recent years, mainly because of technological a...

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“…[101][102][103][104][105][106] The challenge is establishing a direct link from the identified polymorphisms to receptor expression or function, and ultimately to a physiological output. For example, a polymorphism in an intron of the PAR1 gene (f2r) results in a lower density of PAR1 on the platelet surface and decreased aggregation in response to PAR1 agonists.…”

mentioning

confidence: 99%

Protease-activated receptors in hemostasis

Nieman

2016

Blood

122

123

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Protease signaling in cells elicits multiple physiologically important responses via protease-activated receptors (PARs). There are 4 members of this family of G-protein–coupled receptors (PAR1-4). PARs are activated by proteolysis of the N terminus to reveal a tethered ligand. The rate-limiting step of PAR signaling is determined by the efficiency of proteolysis of the N terminus, which is regulated by allosteric binding sites, cofactors, membrane localization, and receptor dimerization. This ultimately controls the initiation of PAR signaling. In addition, these factors also control the cellular response by directing signaling toward G-protein or β-arrestin pathways. PAR1 signaling on endothelial cells is controlled by the activating protease and heterodimerization with PAR2 or PAR3. As a consequence, the genetic and epigenetic control of PARs and their cofactors in physiologic and pathophysiologic conditions have the potential to influence cellular behavior. Recent studies have uncovered polymorphisms that result in PAR4 sequence variants with altered reactivity that interact to influence platelet response. This further demonstrates how interactions within the plasma membrane can control the physiological output. Understanding the structural rearrangement following PAR activation and how PARs are allosterically controlled within the plasma membrane will determine how best to target this family of receptors therapeutically. The purpose of this article is to review how signaling from PARs is influenced by alternative cleavage sites and the physical interactions within the membrane. Going forward, it will be important to relate the altered signaling to the molecular arrangement of PARs in the cell membrane and to determine how these may be influenced genetically.

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Polymorphism in the protease‐activated receptor‐4 gene region associates with platelet activation and perioperative myocardial injury

Cited by 15 publications

References 44 publications

Common variants in the human platelet PAR4 thrombin receptor alter platelet function and differ by race

Common variants in the human platelet PAR4 thrombin receptor alter platelet function and differ by race

Current Genetics and Epigenetics of Smoking/Tobacco-Related Cardiovascular Disease

Protease-activated receptors in hemostasis

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