Ignite Creation Date:
2024-05-06 @ 10:52 AM
Last Modification Date:
2024-10-26 @ 12:36 PM
Study NCT ID:
NCT03373552
Status:
ACTIVE_NOT_RECRUITING
Last Update Posted:
2023-09-15
First Post:
2017-12-07
Brief Title:
Genetic Polymorphism Associated With Coronary Heart Disease Susceptibility and Variability of Clopidogrel Response
Sponsor:
Hôpital Universitaire Fattouma Bourguiba
Organization:
Hôpital Universitaire Fattouma Bourguiba
Study Overview
Official Title:
Determination of Genetic Polymorphisms Contributing to the Coronary Heart Disease Susceptibility and Variability of Clopidogrel Response
Status:
ACTIVE_NOT_RECRUITING
Status Verified Date:
2023-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The pathogenesis of CHD remains poorly known despite much research over the last few decades Numerous non-genetic variables have been demonstrated to have a significant impact on the risk of CHD However the fact that many individuals with severe CHD do not have any of these non-genetic risk factors supports the notion that genetic factors play a role in the occurrence and progression of CHD In this study we investigated the association of polymorphisms affecting Vascular endothelial factors A VEGFA and its receptor VEGFR2 rs3025039 rs699947 rs2305948 rs1870377 CXCR4 rs2228014 CCR2 rs1799864 C3 rs2230199 CCL2 rs1024611 and rs2857656 and CCL5 rs2107538 and rs22280789 with CHD susceptibility and the severity of coronary lesion
On another side clopidogrel is largely prescribed in association with aspirin in order to prevent atherothrombotic complications in patients with acute coronary syndrome Its effectiveness is undeniably proven by several studies and clinical trials over the years however some patients have presented ischemic events such as thrombosis on stent or myocardial infarction despite a well-conducted treatment This clopidogrel non-responsiveness is probably multifactorial several genetic and non genetic factors may contribute to impaired platelet inhibition by clopidogrel In this regard it is meaningful to determine genetic polymorphisms contributing to the variability of clopidogrel response in patients with Coronary Artery Therefore the goal of this study is to determine the impact of the polymorphisms affecting CYP2C19 PON ABCB1 ITGB3 and P2RY12 genes on the response to clopidogrel in patients with CADDisease CAD In fact the recognition of these factors might predict the exposure to the risk of thrombosis and cardiovascular death in these patients
On another side clopidogrel is largely prescribed in association with aspirin in order to prevent atherothrombotic complications in patients with acute coronary syndrome Its effectiveness is undeniably proven by several studies and clinical trials over the years however some patients have presented ischemic events such as thrombosis on stent or myocardial infarction despite a well-conducted treatment This clopidogrel non-responsiveness is probably multifactorial several genetic and non genetic factors may contribute to impaired platelet inhibition by clopidogrel In this regard it is meaningful to determine genetic polymorphisms contributing to the variability of clopidogrel response in patients with Coronary Artery Therefore the goal of this study is to determine the impact of the polymorphisms affecting CYP2C19 PON ABCB1 ITGB3 and P2RY12 genes on the response to clopidogrel in patients with CADDisease CAD In fact the recognition of these factors might predict the exposure to the risk of thrombosis and cardiovascular death in these patients
Detailed Description:
The pathological basis of CHD is atherosclerosis and its clinical manifestations such as ischemia The formation of functional collateral circulation around obstructed arteries in ischemic myocardial is an important process associated with improved survival in CHD patients Vascular endothelial factors A VEGFA and its receptor VEGFR2 have been cited as crucial players in angiogenesis the process of creating new blood vessels and the control of vasopermeability They are essentially made by blood vessel endothelial and smooth muscle cells The VEGFA and VEGFR2 signaling pathway govern inflammation and modify the process of thrombus formation in addition to their role in angiogenesis Moreover the atherosclerotic process in human coronary arteries has been established in prior research to be accompanied with higher serum levels of VEGF
Consequently atherosclerosis is considered now to be an inflammatory disease Chemokines are inflammatory chemotactic cytokines that play a role in leucocyte recruitment and the chemokine CCL2 monocyte chemoattractant protein-1 or MCP-1 has been found to be highly expressed in human atherosclerotic plaques CCL2 attracts monocytes as well as T lymphocytes and mediates its effects by binding to G protein coupled receptors expressed on the surface of target cells The most prominent receptor for CCL2 is CCR2 and its binding to this receptor has been shown to result in recruitment of monocytes into the subendothelial space Another chemokine that plays a critical role in development of CHD is CCL5 or RANTES regulation upon activation normal T cell expressed and secreted which belongs to the CC chemokines family and secreted from CD8 T cells epithelial cells fibroblasts and platelets The CCL5-mediated cell migration is facilitated through its interaction with chemokine receptors CCR1-3 and CCR5 Increased serum concentrations of CCL5 are associated with obesity type 2 diabetes T2D coronary atherosclerosis and other cardiovascular risk factors including atherosclerosis
Additionally previous studies have shown that C3 is associated with atherosclerosis and cardiovascular risk factors Increased deposition of C3 within the intima of atherosclerotic lesions suggests that complement may play a direct functional role in atherosclerosis Preclinical and clinical evidence suggested that complement C3 might be a biomarker of insulin resistance and cardio-metabolic diseases in CHD patients serum C3 was significantly higher than in controls and was positively associated with the severity of CHD
Clopidogrel with or without aspirin has been proven to reduce the occurrence of new stroke in patients with acute ischemic stroke or transient ischemic attack Previous studies showed that genetic polymorphisms especially those associated with reduced function of cytochrome P450 2C19 CYP2C19 were associated with excess cardiovascular risk and mortality in patients with coronary artery disease treated with Clopidogrel In Addition Clopidogrel binds to ADP receptor P2Y12 and genetic polymorphisms in P2Y12 gene H1 and H2 haplotypes affect the phenotypic response to the drug
Clopidogrel absorption is mainly limited by P-glycoprotein P-gp 2 encoded by ABCB1 an ATP-dependent transporter located in the intestinal epithelial cell wall which expels the drug into the intestinal lumen mutations in ABCB1 appeared as a predictor of a better response
P2Y12 is the ADP receptor expressed on platelets surface and when clopidogrel irreversibly binds to it makes impossible the bond of its natural ligand thus inhibiting platelets aggregation This receptor is highly polymorphic and many SNPs have been found to increase the risk of CAD and hight platelet aggregation resulting in less clinical response to clopidogrel
Collected data for patients encompasse baseline characteristics including age gender obesity defined as a body mass index 30 kgm2 smoking medical history and coadministered drugs
The study protocol was approved by the Ethics Committee for Clinical Research at our center and all subjects gave informed consent for study participation
Platelet function assay is assessed by the VerifyNow P2Y12 analyzer following manufacturer instructions Accumetrics Inc San Diego CA USA using venous blood samples collected in tube containing 32 sodium citrate
Genotyping is performed using the polymerase chain reaction-restriction fragment length polymorphism PCR-RFLP and sequencing
Consequently atherosclerosis is considered now to be an inflammatory disease Chemokines are inflammatory chemotactic cytokines that play a role in leucocyte recruitment and the chemokine CCL2 monocyte chemoattractant protein-1 or MCP-1 has been found to be highly expressed in human atherosclerotic plaques CCL2 attracts monocytes as well as T lymphocytes and mediates its effects by binding to G protein coupled receptors expressed on the surface of target cells The most prominent receptor for CCL2 is CCR2 and its binding to this receptor has been shown to result in recruitment of monocytes into the subendothelial space Another chemokine that plays a critical role in development of CHD is CCL5 or RANTES regulation upon activation normal T cell expressed and secreted which belongs to the CC chemokines family and secreted from CD8 T cells epithelial cells fibroblasts and platelets The CCL5-mediated cell migration is facilitated through its interaction with chemokine receptors CCR1-3 and CCR5 Increased serum concentrations of CCL5 are associated with obesity type 2 diabetes T2D coronary atherosclerosis and other cardiovascular risk factors including atherosclerosis
Additionally previous studies have shown that C3 is associated with atherosclerosis and cardiovascular risk factors Increased deposition of C3 within the intima of atherosclerotic lesions suggests that complement may play a direct functional role in atherosclerosis Preclinical and clinical evidence suggested that complement C3 might be a biomarker of insulin resistance and cardio-metabolic diseases in CHD patients serum C3 was significantly higher than in controls and was positively associated with the severity of CHD
Clopidogrel with or without aspirin has been proven to reduce the occurrence of new stroke in patients with acute ischemic stroke or transient ischemic attack Previous studies showed that genetic polymorphisms especially those associated with reduced function of cytochrome P450 2C19 CYP2C19 were associated with excess cardiovascular risk and mortality in patients with coronary artery disease treated with Clopidogrel In Addition Clopidogrel binds to ADP receptor P2Y12 and genetic polymorphisms in P2Y12 gene H1 and H2 haplotypes affect the phenotypic response to the drug
Clopidogrel absorption is mainly limited by P-glycoprotein P-gp 2 encoded by ABCB1 an ATP-dependent transporter located in the intestinal epithelial cell wall which expels the drug into the intestinal lumen mutations in ABCB1 appeared as a predictor of a better response
P2Y12 is the ADP receptor expressed on platelets surface and when clopidogrel irreversibly binds to it makes impossible the bond of its natural ligand thus inhibiting platelets aggregation This receptor is highly polymorphic and many SNPs have been found to increase the risk of CAD and hight platelet aggregation resulting in less clinical response to clopidogrel
Collected data for patients encompasse baseline characteristics including age gender obesity defined as a body mass index 30 kgm2 smoking medical history and coadministered drugs
The study protocol was approved by the Ethics Committee for Clinical Research at our center and all subjects gave informed consent for study participation
Platelet function assay is assessed by the VerifyNow P2Y12 analyzer following manufacturer instructions Accumetrics Inc San Diego CA USA using venous blood samples collected in tube containing 32 sodium citrate
Genotyping is performed using the polymerase chain reaction-restriction fragment length polymorphism PCR-RFLP and sequencing
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None