Determination of Genetic Polymorphisms Contributing to the Coronary Heart Disease Susceptibility and Variability of Clopidogrel Response

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.