STUDY OF INDIVIDUAL’S PRAKRITI AND GENE POLYMORPHISM CORRELATION OF P2Y12 GENE

Ayurveda is a science of self understanding. It is understood by its own unique nature or constitution i.e. Prakruti. Ayurveda believes that the individual’s constitution (Prakruti) is framed at the time of conception as a genetic code or predominant Panchamahabhautic dosha. Ayurveda classifies human beings into three distinct types: Vata, Pitta and Kapha with multiple subtypes. Rakta is said to be the 4th Dosha, i.e. it has the importance as that of Tridosha. All Dhatus are dependent for their nourishment on Raktadhatu. Chakrapani explains different shades of Raktadhatu according to different Prakriti. So there is close relation between Raktadhatu and Prakriti. Doshas which are responsible for Prakriti remain constant and they do not change until death. Genetic constitution is identical and unique for every person, the same as Prakriti. Every gene performs a specific function. So Prakriti can be correlated with genetics whether there is any particular genetic pattern for the particular Prakriti with the help of a tool like Single Nucleotide Polymorphism. P2Y12, the receptor present on the platelet surface, initiates platelet aggregation. To analyse polymorphism in the P2Y12 gene, in exhibiting platelet aggregative response, in correlation with Prakriti. &nbsp

Gene sequence variations of the platelet P2Y12 receptor are associated with coronary artery disease

<p>Abstract</p> <p>Background</p> <p>The platelet P2Y₁₂receptor plays a key role in platelet activation. The H2 haplotype of the P2Y₁₂receptor gene (<it>P2RY12</it>) has been found to be associated with maximal aggregation response to adenosine diphosphate (ADP) and with increased risk for peripheral arterial disease. No data are available on its association with coronary artery disease (CAD).</p> <p>Methods </p> <p>The H2 haplotype of the <it>P2RY12 </it>was determined in 1378 unrelated patients of both sexes selected according to the presence of significant coronary artery disease (CAD group) or having normal coronary angiogram at cardiac catheterization (CAD-free group). Significant coronary artery disease was angiographically determined, and was defined as a greater than 50% visually estimated luminal diameter stenosis in at least one major epicardial coronary artery.</p> <p>Results</p> <p>In the studied population 71.9% had CAD (n = 991) and 28.1% had normal coronary angiogram (n = 387). H2 haplotype carriers were more frequent in the CAD group (p = 0.03, OR = 1.36, 95%CI = 1.02–1.82). The H2 haplotype was significantly associated with CAD in non-smokers (p = 0.007, OR = 1.83 95%CI = 1.17–2.87), but not in smokers. The association remained significant after adjustment for other covariates (age, triglycerides, HDL, hypertension, diabetes) by multivariate logistic regression (p = 0.004, OR = 2.32 95%CI = 1.30–4.15).</p> <p>Conclusion</p> <p>Gene sequence variations of the P2Y₁₂receptor gene are associated with the presence of significant CAD, particularly in non-smoking individuals.</p

Severe bleeding and absent ADP-induced platelet aggregation associated with inherited combined CalDAG-GEFI and P2Y12 deficiencies

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The Personalization of Clopidogrel Antiplatelet Therapy: The Role of Integrative Pharmacogenetics and Pharmacometabolomics

Dual antiplatelet therapy of aspirin and clopidogrel is pivotal for patients undergoing percutaneous coronary intervention. However, the variable platelets reactivity response to clopidogrel may lead to outcome failure and recurrence of cardiovascular events. Although many genetic and nongenetic factors are known, great portion of clopidogrel variable platelets reactivity remain unexplained which challenges the personalization of clopidogrel therapy. Current methods for clopidogrel personalization include CYP2C19 genotyping, pharmacokinetics, and platelets function testing. However, these methods lack precise prediction of clopidogrel outcome, often leading to insufficient prediction. Pharmacometabolomics which is an approach to identify novel biomarkers of drug response or toxicity in biofluids has been investigated to predict drug response. The advantage of pharmacometabolomics is that it does not only predict the response but also provide extensive information on the metabolic pathways implicated with the response. Integrating pharmacogenetics with pharmacometabolomics can give insight on unknown genetic and nongenetic factors associated with the response.This review aimed to review the literature on factors associated with the variable platelets reactivity response to clopidogrel, as well as appraising current methods for the personalization of clopidogrel therapy. We also aimed to review the literature on using pharmacometabolomics approach to predict drug response, as well as discussing the plausibility of using it to predict clopidogrel outcome

Genetic variation of CYP2C19 affects both pharmacokinetic and pharmacodynamic responses to clopidogrel but not prasugrel in aspirin-treated patients with coronary artery disease

The metabolic pathways leading to the formation of prasugrel and clopidogrel active metabolites differ. We hypothesized that decreased CYP2C19 activity affects the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. Ninety-eight patients with coronary artery disease (CAD) taking either clopidogrel 600 mg loading dose (LD)/75 mg maintenance dose (MD) or prasugrel 60 mg LD/10 mg MD were genotyped for variation in six CYP genes. Based on CYP genotype, patients were segregated into two groups: normal function (extensive) metabolizers (EM) and reduced function metabolizers (RM). Plasma active metabolite concentrations were measured at 30 min, 1, 2, 4, and 6 h post-LD and during the MD period on Day 2, Day 14, and Day 29 at 30 min, 1, 2, and 4 h. Vasodilator-stimulated phosphoprotein (VASP) and VerifyNow (TM) P2Y12 were measured predose, 2, and 24 +/- 4 h post-LD and predose during the MD period on Day 14 +/- 3 and Day 29 +/- 3. For clopidogrel, active metabolite exposure was significantly lower (P = 0.0015) and VASP platelet reactivity index (PRI, %) and VerifyNow (TM) P2Y(12) reaction unit (PRU) values were significantly higher (P < 0.05) in the CYP2C19 RM compared with the EM group. For prasugrel, there was no statistically significant difference in active metabolite exposure or pharmacodynamic response between CYP2C19 EM and RM. Variation in the other five genes demonstrated no statistically significant differences in pharmacokinetic or pharmacodynamic responses. Variation in the gene encoding CYP2C19 in patients with stable CAD contributes to reduced exposure to clopidogrel's active metabolite and a corresponding reduction in P2Y(12) inhibition, but has no significant influence on the response to prasugrel

Investigating the Mechanisms of Hyporesponse to Antiplatelet Approaches

Hyporesponsiveness, or resistance, to antiplatelet therapy may be a major contributor to poorer outcomes among cardiac patients and may be attributed to an array of mechanisms—both modifiable and unmodifiable. Recent evidence has uncovered clinical, cellular, and genetic factors associated with hyporesponsiveness. Patients with severe acute coronary syndromes (ACS), type 2 diabetes, and increased body mass index appear to be the most at risk for hyporesponsiveness. Addressing modifiable mechanisms may offset hyporesponsiveness, while recognizing unmodifiable mechanisms, such as genetic polymorphisms and diseases that affect response to antiplatelet therapy, may help identify patients who are more likely to be hyporesponsive. Hyporesponsive patients might benefit from different dosing strategies or additional antiplatelet therapies. Trials correlating platelet function test results to clinical outcomes are required. Results from these studies could cause a paradigm shift toward individualized antiplatelet therapy, improving predictability of platelet inhibition, and diminishing the likelihood for hyporesponsiveness. Copyright © 2008 Wiley Periodicals, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/58554/1/20360_ftp.pd

Clopidogrel non- responsiveness in patients with coronary heart disease

Summary Background Clopidogrel is an antiplatelet drug, blocking the ADP-pathway of platelet activation. Currently there is no universally accepted definition of clopidogrel non- responsiveness. The difference between pre-treatment and posttreatment ADP- induced platelet aggregation has been used as an estimate of clopidogrel non- responsiveness. The aim of the present study was to define a cut- off point for clopidogrel non- responsiveness in a study population of patients with stable coronary heart disease (CHD), and possibly give an estimation of the prevalence of non- responders in patients with stable CHD. Methods The study population consists of 227 consecutively enrolled patients from the ASCET-study, all treated with ASA, of which 91 were later randomized to clopidogrel. Analysis on venous blood samples were performed using VerifyNow P2Y12 assay, which measures ADP-induced platelet aggregation. We performed descriptive statistics on the outcome. Results The 5% percentile of Platelet Reaction Units (PRU) at baseline was close to 170, and we used this as our cut- off- point for non- responsiveness. The equivalent 95% percentile value in % inhibition was 24%. After one month on clopidogrel treatment, we calculated a prevalence of non- responsiveness to clopidogrel of 35% and 28% for PRU and % inhibition respectively. Conclusions We found a frequency of clopidogrel non- responsiveness (28-35%) that corresponds with current literature (5-44%). As ex vivo platelet function tests not necessarily give an accurate measurement of in vivo platelet function, clinical non- responsiveness needs to be explored in larger prospective studies