| Cerebrovascular diseases is a leading cause of death in China, which characterized with high mortality, morbidity and recurrence. Theexpertsof the Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010) estimated the global and regional burden of first-ever ischemic stroke during 1990-2010among 119 studies (58 from high-income countries and 61 from low-income and middle-income countries). The data shows that the morbidity of ischemic stroke in China (400/100000). And the latest research, the Global Burden of Disease Study 2013 (GBD 2013) have estimated yearly deaths for 188 countries between 1990, and 2013. Stroke is a major cause of death and long-term disability worldwide,among them 70-85% were ischemic stroke. In addition, it induces heavy economic burden to families and governments. To date, it has become the leading cause of death in China. Stroke is deterioratingin China, because the western lifestyle (such as smoking, drinking, exercise decrease), and unhealthy diets (such as high-sugar, high-fat diet). Antiplatelet therapy is proven to be one of the most effective therapies for ischemia stroke, excepting control the risk factors such as diabetes mellitus, hypertension etc.Aspirin also named acetylsalicylic acid, is the cornerstone of antiplatelet therapy in ischemic stroke patients. As a historical agent, aspirin have thousands of year history, the ancient Greeks always use willow bark to antipyretic and analgesic.Dates to 1800, people gets salicylic acid from willow bark. Until 1898, the German chemistFelix Hoffman successfully synthetized acetylsalicylic acid.In addition, aspirin has the capacity of antipyretic, analgesic and anti-inflammatory. Aspirin, approved by the Food and Drug Administration (FDA) in 1980, has been widely used for secondary prevention of ischemic stroke.As well known, aspirin can irreversibly inhibits cyclooxygenase-1 (COX-1) and prevents arachidonic acid (AA) transfer into thromboxane A2 (TXA2), which can induce the activation and aggregation of platelets. COX, as a key enzyme inAA pathway, can convert AA intoTXA2 and prostaglandins. Aspirin has a higher efficiency to COX-1 than COX-2, blocks COX-150 to 100 times powerful than COX-2. COX is a key enzyme in AA pathway, which convert AA intoTXA2 and prostaglandins. Aspirin can irreversibly inhibits COX-1 and prevents the formation of thromboxane A2 (TXA2)to inhibit the activation and aggregation of platelets. Aspirin can also reversibly block COX-2, and the catalytic activity of COX-2 is lower than COX-1. Although treated with aspirin, a proportion of ischemic stroke patients were still insufficient to achieve an anticipated level of platelet inhibition. This phenomenon has been termed as aspirin resistance (AR) or aspirin low responsiveness (ALR). The prevalence of AR varied from 5% to 65%. There are lots of contributing factors to aspirin resistance, such as poor compliance of patients, drug interactions, genetic polymorphisms of genes, and increased platelet activity or turnover. Lots of factors are correlated to aspirin low responsiveness, such as dose,patients’ compliance, age, smoking, and other independent platelet activation pathway. Except for environmental factors, genetic predisposition may also play an important role in aspirin resistance.These differences maybe induce some people more likely to occur aspirin low responsiveness. The polymorphism of genes which associated with platelet function, such as cyclooxygenase-1, cyclooxygenase-2, GPⅡ b/Ⅲa, P1Y1, and P2Y12 were associated aspirin low responsiveness. Pharmacogenomics is the study to explore the role of genetics in drug response. It reveals that single nucleotide polymorphisms (SNPs) or variable gene expression related to drug metabolizing enzymes (DMEs) can affect individuals’ drug response. Pharmacogenomics aims to transfer general therapies from "one fit all" to "personalized medicine", which can help physicians to optimize drug selection, dose, and treatment duration. Uridine diphosphate glucuronosyltransferases enzymes (UGTs)isan important superfamily of phase II DMEs. UGTs can detoxicate and eliminate various endogenous and exogenous compounds via catalyzing the conjugation of glucuromic acid group to a nucleophilic substrate. The UGTs have been classified into two subfamilies in humans, UGT1 and UGT2. Owning 13 unique exon 1 and 4 common downstream exons, UGT1 genes include nine functional genes (UGT1AL UGT1A3-UGT1A10) and four pseudogenes (UGT1A2p, UGT1A11p-UGT1A13p). Among them, UGT1A6 plays a major role in the biotransformation of many drugs, such as aspirin, acetaminophen and P-blockers.SNPs of UGT1A6 generated a wide spectrum activities of UGT1A6 and resulted in modified pharmacokinetic and therapeutic effects of aspirin. Nagar S et.al indicated that SNPs (rs6759892 (S7A), rs2070959 (T181A), and rs1105879 (A184S)) and haplotype UGT1A6*2 (7A+181A+184S) of human UGT1A6 can influence the biochemical and clinical efficacy of drugs. In addition, two studies found that individuals genotyped as UGT1A6*2 (181A+184S) accompanied with a higher glucuronidation rate and a faster pharmacokinetic s of aspirin than wild genotype UGT1A6*1. Nevertheless, other studies reported conflicting results that UGT1A6*2 was associated with lower enzyme activity and impaired metabolism of aspirin, since T181A variants can change the binding site of UGT1A6 enzyme. Thus, genetic polymorphisms in UGT1A6 may contribute to inter-individual different metabolic activities of aspirin, although no unified conclusion has been made.Therefore, we hypothesized that patients with different UGT1A6 genotypes may have different response to aspirin. In this study we aimed to examine the relationships between SNPs of UGT1A6 (rs6759892, rs2070959 and rs1105879) and individual’s aspirin response.Background:UGT1A6 is a major enzyme which catalyze the glucuronidation of aspirin. Genetic polymorphism plays an important role in aspirin resistance. However, few studies concentrated on the correlation between UGT1A6 polymorphisms and inter-individuals’ aspirin response to date. This study was designed to explore the relationship between genetic variations of UGT1A6 and aspirin response in a cohort of Chinese Han population. Materials and Methods:Three SNPs (rs6759892, rs2070959 and rs1105879) of UGT1A6 were genotyped in 323 ischemic stroke patients. Association of genotypes and aspirin response was evaluated by generalized linear model. Indicated with the inhibition rate of platelets, aspirin response, was assessed by thromboelastograph.Results:The general characteristics of the 323 patients,253 (78.3%) were male; the median (IQR) age was 63.0 (55.0-70.0) years; 255 (78.9%) patients with hypertension; 105 (32.5%) with diabetes mellitus; 151(46.7%) were smokers. The distributions of genotypes for the SNPs were in accordance with Hardy-Weinberg equilibrium (P> 0.05). The minor allele frequencies (MAFs) of rs6759892, rs2070959 and rs1105879 were 25.7%,23.1% and 25.7% respectively. The dominant (β= 0.084 ± 0.032, P= 0.010) and additive model (Odds ratio [OR]= 1.062,95% confidence interval [CI] 1.006-1.121, P= 0.030) of rs2070959 were positively related with inhibition rate of platelets. The correlations were also significant in male, dominant model (P= 0.098 ± 0.036, P= 0.006), additive model (OR= 1.074,95% CI 1.011-1.142, P= 0.021). The mutation allele (G) ofrs2070959 was positively related to aspirin response (p= 0.084 ± 0.032, P= 0.010,Pcorrect= 0.029), especially in male(β = 0.098 ± 0.036, P= 0.006, Pcorrect= 0.019). The dominant models of rs6759892, rs1105879were also modestly related to aspirin response (P= 0.015, Pcorrect= 0.046 in both SNPs) in male. Thus the polymorphisms of UGT1A6 showed a positive correlation with aspirin response, especially in males.Conclusions:This study indicated that genetic polymorphism of UGT1A6 may have an effect on individual’s aspirin response, especially in males. These findings can help clinicians to optimize the antiplatelet therapy for ischemic stroke patients. |
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