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Exploratory Aspirin Resistance Trial in Healthy Japanese Volunteers (J-ART) Using Platelet Aggregation As a Measure of Thrombogenicity

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The Pharmacogenomics Journal (2007) 7, 395–403 & 2007 Nature Publishing Group All rights reserved 1470-269X/07 $30.00 www.nature.com/tpj ORIGINAL ARTICLE Exploratory aspirin resistance trial in healthy Japanese volunteers (J-ART) using platelet aggregation as a measure of thrombogenicity T Fujiwara1, M Ikeda2, K Esumi3, Aspirin prevents the production of thromboxane A2 (TXA2) by irreversibly 4 5 inhibiting platelet cyclooxygenase, exhibiting antiplatelet actions. This agent TD Fujita , M Kono , has been reported to prevent relapse in patients with ischemic heart disease 6 4 H Tokushige , T Hatoyama , or cerebral infarction via this action mechanism. However, there are T Maeda7, T Asai4, T Ogawa6, individual differences in this action, and aspirin is not effective in some T Katsumata4, S Sasaki8, patients, which is referred to as ‘aspirin resistance’. In this study, we analyzed E Suzuki7, M Suzuki5, F Hino9, laboratory aspirin resistance by platelet aggregation in 110 healthy adult 10 10 Japanese males using 24 single-nucleotide polymorphisms (SNPs) of nine TK Fujita , H Zaima , genes involved in platelet aggregation/hemorrhage. Among SNPs involved M Shimada9, T Sugawara8, in platelet aggregation, aspirin was less effective for 924T homozygote of a 10 3 Y Tsuzuki , Y Hashimoto , TXA2 receptor, 924T4C, and 1018C homozygote of a platelet membrane H Hishigaki1, S Horimoto5, glycoprotein GPIba, 1018C4T, suggesting that 924T and 1018C alleles are 2 4 involved in aspirin resistance. N Miyajima , T Yamamoto , The Pharmacogenomics Journal (2007) 7, 395–403; doi:10.1038/sj.tpj.6500435; K Imagawa1, S Sesoko11 and published online 23 January 2007 Y Fujisawa12 Keywords: J-ART; aspirin; resistance; aggregation; Japanese 1Otsuka Pharmaceutical Co., Ltd., Osaka, Japan; 2Takeda Pharmaceutical Company, Osaka, Japan; 3Astellas Pharma Inc., Tokyo, Japan; 4Dainippon Sumitomo Pharma Co., Ltd., Osaka, Introduction Japan; 5Tanabe Seiyaku Co., Ltd., Osaka, Japan; 6Senju Pharmaceutical Co., Ltd., Osaka, Japan; In 1897, Felix Hoffman of the Bayer company first synthesized acetylsalicylic 7 Sanwa Kagaku Kenkyusho Co., Ltd., Nagoya, acid. Aspirin as a trade name of acetylsalicylic acid became commercially Japan; 8Shionogi & Co., Ltd., Osaka, Japan; 9Takara Bio Inc., Otsu, Japan; 10Hitachi, Ltd., available in 1899. Since then, aspirin has commonly been prescribed as an Kawagoe, Japan; 11Maruyama Hospital, antipyretic analgesic agent. In 1953, the antithrombotic effects of aspirin were Hamamatsu, Japan and 12Osaka University, initially reported.1 In 1967, the antiplatelet actions of aspirin were found.2 In Suita, Japan 1971, Smith and Willis3 and Vane4 independently proposed that the action Correspondence: mechanism of aspirin involves inhibition of cyclooxygenase 1 (COX-1). 5 Dr T Fujiwara, Department of Clinical Research In addition, in 1991, Funk et al. found aspirin-related acetylation and and Development, Otsuka Pharmaceutical Co. inactivation of the active site of COX-1, Ser at position 529. In platelets, aspirin Ltd., 3-2-27, Otedori Chuo-ku, Osaka, 540- inhibits production of a potent platelet-aggregating substance, thromboxane A2 0021, Japan. E-mail: [email protected] (TXA2), via inhibition of COX-1, suppressing platelet aggregation. Based on this pharmacologic action, a large-scale clinical trial demonstrated the preventive effects of aspirin on recurrent ischemic heart disease and cerebral infarction. In meta-analysis by Antithrombotic Trialists’ Collaboration, the incidence of vascular events, including nonfatal myocardial/cerebral infarction and vascular event-related death, in approximately 60 000 patients taking aspirin was 25% lower than that in controls.6 Furthermore, there were individual differences in the antiplatelet effects of aspirin: inhibition of thrombus formation, prolonga- Received 28 November 2005; revised 26 October 2006; accepted 30 October 2006; tion of the bleeding time, inhibition of platelet aggregation ex vivo and inhibition published online 23 January 2007 of thromboxane production in platelets. The entity of ‘aspirin resistance’, which Japanese aspirin-resistance PG trial T Fujiwara et al 396 represents a state in which aspirin is not effective or less imum: 45 years)). Normal health status was determined at effective, was proposed. Eikelboom et al.7 performed 4.5-year the beginning of this study by medical history, physical follow-up of 976 patients undergoing aspirin therapy, and examination and biochemical and hematological screening. reported an association between urinary excretion of a TXA2 In two of the subjects, this study was not completed, and metabolite and cardiovascular events. Gum et al.8 adminis- parameters other than the frequency of alleles were tered aspirin to 326 patients with coronary disease or investigated in 108 subjects. The background factors of the cerebral infarction, and investigated the relationship be- subjects are shown in Table 1. No subject showed any tween platelet aggregation and the development of cardio- abnormal value of body mass index(21.672.4 kg/m2 (mini- vascular events. In an aspirin-resistant group in which mum: 16.5, maximum: 27.2)). The hematological and platelet aggregation was not inhibited, the hazard ratio of biochemical data were within the normal ranges. There cardiovascular events was 4.1 times higher than that in an were no abnormalities in the blood total cholesterol or aspirin-sensitive group. triglyceride levels, which may influence platelet aggregation Quinn et al.9 have indicated that, in approximately 30% and the bleeding time; the mean values were 170728 and of patients with differences in the platelet responsiveness to 89756 mg/dl, respectively. We examined the presence or antiplatelet agents, it is associated with heredity, suggesting absence of a smoking history; 44 subjects had a history, but the importance of genetic polymorphism. Concerning 64 subjects did not. platelet membrane glycoproteins, it has been reported that genetic polymorphisms of GPIa,10 GPIba,11 GPIIIa12,13 and Frequency of alleles GPVI14 influence the efficacy of aspirin or platelet respon- In the 110 subjects, we performed genotyping of 24 single- siveness. Furthermore, Halushka et al.15 reported the associa- nucleotide polymorphisms (SNPs), which are present in tion of platelet aggregation with genetic mutation of COX-1, nine genes, COX-1 (PTGS1), COX-2 (PTGS2), TP (TBXA2R), Papafili et al.16 the association with genetic mutation of GPIa (ITGA2), GPIba (GP1BA), GPIIIa (ITGB3), GPVI (GP6), COX-2, Higuchi et al.17 the association with genetic muta- FXIII (F13A) and PAFAH, which may be related to platelet 18 tion of TXA2 receptors (TP), Stafforini et al. the association responsiveness, and calculated the frequency of alleles with genetic mutation of platelet activating factor acetylhy- (Table 2). In nine of the 24 SNPs, the frequency of minor drolase (PAFAH) and Undas et al.19 the association with alleles exceeded 10%. The 24 SNPs suited the Hardy– genetic mutation of coagulation factor XIII (FXIII). Weinberg equilibrium. The frequency of alleles is shown Thus, many studies have investigated the platelet respon- in Table 2. There were strong linkage disequilibriums siveness to aspirin in Caucasians at the gene level. However, between COX-2 À163C4G and COX-2 10T4G few studies have reported this issue in Japanese patients or (D0 ¼ 1.000, r2 ¼ 1.000), between GPIa 807C4T and GPIa healthy volunteers. In this study, we focused on the 873G4A(D0 ¼ 1.000, r2 ¼ 1.000), between TP 795T4C and arachidonic acid cascade and genes involved in platelet TP 924T4C(D0 ¼ 1.000, r2 ¼ 0.375), between GPVI aggregation, and evaluated the aspirin resistance in Japanese 19871A4G and GPVI 21908A4G(D0 ¼ 0.912, r2 ¼ 0.808), based on the suppressive degree of platelet aggregation before and after aspirin administration. Here, the low suppressive degree of platelet aggregation after aspirin Table 1 Baseline characteristics of study participants administration was defined as aspirin resistance. This study was designed by the Japan Pharmacogenomics Characteristic Mean7s.d. (JPG) Consortium. This organization consists of 11 pharma- ceutical-related companies in Japan. From July 2003 to July Age (years) 26.976.3 2005, these companies collaboratively arranged environ- Height (cm) 17175 ments, and established basic techniques for pharmaco- Body weight (kg) 63.277.8 2 7 genomics (PG) studies in Japan to promote the research BMI (kg/m ) 21.6 2.4 7 and development of agents in Japan. Recently, it has been SBP (mm Hg) 111 9 Heart rate (b.p.m.) 60711 proposed that data on PG should be submitted to the Platelet count ( Â 104/ ml) 21.874.1 authorities concerned with medicinal development in RBC count ( Â 104/ ml) 482733 Japan, the United States and Europe. In the future, PG WBC count ( Â 102/ ml) 56714 studies may lead to individualized medical practices, that is, PT (s) 11.570.55 the essential target of medical practice, ‘a necessary agent at APTT (s) 29.672.1 a required dose is administered to patients requiring it for a History of smoking +: 44, À: 64 persons required period’. History of caffeine drinking +: 12, À: 96 persons Abbreviations: APTT, activated partial thromboplastin time; BMI, body mass index; PT, prothrombin time; RBC, red blood cells; SBP, systolic blood pressure; Results WBC, white blood cells. Serial values are expressed as the mean7s.d. (n ¼ 108). Smoking (+) indicates Patient background current or past smokers, and smoking (À) indicates nonsmokers. Ingestion of a caffeine-containing drink at 750 ml
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  • Related Cardiometabolic and Renal Biomarkers in Human Plasma And

    Related Cardiometabolic and Renal Biomarkers in Human Plasma And

    www.nature.com/scientificreports OPEN Comparative analysis of obesity- related cardiometabolic and renal biomarkers in human plasma and serum Meenu Rohini Rajan1,2,16, Matus Sotak 1,2,16, Fredrik Barrenäs1,2,3, Tong Shen4, Kamil Borkowski4, Nicholas J. Ashton2,5,6,7, Christina Biörserud9, Tomas L. Lindahl10, Sofa Ramström10,11, Michael Schöll2,5,8, Per Lindahl1, Oliver Fiehn 4, John W. Newman 4,12,13, Rosie Perkins 1, Ville Wallenius9, Stephan Lange 1,14 & Emma Börgeson 1,2,15,17* The search for biomarkers associated with obesity-related diseases is ongoing, but it is not clear whether plasma and serum can be used interchangeably in this process. Here we used high-throughput screening to analyze 358 proteins and 76 lipids, selected because of their relevance to obesity- associated diseases, in plasma and serum from age- and sex-matched lean and obese humans. Most of the proteins/lipids had similar concentrations in plasma and serum, but a subset showed signifcant diferences. Notably, a key marker of cardiovascular disease PAI-1 showed a diference in concentration between the obese and lean groups only in plasma. Furthermore, some biomarkers showed poor correlations between plasma and serum, including PCSK9, an important regulator of cholesterol homeostasis. Collectively, our results show that the choice of biofuid may impact study outcome when screening for obesity-related biomarkers and we identify several markers where this will be the case. Obesity-related illness is an increasingly important global health issue that places a tremendous economic burden on society1. Te negative health efects of prolonged obesity are partly fuelled by chronic low-grade infammation, which contributes to cardiometabolic and kidney pathophysiology2–4.