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Alsulaim AY, Azam F, Sebastian T, Mahdi Hassan F, AbdulAzeez S, Borgio JF, Alzahrani FM. The association between two genetic polymorphisms in ITGB3 and increase risk of venous thromboembolism in cancer patients in Eastern Province of Saudi Arabia. Saudi J Biol Sci 2022; 29:183-189. [PMID: 35002407 PMCID: PMC8716864 DOI: 10.1016/j.sjbs.2021.08.073] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 08/20/2021] [Accepted: 08/22/2021] [Indexed: 12/14/2022] Open
Abstract
Venous thromboembolism (VTE) is one of the major complications in most cancer patients leading to poor prognosis and short survival. Several common clinical risk factors coexist in cancer patients are used as risk predictive biomarkers to help in the management and prevention of VTE. These include cancer site and stage, chemotherapy regimen and elevated biological markers. However, Genetic polymorphisms in genes controlling coagulation and fibrinolysis are significantly associated with VTE if detected, then they might be more sensitive individual predictive biomarkers for VTE risk assessment. This study was conducted to evaluate the association between ITGB3 rs3809865 and rs5918 with VTE risk as well as monitor the effect of VTE on overall survival of these cancer patients. In this retrospective case-control study, 195 cancer patients' formalin-fixed paraffin embedded tissue (FFPE) samples were collected (controls n = 157, case n = 38) using the stored data through Jan 2010 to Sep 2018 from King Fahad Specialist Hospital in Dammam. Samples were genotyped using TaqMan genotyping assay, then logistic regression analysis and Chi-square were used to predict the association between risk factors and VTE. Survival Comparison was tested by the log-rank test. Genetic polymorphisms in ITGB3 (rs3809865 and rs5918) found not to be associated with VTE increasing risk in cancer patients (p>0.05). While the advanced stage was potentially increasing the risk of VTE events (OR 5.1 CI 2.01-12.9p = 0.001). Patients with VTE showed a poor overall survival reflected by the median survival rate of only three years compared to seven years for cancer patients without VTE. This study highlighted the potential influence of VTE on prognosis and survival of cancer patients and raised the importance of exploring risk predictive biomarkers in our population. This will improve the risk prediction biomarkers leading to implementing safe and effective thrombosis prophylaxis strategies.
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Affiliation(s)
- Asma Y. Alsulaim
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Faisal Azam
- Consultant Medical Oncologist, King Fahad specialist Hospital, Dammam, Saudi Arabia
| | - Tunny Sebastian
- Department of Clinical Nutrition, College of Applied Medical Sciences, Imam Abdulrahman bin Faisal University, Dammam, Saudi Arabia
| | - Fathelrahman Mahdi Hassan
- Department of Hematology and Immunohematology, College of Medical Laboratory Science, Sudan University of Science and Technology, Khartoum, Sudan
| | - Sayed AbdulAzeez
- Department of Genetic Research, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - J. Francis Borgio
- Department of Genetic Research, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Faisal M. Alzahrani
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
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Fan Y, Zhu L, Sun X, Lyu W, Xu L, Yin Y, Zhao J, Huang J, Den Y, Jiang Z, Xu S, Mao X, Xu Z. Exploring the tissue tropism of pseudorabies virus based on miRNA level analysis. BMC Microbiol 2019; 19:125. [PMID: 31185898 PMCID: PMC6558711 DOI: 10.1186/s12866-019-1497-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Accepted: 05/29/2019] [Indexed: 11/26/2022] Open
Abstract
Background Pseudorabies virus (PRV, or suid herpesvirus, SuHV-1), a member of the herpesvirus family, has an extremely broad host range and threatens the pig industry in China. PRV can evade host innate immunity and infect the kidney, lung, brain and other tissues. At the same time, many studies have reported that microRNA (miRNA) can affect the replication of viruses by regulating gene expression levels. Results Here, to identify changes in miRNA expression and post-transcriptional regulation associated with PRV infection in the lung, spleen, and olfactory bulb, we sequenced small RNAs in tissues of rats infected or uninfected with PRV strain XJ (PRV-XJ). Sixty-one, 199 and 29 differentially-expressed miRNAs were identified in the lung, spleen, and olfactory bulb, respectively, of infected compared with uninfected rats. Among the miRNAs differentially-expressed in PRV-infected rats, 36, 171, and 15 miRNAs showed tissue-selective expression in the olfactory bulb, lung and spleen, respectively. All differentially-expressed miRNAs were analyzed for their GO functional annotations and KEGG pathway associations . Conclusions In PRV-XJ-infected rats, miRNAs were differentially expressed in the lung, spleen and olfactory bulb. These miRNAs were involved in regulating various pathways of the nervous, respiratory and immune systems, and may affect the tissue tropism of the virus and play pivotal roles in viral infection and proliferation.
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Affiliation(s)
- Yi Fan
- Present Address: College of Veterinary Medicine, Sichuan Agricultural University, Huimin Road 211, weenjiang district, Chengdu, Sichuan, China.,Key Laboratory of Animal Diseases and Human Health of Sichuan Province, Chengdu, Sichuan, China
| | - Ling Zhu
- Present Address: College of Veterinary Medicine, Sichuan Agricultural University, Huimin Road 211, weenjiang district, Chengdu, Sichuan, China.,Key Laboratory of Animal Diseases and Human Health of Sichuan Province, Chengdu, Sichuan, China
| | - Xiangang Sun
- Present Address: College of Veterinary Medicine, Sichuan Agricultural University, Huimin Road 211, weenjiang district, Chengdu, Sichuan, China
| | - Wenting Lyu
- Present Address: College of Veterinary Medicine, Sichuan Agricultural University, Huimin Road 211, weenjiang district, Chengdu, Sichuan, China.,Key Laboratory of Animal Diseases and Human Health of Sichuan Province, Chengdu, Sichuan, China
| | - Lei Xu
- Present Address: College of Veterinary Medicine, Sichuan Agricultural University, Huimin Road 211, weenjiang district, Chengdu, Sichuan, China.,Key Laboratory of Animal Diseases and Human Health of Sichuan Province, Chengdu, Sichuan, China
| | - Yue Yin
- Present Address: College of Veterinary Medicine, Sichuan Agricultural University, Huimin Road 211, weenjiang district, Chengdu, Sichuan, China.,Key Laboratory of Animal Diseases and Human Health of Sichuan Province, Chengdu, Sichuan, China
| | - Jun Zhao
- Present Address: College of Veterinary Medicine, Sichuan Agricultural University, Huimin Road 211, weenjiang district, Chengdu, Sichuan, China.,Key Laboratory of Animal Diseases and Human Health of Sichuan Province, Chengdu, Sichuan, China
| | - Jianbo Huang
- Present Address: College of Veterinary Medicine, Sichuan Agricultural University, Huimin Road 211, weenjiang district, Chengdu, Sichuan, China.,Key Laboratory of Animal Diseases and Human Health of Sichuan Province, Chengdu, Sichuan, China
| | - Yichao Den
- Present Address: College of Veterinary Medicine, Sichuan Agricultural University, Huimin Road 211, weenjiang district, Chengdu, Sichuan, China.,Key Laboratory of Animal Diseases and Human Health of Sichuan Province, Chengdu, Sichuan, China
| | - Zhiyi Jiang
- Present Address: College of Veterinary Medicine, Sichuan Agricultural University, Huimin Road 211, weenjiang district, Chengdu, Sichuan, China.,Key Laboratory of Animal Diseases and Human Health of Sichuan Province, Chengdu, Sichuan, China
| | - Shiyao Xu
- Present Address: College of Veterinary Medicine, Sichuan Agricultural University, Huimin Road 211, weenjiang district, Chengdu, Sichuan, China.,Key Laboratory of Animal Diseases and Human Health of Sichuan Province, Chengdu, Sichuan, China
| | - Xiyu Mao
- Present Address: College of Veterinary Medicine, Sichuan Agricultural University, Huimin Road 211, weenjiang district, Chengdu, Sichuan, China.,Key Laboratory of Animal Diseases and Human Health of Sichuan Province, Chengdu, Sichuan, China
| | - Zhiwen Xu
- Present Address: College of Veterinary Medicine, Sichuan Agricultural University, Huimin Road 211, weenjiang district, Chengdu, Sichuan, China. .,Key Laboratory of Animal Diseases and Human Health of Sichuan Province, Chengdu, Sichuan, China.
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Zhou D, Thinn AMM, Zhao Y, Wang Z, Zhu J. Structure of an extended β 3 integrin. Blood 2018; 132:962-972. [PMID: 30018079 PMCID: PMC6117741 DOI: 10.1182/blood-2018-01-829572] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2018] [Accepted: 07/10/2018] [Indexed: 12/23/2022] Open
Abstract
Cells use adhesion receptor integrins to communicate with their surroundings. Integrin activation and cellular signaling are coupled with change from bent to extended conformation. β3 integrins, including αIIbβ3, which is essential for the function of platelets in hemostasis and thrombosis, and αVβ3, which plays multiple roles in diverse cell types, have been prototypes in understanding integrin structure and function. Despite extensive structural studies, a high-resolution integrin structure in an extended conformation remains to be determined. The human β3 Leu33Pro polymorphism, located at the PSI domain, defines human platelet-specific alloantigens 1a and 1b (HPA-1a/b), immune response to which is a cause of posttransfusion purpura and fetal/neonatal alloimmune thrombocytopenia. Leu33Pro substitution has also been suggested to be a risk factor for thrombosis. Here we report the crystal structure of the β3 headpiece in either Leu33 or Pro33 form, both of which reveal intermediate and fully extended conformations coexisting in 1 crystal. These were used to build high-resolution structures of full-length β3 integrin in the intermediate and fully extended states, agreeing well with the corresponding conformations observed by electron microscopy. Our structures reveal how β3 integrin becomes extended at its β-knee region and how the flexibility of β-leg domains is determined. In addition, our structures reveal conformational changes of the PSI and I-EGF1 domains upon β3 extension, which may affect the binding of conformation-dependent anti-HPA-1a alloantibodies. Our structural and functional data show that Leu33Pro substitution does not directly alter the conformation or ligand binding of β3 integrin.
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Affiliation(s)
- Dongwen Zhou
- Blood Research Institute, BloodCenter of Wisconsin, part of Versiti, Milwaukee, WI
| | - Aye Myat Myat Thinn
- Blood Research Institute, BloodCenter of Wisconsin, part of Versiti, Milwaukee, WI
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI; and
| | - Yan Zhao
- Blood Research Institute, BloodCenter of Wisconsin, part of Versiti, Milwaukee, WI
- Department of Physiology, School of Basic Medical Science, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhengli Wang
- Blood Research Institute, BloodCenter of Wisconsin, part of Versiti, Milwaukee, WI
| | - Jieqing Zhu
- Blood Research Institute, BloodCenter of Wisconsin, part of Versiti, Milwaukee, WI
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI; and
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Fawzy MS, Toraih EA, Aly NM, Fakhr-Eldeen A, Badran DI, Hussein MH. Atherosclerotic and thrombotic genetic and environmental determinants in Egyptian coronary artery disease patients: a pilot study. BMC Cardiovasc Disord 2017; 17:26. [PMID: 28086795 PMCID: PMC5237236 DOI: 10.1186/s12872-016-0456-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2016] [Accepted: 12/22/2016] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND Coronary artery disease (CAD) is the leading cause of morbidity and mortality worldwide. Multiple genetic variants in combination with various environmental risk factors have been implicated. This study aimed to investigate the association of twelve thrombotic and atherosclerotic gene variants in combination with other environmental risk factors with CAD risk in a preliminary sample of Egyptian CAD patients. METHODS Twenty three consecutive CAD patients undergoing diagnostic coronary angiography and 34 unrelated controls, have been enrolled in the study. Genotyping was based on polymerase chain reaction and reverse multiplex hybridization. Five genetic association models were tested. Data distribution and variance homogeneity have been checked by Shapiro-Wilk test and Levene test, respectively; then the appropriate comparison test was applied. Spearman's rank correlation coefficient was used for correlation analysis and logistic regression has been performed to adjust for significant risk factors. Clustering the study participants according to gene-gene and gene-environment interaction has been done by Detrended Correspondence Analysis (DCA). RESULTS The univariate analysis indicated that the five variants; rs1800595 (FVR2; factor 5), rs1801133 (MTHFR; 5,10-methylenetetrahydrofolate reductase), rs5918 (HPA-1; human platelet antigen 1), rs1799752 (ACE; angiotensin-converting enzyme), and rs7412 and rs429358 (ApoE; apolipoprotein E) were significantly associated with CAD susceptibility under different genetic models. Multivariate analysis revealed clustering of the study population into three patient groups (P) and one control group. FVR2 was the most variant associated with CAD patients, combined with the factor V Leiden (FVL) variant in P1 cluster and with both ACE and MTHFR 667C > T in P2. Whereas, P3 was mostly affected by both MTHFR 667C > T and FXIII (factor 13) V89L mutations. When combined with traditional risk factors, P1 was mostly affected by dyslipidemia, smoking and hypertension, while P2 was mostly affected by their fasting blood sugar levels and ApoE variant. CONCLUSIONS Taken together, these preliminary results could have predictive value to be applied in refining a risk profile for our CAD patients, in order to implement early preventive interventions including specific antithrombotic therapy. Further large scale and follow-up studies are highly recommended to confirm the study findings.
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Affiliation(s)
- Manal S Fawzy
- Department of Medical Biochemistry, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
| | - Eman A Toraih
- Department of Histology and Cell Biology (Genetics Unit), Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
| | - Nagwa M Aly
- Department of Medical Biochemistry, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Abeer Fakhr-Eldeen
- Clinical Pathology Department, Faculty of Medicine, Sohag University, Sohag, Egypt
| | - Dahlia I Badran
- Department of Medical Biochemistry, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
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Vijayan KV, Bray PF. Molecular Mechanisms of Prothrombotic Risk Due to Genetic Variations in Platelet Genes: Enhanced Outside-In Signaling Through the Pro33 Variant of Integrin β3. Exp Biol Med (Maywood) 2016; 231:505-13. [PMID: 16636298 DOI: 10.1177/153537020623100504] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
In recent years inherited variations in platelet proteins have emerged as potential risk factors that could predispose individuals to arterial thrombosis. Although many studies have examined the association of platelet gene polymorphisms with particular disease states, the underlying mechanisms by which most of these polymorphisms contribute to the pathophysiology of thrombosis have remained largely unexplored. This review will focus on the cellular and molecular features by which these genetic changes affect platelet physiology. Although many genes have been investigated in this regard, only the genes encoding integrins β3 and α2, and the platelet Fc receptor, FcγRIIA, have been studied in any depth. In some cases (such as integrin α2), evidence supports a quantitative trait locus. For other genes, nonsynonymous nucleotide substitutions lead to structural and functional consequences. A large portion of this review will focus on the widely studied Leu33Pro (PIA) polymorphism of integrin β3, and will consider the potential mechanisms by which the Pro33 polymorphism could induce a prothrombotic risk. A detailed understanding of how polymorphisms modulate platelet physiology will be important for understanding individual differences in response to antiplatelet therapy.
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Affiliation(s)
- K Vinod Vijayan
- Department of Medicine, Baylor College of Medicine, One Baylor Plaza, BCM 286, N1319, Houston, TX 77030, USA
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Identification of ITGA2B and ITGB3 Single-Nucleotide Polymorphisms and Their Influences on the Platelet Function. BIOMED RESEARCH INTERNATIONAL 2016; 2016:5675084. [PMID: 27965976 PMCID: PMC5124636 DOI: 10.1155/2016/5675084] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Accepted: 04/18/2016] [Indexed: 12/20/2022]
Abstract
The aim of the study was to investigate ITGA2B and ITGB3 genetic polymorphisms and to evaluate the variability in the platelet function in healthy Chinese subjects. The genetic sequence of the entire coding region of the ITGA2B and ITGB3 genes was investigated. Adenosine diphosphate-induced platelet aggregation, glycoprotein IIb/IIIa content, bleeding time, and coagulation indexes were detected. Thirteen variants in the ITGA2B locus and 29 variants in the ITGB3 locus were identified in the Chinese population. The rs1009312 and rs2015049 were associated with the mean platelet volume. The rs70940817 was significantly correlated with the prothrombin time. The rs70940817 and rs112188890 were related with the activated partial thromboplastin time, and ITGB3 rs4642 was correlated with the thrombin time and fibrinogen. The minor alleles of rs56197296 and rs5919 were associated with decreased ADP-induced platelet aggregation, and rs55827077 was related with decreased GPIIb/IIIa per platelet. The rs1009312, rs2015049, rs3760364, rs567581451, rs7208170, and rs117052258 were related with bleeding time. Further studies are needed to explore the clinical importance of ITGA2B and ITGB3 SNPs in the platelet function.
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Floyd CN, Ferro A, Warner TD. Expression of the PlA2 allele of glycoprotein IIIa and its impact on platelet function. JRSM Cardiovasc Dis 2016; 4:2048004015610252. [PMID: 26858830 PMCID: PMC4734162 DOI: 10.1177/2048004015610252] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 08/04/2015] [Accepted: 08/06/2015] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND The platelet fibrinogen receptor represents the final common pathway of platelet activation, and is formed from two glycoprotein (GP) subunits (GPIIb/IIIa). Carriage of the mutant PlA2 allele of GPIIIa has been shown to confer an increased risk of cardiovascular events, but published studies have disagreed as to the mechanism for this association. OBJECTIVES To assess whether carriage of the PlA2 allele conforms to Mendelian patterns of expression and to identify whether carriage of the mutant allele modulates platelet function. METHODS Expression of the PlA2 allele was assessed in both healthy subjects (n = 25) and patients with known coronary artery disease (n = 90) through the development and validation of a liquid chromatography, tandem mass spectrometry (LC-MS/MS) assay. Platelet function was assessed in the patient cohort in response to multiple agonists, and these data were analysed in the context of the proteomic data. RESULTS Expression of the wild-type PlA1 allele and mutant PlA2 alleles was readily quantifiable and conformed to Mendelian patterns in both healthy and patient cohorts. Patients who were homozygous for the mutant PlA2 allele had an increased aggregatory response to adenosine diphosphate, collagen, adrenaline, ristocetin, thrombin receptor-activating peptide 6 and U46619, when assessed using agonist-concentration response curves. CONCLUSIONS These findings support the hypothesis that carriage of the mutant PlA2 allele mediates an increased risk of cardiovascular events through the modulation of platelet reactivity.
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Affiliation(s)
- Christopher N Floyd
- Department of Clinical Pharmacology, Cardiovascular Division, British Heart Foundation Centre of Research Excellence, King's College London, London, UK
| | - Albert Ferro
- Department of Clinical Pharmacology, Cardiovascular Division, British Heart Foundation Centre of Research Excellence, King's College London, London, UK
| | - Timothy D Warner
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, London, UK
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Osadnik T, Strzelczyk J, Bujak K, Reguła R, Wasilewski J, Fronczek M, Kurek A, Gawlita M, Gonera M, Gierlotka M, Lekston A, Hawranek M, Myrda K, Wiczkowski A, Ostrowska Z, Gąsior M, Poloński L. Functional polymorphism rs710218 in the gene coding GLUT1 protein is associated with in-stent restenosis. Biomark Med 2015; 9:743-50. [DOI: 10.2217/bmm.15.36] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Aim: To analyze the association between in-stent restenosis (ISR) and polymorphisms in genes coding IGF-1, IGFBP3, ITGB3 and GLUT1, which play an important role in the smooth muscle cell proliferation and extracellular matrix synthesis – the main components of neointima. Materials & methods: We analyzed 265 patients who underwent bare metal stent implantation. Results: The differences in the occurrence of ISR between genotypes of the analyzed polymorphisms in the IGF-1, IGFBP3 and ITGB3 were not statistically significant. The T/T genotype of the rs710218 polymorphism in the GLUT1 (SLC2A1) gene was more common in the ISR group compared with non-ISR patients (81.1 vs 64.8%; p = 0.02). In a multivariable model the A/A and A/T genotype remained correlated with lower occurrence of ISR (odds ratio: 0.45; 95% CI: 0.21–0.97; p = 0.03). Conclusion: The rs710218 polymorphism in the gene coding GLUT1 protein is a novel risk factor for ISR.
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Affiliation(s)
- Tadeusz Osadnik
- Medical University of Silesia, School of Medicine with the Division of Dentistry, 3rd Department of Cardiology, Silesian Centre for Heart Diseases, Marii Skłodowskiej Curie Street 9, 41-800 Zabrze, Poland
| | - Joanna Strzelczyk
- Medical University of Silesia, School of Medicine with the Division of Dentistry, Department of Medical and Molecular Biology, Jordana Street 19, 41-808 Zabrze, Poland
| | - Kamil Bujak
- Medical University of Silesia, School of Medicine with the Division of Dentistry, 3rd Department of Cardiology, Silesian Centre for Heart Diseases, Marii Skłodowskiej Curie Street 9, 41-800 Zabrze, Poland
| | - Rafał Reguła
- Medical University of Silesia, School of Medicine with the Division of Dentistry, 3rd Department of Cardiology, Silesian Centre for Heart Diseases, Marii Skłodowskiej Curie Street 9, 41-800 Zabrze, Poland
| | - Jarosław Wasilewski
- Medical University of Silesia, School of Medicine with the Division of Dentistry, 3rd Department of Cardiology, Silesian Centre for Heart Diseases, Marii Skłodowskiej Curie Street 9, 41-800 Zabrze, Poland
| | - Martyna Fronczek
- Medical University of Silesia, School of Medicine with the Division of Dentistry, Department of Medical and Molecular Biology, Jordana Street 19, 41-808 Zabrze, Poland
| | - Anna Kurek
- Medical University of Silesia, School of Medicine with the Division of Dentistry, 3rd Department of Cardiology, Silesian Centre for Heart Diseases, Marii Skłodowskiej Curie Street 9, 41-800 Zabrze, Poland
| | - Marcin Gawlita
- Medical University of Silesia, School of Medicine with the Division of Dentistry, 3rd Department of Cardiology, Silesian Centre for Heart Diseases, Marii Skłodowskiej Curie Street 9, 41-800 Zabrze, Poland
| | - Małgorzata Gonera
- Medical University of Silesia, School of Medicine with the Division of Dentistry, 3rd Department of Cardiology, Silesian Centre for Heart Diseases, Marii Skłodowskiej Curie Street 9, 41-800 Zabrze, Poland
| | - Marek Gierlotka
- Medical University of Silesia, School of Medicine with the Division of Dentistry, 3rd Department of Cardiology, Silesian Centre for Heart Diseases, Marii Skłodowskiej Curie Street 9, 41-800 Zabrze, Poland
| | - Andrzej Lekston
- Medical University of Silesia, School of Medicine with the Division of Dentistry, 3rd Department of Cardiology, Silesian Centre for Heart Diseases, Marii Skłodowskiej Curie Street 9, 41-800 Zabrze, Poland
| | - Michał Hawranek
- Medical University of Silesia, School of Medicine with the Division of Dentistry, 3rd Department of Cardiology, Silesian Centre for Heart Diseases, Marii Skłodowskiej Curie Street 9, 41-800 Zabrze, Poland
| | - Krzysztof Myrda
- Medical University of Silesia, School of Medicine with the Division of Dentistry, 3rd Department of Cardiology, Silesian Centre for Heart Diseases, Marii Skłodowskiej Curie Street 9, 41-800 Zabrze, Poland
| | - Andrzej Wiczkowski
- Medical University of Silesia, School of Medicine with the Division of Dentistry, Department of Medical and Molecular Biology, Jordana Street 19, 41-808 Zabrze, Poland
| | - Zofia Ostrowska
- Medical University of Silesia, School of Medicine with the Division of Dentistry, Department of Medical and Molecular Biology, Jordana Street 19, 41-808 Zabrze, Poland
| | - Mariusz Gąsior
- Medical University of Silesia, School of Medicine with the Division of Dentistry, 3rd Department of Cardiology, Silesian Centre for Heart Diseases, Marii Skłodowskiej Curie Street 9, 41-800 Zabrze, Poland
| | - Lech Poloński
- Medical University of Silesia, School of Medicine with the Division of Dentistry, 3rd Department of Cardiology, Silesian Centre for Heart Diseases, Marii Skłodowskiej Curie Street 9, 41-800 Zabrze, Poland
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Floyd CN, Ferro A. The PlA1/A2 polymorphism of glycoprotein IIIa in relation to efficacy of antiplatelet drugs: a systematic review and meta-analysis. Br J Clin Pharmacol 2014; 77:446-57. [PMID: 23834376 DOI: 10.1111/bcp.12204] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2013] [Accepted: 06/24/2013] [Indexed: 11/29/2022] Open
Abstract
AIM The PlA1/A2 polymorphism of glycoprotein IIIa (GPIIIa) has been associated with both antiplatelet drug resistance and increased cardiovascular events. The aim of this study was to conduct the first meta-analysis investigating the association between carriage of the PlA2 allele and resistance to currently licensed antiplatelet drugs. METHODS Electronic databases (MEDLINE and EMBASE) were searched for all articles evaluating genetic polymorphisms of GPIIIa. For studies where antiplatelet resistance was measured using validated techniques, pooled odds ratios (ORs) were calculated using fixed effects and random effects models. RESULTS Sixteen studies were eligible for statistical analysis and included 1650 PlA1 homozygous subjects and 668 carriers of the PlA2 allele. For carriers of the PlA2 allele, OR 0.924 (n = 2318; 95% CI 0.743, 1.151; P = 0.481) was observed for resistance to any antiplatelet drug, OR 0.862 (n = 2085; 95% CI 0.685, 1.086; P = 0.208) for resistance to aspirin and OR 1.429 (n = 233; 95% CI 0.791, 2.582; P = 0.237) for resistance to clopidogrel. In the aspirin cohort, sub-group analysis revealed no statistical association in either healthy subjects or those with cardiovascular disease. PlA2 carriage was marginally associated with aspirin sensitivity using the fixed effects model when identified by the PFA-100 assay (n = 1151; OR 0.743, 95% CI 0.558, 0.989; P = 0.041) but with significant heterogeneity (I(2) = 55%; P = 0.002). Significance was lost with analysis using a random effects model. CONCLUSIONS The totality of published data does not support an association between carriage of the PlA2 allele and antiplatelet drug resistance. Significant heterogeneity indicates the need for larger studies using validated and standardized assays.
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Affiliation(s)
- Christopher N Floyd
- Department of Clinical Pharmacology, Cardiovascular Division, British Heart Foundation Centre of Research Excellence, King's College London, London, UK
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Floyd CN, Ellis BH, Ferro A. The PlA1/A2 polymorphism of glycoprotein IIIa as a risk factor for stroke: a systematic review and meta-analysis. PLoS One 2014; 9:e100239. [PMID: 24988537 PMCID: PMC4079245 DOI: 10.1371/journal.pone.0100239] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2014] [Accepted: 05/19/2014] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND The PlA1/A2 polymorphism of glycoprotein IIIa (GPIIIa) has been reported to be associated with risk of stroke in some studies, although other studies suggest no such association. This meta-analysis and systematic review was conducted to investigate the hypothesis that carriage of the PlA2 allele is a risk factor for stroke. METHODS Electronic databases (MEDLINE and EMBASE) were searched for all articles evaluating carriage of the PlA2 allele and the incidence of stroke. Pooled odds ratios (ORs) were calculated using fixed-effect and random-effect models. FINDINGS A total of 35 articles were eligible for inclusion, of which 25 studies were suitable for statistical analysis. For carriage of the PlA2 allele, OR 1.12 (n = 11,873; 95% CI = 1.03-1.22; p = 0.011) was observed for the incidence of stroke in adults, with subgroup analyses identifying the association driven by stroke of an ischaemic (n = 10,494; OR = 1.15, 95% CI = 1.05-1.27; p = 0.003) but not haemorrhagic aetiology (n = 2,470; OR = 0.90, 95% CI = 0.71-1.14; p = 0.398). This association with ischaemic stroke was strongest in individuals homozygous for the PlA2 allele compared to those homozygous for wild-type PlA1 (n = 5,906; OR = 1.74, 95% CI = 1.34-2.26; p<0.001). Subgroup analysis of ischaemic stroke subtypes revealed an increased association with stroke of cardioembolic (n = 1,271; OR 1.56, 95% CI 1.14-2.12; p = 0.005) and large vessel (n = 1,394; OR = 1.76, 95% CI 1.34-2.31; p<0.001) aetiology, but not those of small vessel origin (n = 1,356; OR = 0.99, 95% CI 0.74-1.33; p = 0.950). Egger's regression test suggested a low probability of publication bias for all analyses (p>0.05). CONCLUSIONS The totality of published data supports the hypothesis that carriage of the PlA2 polymorphism of GPIIIa is a risk factor for ischaemic strokes, and specifically those of cardioembolic and large vessel origin.
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Affiliation(s)
- Christopher N. Floyd
- Department of Clinical Pharmacology, Cardiovascular Division, British Heart Foundation Centre of Research Excellence, King's College London, London, United Kingdom
| | - Benjamin H. Ellis
- Department of Clinical Pharmacology, Cardiovascular Division, British Heart Foundation Centre of Research Excellence, King's College London, London, United Kingdom
| | - Albert Ferro
- Department of Clinical Pharmacology, Cardiovascular Division, British Heart Foundation Centre of Research Excellence, King's College London, London, United Kingdom
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11
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Joshi P, Middleton J, Jeon YJ, Garofalo M. MicroRNAs in lung cancer. World J Methodol 2014; 4:59-72. [PMID: 25332906 PMCID: PMC4202482 DOI: 10.5662/wjm.v4.i2.59] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Revised: 01/23/2014] [Accepted: 03/17/2014] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs have become recognized as key players in the development of cancer. They are a family of small non-coding RNAs that can negatively regulate the expression of cancer-related genes by sequence-selective targeting of mRNAs, leading to either mRNA degradation or translational repression. Lung cancer is the leading cause of cancer-related death worldwide with a substantially low survival rate. MicroRNAs have been confirmed to play roles in lung cancer development, epithelial-mesenchymal transition and response to therapy. They are also being studied for their future use as diagnostic and prognostic biomarkers and as potential therapeutic targets. In this review we focus on the role of dysregulated microRNA expression in lung tumorigenesis. We also discuss the role of microRNAs in therapeutic resistance and as biomarkers. We further look into the progress made and challenges remaining in using microRNAs for therapy in lung cancer.
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12
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Zhao B, Han H, Chen J, Zhang Z, Li S, Fang F, Zheng Q, Ma Y, Zhang J, Wu N, Yang Y. MicroRNA let-7c inhibits migration and invasion of human non-small cell lung cancer by targeting ITGB3 and MAP4K3. Cancer Lett 2013; 342:43-51. [PMID: 23981581 DOI: 10.1016/j.canlet.2013.08.030] [Citation(s) in RCA: 146] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2013] [Revised: 07/09/2013] [Accepted: 08/18/2013] [Indexed: 01/10/2023]
Abstract
MicroRNAs play an important regulatory role in carcinogenesis and cancer metastasis. Different members of let-7 family have been reported to be decreased in human lung tumors. However, the effect of specific let-7 member on metastasis of NSCLC remains undefined. Our current study detected the expression of let-7 members in 94 cases of NSCLC and a significant association was noticed between low levels of let-7c expression and metastasis, venous invasion, advanced TNM stages and poor survival of NSCLC patients. Consistently, ectopic expression of let-7c in relatively highly metastatic cells remarkably suppressed their migration and invasion. Inhibition of let-7c in cells with relatively low metastatic potential promoted their motility and invasion. We then analyzed the potential targets of let-7c and found that ITGB3 and MAP4K3 were directly repressed by let-7c. Upon restoring the expression of ITGB3 and MAP4K3, the effects of let-7c on tumor metastasis were partially reversed, and more importantly, the expression levels of ITGB3 and MAP4K3 were inversely correlated with let-7c in 64 NSCLC tissues. Collectively, our results suggest that let-7c, by degrading ITGB3 and MAP4K3, prevents NSCLC metastasis.
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MESH Headings
- 3' Untranslated Regions
- Adenocarcinoma/genetics
- Adenocarcinoma/metabolism
- Adenocarcinoma/mortality
- Adenocarcinoma/secondary
- Base Sequence
- Binding Sites
- Carcinoma, Non-Small-Cell Lung/genetics
- Carcinoma, Non-Small-Cell Lung/metabolism
- Carcinoma, Non-Small-Cell Lung/mortality
- Carcinoma, Non-Small-Cell Lung/secondary
- Carcinoma, Squamous Cell/genetics
- Carcinoma, Squamous Cell/metabolism
- Carcinoma, Squamous Cell/mortality
- Carcinoma, Squamous Cell/secondary
- Cell Line, Tumor
- Cell Movement
- Disease-Free Survival
- Female
- Gene Expression
- Gene Expression Regulation, Neoplastic
- Humans
- Integrin beta3/genetics
- Integrin beta3/metabolism
- Kaplan-Meier Estimate
- Lung Neoplasms/genetics
- Lung Neoplasms/metabolism
- Lung Neoplasms/mortality
- Lung Neoplasms/pathology
- Male
- MicroRNAs/genetics
- Middle Aged
- Neoplasm Invasiveness
- Protein Serine-Threonine Kinases/genetics
- Protein Serine-Threonine Kinases/metabolism
- RNA Interference
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
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Affiliation(s)
- Bingtian Zhao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Surgery II, Peking University Cancer Hospital and Institute, Beijing 100142, People's Republic of China
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13
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Abstract
From the initial description of platelets in 1882, their propensity to aggregate and to contribute to thrombosis was apparent. Indeed, excessive platelet aggregation is associated with myocardial infarction and other thrombotic diseases whereas Glanzmann thrombasthenia, in which platelet aggregation is reduced, is a bleeding syndrome. Over the last half of the 20th century, many investigators have provided insights into the cellular and molecular basis for platelet aggregation. The major membrane protein on platelets, integrin αIIbβ3, mediates this response by rapidly transiting from its resting to an activated state in which it serves as a receptor for ligands that can bridge platelets together. Monoclonal antibodies, natural products, and small peptides were all shown to inhibit αIIbβ3 dependent platelet aggregation, and these inhibitors became the forerunners of antagonists that proceeded through preclinical testing and into large patient trials to treat acute coronary syndromes, particularly in the context of percutaneous coronary interventions. Three such αIIbβ3 antagonists, abciximab, eptifibatide, and tirofiban, received Food and Drug Administration approval. Over the past 15 years, millions of patients have been treated with these αIIbβ3 antagonists and many lives have been saved by their administration. With the side effect of increased bleeding and the development of new antithrombotic drugs, the use of αIIbβ3 antagonists is waning. Nevertheless, they are still widely used for the prevention of periprocedural thrombosis during percutaneous coronary interventions. This review focuses on the biology of αIIbβ3, the development of its antagonists, and some of the triumphs and shortcomings of αIIbβ3 antagonism.
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Affiliation(s)
- Kamila Bledzka
- Department of Molecular Cardiology, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
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14
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Williams MS. Platelets and depression in cardiovascular disease: A brief review of the current literature. World J Psychiatry 2012; 2:114-23. [PMID: 24175177 PMCID: PMC3782186 DOI: 10.5498/wjp.v2.i6.114] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2011] [Revised: 09/19/2012] [Accepted: 11/17/2012] [Indexed: 02/05/2023] Open
Abstract
Major depression is an independent risk factor for cardiovascular mortality and morbidity. The exact mechanisms linking depression and increased cardiovascular risk remain poorly understood. Several mechanisms have been proposed including increased platelet reactivity. This review focuses on the current literature that examines the platelet hypothesis of depression. To date studies show increased serotonin response, increased platelet serotonin receptor density, decreased serotonin transporter binding, and decreased platelet serotonin levels in individuals with depression. However other studies have shown no change in serotonin uptake. In addition to platelet serotonin specific pathways, other platelet pathways that have shown significant changes in depressed individuals include blunting of the platelet adenosine response, increased platelet thrombin response, increased glycoprotein Ib expression, increased P-selectin, β thromboglobulin, and platelet factor four, as well as decreased platelet brain derived neurotrophic factor. However there are other studies that show conflicting evidence of increased platelet activation as measured by integrin receptor α2bβ3. Other conflicting data include α adrenergic density and platelet response to augmented serotonin. The direction of future research in platelet functional changes in depression and coronary artery disease should continue to focus on serotonin specific pathways with emphasis on potential mechanisms of specific pathway changes.
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Affiliation(s)
- Marlene S Williams
- Marlene S Williams, Division of Cardiology, Johns Hopkins Bayview Medical Center, The Johns Hopkins University, Baltimore, MD 21224, United States
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15
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Abstract
PURPOSE OF REVIEW This review summarizes our current knowledge of common gene variants (polymorphisms) that have small individual effects on platelet function in humans, but can cumulatively lead to hyperreactive platelets and increase risk for negative outcomes in thrombotic disorders. RECENT FINDINGS Candidate gene association and genome-wide association studies (GWAS) have identified loci that include single nucleotide polymorphisms, which exert a cumulative effect on platelet function by modifying basic platelet parameters, such as mean platelet volume (MPV) or platelet count, by altering the expression or activity of key platelet receptors, or by influencing downstream effector pathways utilized by these receptors. SUMMARY Variation in MPV between normal individuals is responsible for roughly a two-fold range in platelet protein content, including key surface receptors and reactive granule constituents, the association of ADRA2, GP1BA, GP6, ITGA2 and P2Y12 variants with platelet reactivity, initially identified by candidate gene analyses, has now been validated by genome-wide approaches in much larger individual cohorts, and GWAS have identified novel gene variants, most notably PEAR1, that participate in variation in platelet reactivity among normal individuals, all of which contribute to a genetic basis for differences in platelet reactivty among normal individuals.
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16
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Jallu V, Poulain P, Fuchs PFJ, Kaplan C, de Brevern AG. Modeling and molecular dynamics of HPA-1a and -1b polymorphisms: effects on the structure of the β3 subunit of the αIIbβ3 integrin. PLoS One 2012; 7:e47304. [PMID: 23155369 PMCID: PMC3498292 DOI: 10.1371/journal.pone.0047304] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2012] [Accepted: 09/11/2012] [Indexed: 11/18/2022] Open
Abstract
Background The HPA-1 alloimmune system carried by the platelet integrin αIIbβ3 is the primary cause of alloimmune thrombocytopenia in Caucasians and the HPA-1b allele might be a risk factor for thrombosis. HPA-1a and -1b alleles are defined by a leucine and a proline, respectively, at position 33 in the β3 subunit. Although the structure of αIIbβ3 is available, little is known about structural effects of the L33P substitution and its consequences on immune response and integrin functions. Methodology/Principal Findings A complete 3D model of the L33-β3 extracellular domain was built and a P33 model was obtained by in silico mutagenesis. We then performed molecular dynamics simulations. Analyses focused on the PSI, I-EGF-1, and I-EGF-2 domains and confirmed higher exposure of residue 33 in the L33 β3 form. These analyses also showed major structural flexibility of all three domains in both forms, but increased flexibility in the P33 β3 form. The L33P substitution does not alter the local structure (residues 33 to 35) of the PSI domain, but modifies the structural equilibrium of the three domains. Conclusions These results provide a better understanding of HPA-1 epitopes complexity and alloimmunization prevalence of HPA-1a. P33 gain of structure flexibility in the β3 knee may explain the increased adhesion capacity of HPA-1b platelets and the associated thrombotic risk. Our study provides important new insights into the relationship between HPA-1 variants and β3 structure that suggest possible effects on the alloimmune response and platelet function.
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Affiliation(s)
- Vincent Jallu
- Laboratoire d'Immunologie Plaquettaire, INTS, Paris, France
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17
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Yakushkin V, Zyuryaev I, Khaspekova S, Sirotkina O, Ruda M, Mazurov A. Glycoprotein IIb-IIIa content and platelet aggregation in healthy volunteers and patients with acute coronary syndrome. Platelets 2011; 22:243-51. [DOI: 10.3109/09537104.2010.547959] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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18
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Abstract
Genetic and environmental factors contribute to a substantial variation in platelet function seen among normal persons. Candidate gene association studies represent a valiant effort to define the genetic component in an era where genetic tools were limited, but the single nucleotide polymorphisms identified in those studies need to be validated by more objective, comprehensive approaches, such as genome-wide association studies (GWASs) of quantitative functional traits in much larger cohorts of more carefully selected normal subjects. During the past year, platelet count and mean platelet volume, which indirectly affect platelet function, were the subjects of GWAS. The majority of the GWAS signals were located to noncoding regions, a consistent outcome of all GWAS to date, suggesting a major role for mechanisms that alter phenotype at the level of transcription or posttranscriptional modifications. Of 15 quantitative trait loci associated with mean platelet volume and platelet count, one located at 12q24 is also a risk locus for coronary artery disease. In most cases, the effect sizes of individual quantitative trait loci are admittedly small, but the results of these studies have led to new insight into regulators of hematopoiesis and megakaryopoiesis that would otherwise be unapparent and difficult to define.
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19
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Ahmad F, Kannan M, Yadav V, Biswas A, Saxena R. Impact of thrombogenic mutations on clinical phenotypes of von Willebrand disease. Clin Appl Thromb Hemost 2009; 16:281-7. [PMID: 19959486 DOI: 10.1177/1076029609351291] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
von Willebrand disease (VWD) is a most common inherited bleeding disorder. von Willebrand factor (VWF) exists as an extracellular adaptor molecule and generally involves in the hemostasis mechanism through binding with GP (Glycoprotein) Ib-IX-V platelet receptor. Clinical phenotype of bleeding disorders modulated to a decrease in bleeding symptoms by thrombogenic mutations. We made an attempt to investigate the impact of thrombogenic mutations/polymorphisms on the clinical phenotype of 114 different types of patients with VWD, and 120 healthy controls were screened for methylenetetrahydrofolate reductase (MTHFR) 677C/T, factor V (FV) Leiden (1691G/A), beta(3) integrin (HPA-I) (Human platelets antigen-I) gene (1565T/C), and prothrombin 20210G/A mutations. Genotypic analysis was performed using polymerase chain reaction (PCR) and restriction fragment length polymorphism. Forty-five patients (39.5%) were found to be positive for at least one of the prothrombotic risk factors screened. Prothrombin 20210G/A was not found in any patient with VWD as well as healthy control. Eight patients with VWD were carrying the defective alleles of different thrombogenic markers, showing milder phenotypes than expected. A high prevalence was observed for MTHFR 677C/T (677C/C 73.6%, 677C/T 24.6%, 677T/T 1.8%) and PLA1/A2 (1565T/T 88.6%, 1565T/C 10.5%, 1565C/C 0.87%) polymorphism followed by FV Leiden (1691G/G 97.4%, 1691G/ A 2.6%, 1691A/A 0.00%) in patients with VWD with allelic frequencies 11.4% (677T), 5% (1565C), and 1.3% (1691A). Hence, we concluded that thrombophilic markers were seen to be influencing the clinical phenotypes of patients with VWD.
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Affiliation(s)
- Firdos Ahmad
- Department of Hematology, All India Institute of Medical Sciences, New Delhi, India
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20
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The Leu33Pro polymorphism in the ITGB3 gene does not modify BRCA1/2-associated breast or ovarian cancer risks: results from a multicenter study among 15,542 BRCA1 and BRCA2 mutation carriers. Breast Cancer Res Treat 2009; 121:639-49. [PMID: 19876733 DOI: 10.1007/s10549-009-0595-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2009] [Accepted: 10/09/2009] [Indexed: 01/25/2023]
Abstract
Integrins containing the beta(3) subunit are key players in tumor growth and metastasis. A functional Leu33Pro polymorphism (rs5918) in the beta(3) subunit of the integrin gene (ITGB3) has previously been suggested to act as a modifier of ovarian cancer risk in Polish BRCA1 mutation carriers. To investigate the association further, we genotyped 9,998 BRCA1 and 5,544 BRCA2 mutation carriers from 34 studies from the Consortium of Investigators of Modifiers of BRCA1/2 for the ITGB3 Leu33Pro polymorphism. Data were analysed within a Cox-proportional hazards framework using a retrospective likelihood approach. There was marginal evidence that the ITGB3 polymorphism was associated with an increased risk of ovarian cancer for BRCA1 mutation carriers (per-allele Hazard Ratio (HR) 1.11, 95% CI 1.00-1.23, p-trend 0.05). However, when the original Polish study was excluded from the analysis, the polymorphism was no longer significantly associated with ovarian cancer risk (HR 1.07, 95% CI 0.96-1.19, p-trend 0.25). There was no evidence of an association with ovarian cancer risk for BRCA2 mutation carriers (HR 1.09, 95% CI 0.89-1.32). The polymorphism was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers. The ITGB3 Leu33Pro polymorphism does not modify breast or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers.
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21
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Marín F, González-Conejero R, Capranzano P, Bass TA, Roldán V, Angiolillo DJ. Pharmacogenetics in cardiovascular antithrombotic therapy. J Am Coll Cardiol 2009; 54:1041-57. [PMID: 19744613 DOI: 10.1016/j.jacc.2009.04.084] [Citation(s) in RCA: 75] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2008] [Revised: 03/25/2009] [Accepted: 04/14/2009] [Indexed: 01/09/2023]
Abstract
Thrombosis is the most important underlying mechanism of coronary artery disease and embolic stroke. Hence, antithrombotic therapy is widely used in these scenarios. However, not all patients achieve the same degree of benefit from antithrombotic agents, and a considerable number of treated patients will continue to experience a new thrombotic event. Such lack of clinical benefit may be related to a wide variability of responses to antithrombotic treatment among individuals (i.e., interindividual heterogeneity). Several factors have been identified in this interindividual heterogeneity in response to antithrombotic treatment. Pharmacogenetics has emerged as a field that identifies specific gene variants able to explain the variability in patient response to a given drug. Polymorphisms affecting the disposition, metabolism, transporters, or targets of a drug all can be implicated in the modification of an individual's antithrombotic drug response and therefore the safety and efficacy of the aforementioned drug. The present paper reviews the modulating role of different polymorphisms on individuals' responses to antithrombotic drugs commonly used in clinical practice.
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Affiliation(s)
- Francisco Marín
- Department of Cardiology, Hospital Universitario Virgen de Arrixaca, Murcia, Spain
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22
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Jones CI, Bray S, Garner SF, Stephens J, de Bono B, Angenent WGJ, Bentley D, Burns P, Coffey A, Deloukas P, Earthrowl M, Farndale RW, Hoylaerts MF, Koch K, Rankin A, Rice CM, Rogers J, Samani NJ, Steward M, Walker A, Watkins NA, Akkerman JW, Dudbridge F, Goodall AH, Ouwehand WH, Bloodomics Consortium. A functional genomics approach reveals novel quantitative trait loci associated with platelet signaling pathways. Blood 2009; 114:1405-16. [PMID: 19429868 DOI: 10.1182/blood-2009-02-202614] [Citation(s) in RCA: 113] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Platelet response to activation varies widely between individuals but shows interindividual consistency and strong heritability. The genetic basis of this variation has not been properly explored. We therefore systematically measured the effect on function of sequence variation in 97 candidate genes in the collagen and adenosine-diphosphate (ADP) signaling pathways. Resequencing of the genes in 48 European DNA samples nearly doubled the number of known single nucleotide polymorphisms (SNPs) and informed the selection of 1327 SNPs for genotyping in 500 healthy Northern European subjects with known platelet responses to collagen-related peptide (CRP-XL) and ADP. This identified 17 novel associations with platelet function (P < .005) accounting for approximately 46% of the variation in response. Further investigations with platelets of known genotype explored the mechanisms behind some of the associations. SNPs in PEAR1 associated with increased platelet response to CRP-XL and increased PEAR1 protein expression after platelet degranulation. The minor allele of a 3' untranslated region (UTR) SNP (rs2769668) in VAV3 was associated with higher protein expression (P = .03) and increased P-selectin exposure after ADP activation (P = .004). Furthermore the minor allele of the intronic SNP rs17786144 in ITPR1 modified Ca(2+) levels after activation with ADP (P < .004). These data provide novel insights into key hubs within platelet signaling networks.
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Affiliation(s)
- Chris I Jones
- Department of Cardiovascular Science, University of Leicester, Clinical Sciences Wing, Glenfield Hospital, Leicester, United Kingdom
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23
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Martínez C, Antón AI, Corral J, Quiroga T, Panes O, Lozano ML, González-Conejero R, Teruel R, Navarro-Núñez L, Pereira J, Mezzano D, Vicente V, Rivera J. Genotype-phenotype relationship for six common polymorphisms in genes affecting platelet function from 286 healthy subjects and 160 patients with mucocutaneous bleeding of unknown cause. Br J Haematol 2009; 146:95-103. [PMID: 19388931 DOI: 10.1111/j.1365-2141.2009.07713.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Polymorphisms affecting platelet receptors and intracellular proteins have been extensively studied in relation to their potential influence in thrombosis and haemorrhages. However, few reports have addressed their impact on platelet function, with contradictory results. Limitations of these studies include, among others, small number of patients, the platelet functional parameters analyzed and their known variability in the healthy population. We studied the effect of six polymorphisms [ITGB3 1565T > C (HPA-1), GPIBA variable number tandem repeat and 524C > T (HPA-2), ITGA2 807C > T, ADRA2A 1780A > G, and TUBB1 Q43P] on platelet function in 286 healthy subjects and their potential pathogenetic role in 160 patients with hereditary mucocutaneous bleeding of unknown cause. We found no effect of any of these polymorphisms on platelet aggregation, secretion, PFA-100, and thrombin generation in platelet rich plasma. Furthermore, patients and controls showed no significant differences in the frequency of any of these polymorphisms. Thus, our study demonstrated that polymorphisms in genes affecting platelet function do not influence significantly major platelet functions and appear irrelevant in the pathogenesis of bleeding disorders.
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24
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Platelet gene polymorphisms related to atherothrombogenesis and their frequencies in the healthy middle-aged Czech population. COR ET VASA 2009. [DOI: 10.33678/cor.2009.044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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25
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McCaslin J, Ashour H, Bhattacharya V, Cleanthis M, Daly A, Stansby G. Increased Platelet-monocyte Aggregation in Male Claudicants with the PlA1/A2 Polymorphism of Gp IIb/IIIa. Eur J Vasc Endovasc Surg 2008; 36:132-137. [DOI: 10.1016/j.ejvs.2008.02.016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2007] [Accepted: 02/15/2008] [Indexed: 10/22/2022]
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26
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Salles II, Feys HB, Iserbyt BF, De Meyer SF, Vanhoorelbeke K, Deckmyn H. Inherited traits affecting platelet function. Blood Rev 2008; 22:155-72. [DOI: 10.1016/j.blre.2007.11.002] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
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27
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Sirotkina OV, Khaspekova SG, Zabotina AM, Shimanova YV, Mazurov AV. Effects of platelet glycoprotein IIb-IIIa number and glycoprotein IIIa Leu33Pro polymorphism on platelet aggregation and sensitivity to glycoprotein IIb-IIIa antagonists. Platelets 2008; 18:506-14. [PMID: 17957566 DOI: 10.1080/09537100701326739] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
We investigated the influence of glycoprotein (GP) IIIa Leu33Pro polymorphism, platelet GP IIb-IIIa number, and plasma fibrinogen concentration on platelet aggregation and antiaggregatory action of GP IIb-IIIa antagonists. Healthy volunteers with GP IIIa Pro33(-) (Leu33Leu33, n = 20) and Pro33(+) (Leu33Pro33, n = 13, and Pro33Pro33, n = 2) genotypes were included into the study. GP IIIa Leu33Pro substitution was associated with the increase of the level and rate of platelet microaggregate formation induced by GP IIb-IIIa activating antibody CRC54 (100, 200, 400 microg/ml) against the epitope within 1-100 residues of GP IIIa N-terminal part (p from 0.001 to 0.047). No significant differences were detected between parameters of platelet aggregation induced by ADP (1.25, 2.5, 5.0, 20 microM) in GP IIIa Pro33(+) and Pro33(-) donors. GP IIb-IIIa antagonist Monafram (F(ab')(2) fragment of GP-IIb-IIIa blocking antibody CRC64) (1, 2, 3 microg/ml), but not eptifibatide (50, 100, 150 ng/ml) inhibited ADP-induced aggregation slightly less efficiently in GP IIIa Pro33(+) group (p < 0.05 at 1 and 2 microg/ml Monafram). GP IIb-IIIa number (evaluated as maximal binding of (125)I-labelled antibody CRC64) varied from 40.5 to 80.8 x 10(3) per platelet with no significant influence of GP IIIa genotype. Consistent correlations were revealed between GP IIb-IIIa quantity and the level and rate of ADP-induced aggregation (r from 0.353 to 0.583, p from <0.001 to 0.037) as well as resistance (level of residual aggregation) to both GP IIb-IIIa antagonists (r from 0.345 to 0.602, p from <0.001 to 0.042). ADP-induced aggregation was considerably increased and efficiency of GP IIb-IIIa antagonists decreased in donors with high in comparison with low GP IIb-IIIa quantity (>60 and 40-50 x 10(3) per platelet respectively, p < 0.01 for most tests). No correlations were observed between all tested parameters and plasma fibrinogen concentration. Our results indicate that inter-individual variability of platelet GP IIb-IIIa number significantly affects platelet aggregation and antiaggregatory effects of GP IIb-IIIa antagonists. Contribution of this factor is higher than that of GP IIIa Leu33Pro polymorphism and variations of fibrinogen concentration.
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Affiliation(s)
- Olga V Sirotkina
- Petersburg Nuclear Physics Institute, Russian Academy of Sciences, Petersburg Nuclear Physics Institute, Saint-Petersburg, Russia
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Cerhan JR, Ansell SM, Fredericksen ZS, Kay NE, Liebow M, Call TG, Dogan A, Cunningham JM, Wang AH, Liu-Mares W, Macon WR, Jelinek D, Witzig TE, Habermann TM, Slager SL. Genetic variation in 1253 immune and inflammation genes and risk of non-Hodgkin lymphoma. Blood 2007; 110:4455-63. [PMID: 17827388 PMCID: PMC2234796 DOI: 10.1182/blood-2007-05-088682] [Citation(s) in RCA: 129] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Smaller-scale evaluations suggest that common genetic variation in candidate genes related to immune function may predispose to the development of non-Hodgkin lymphoma (NHL). We report an analysis of variants within genes associated with immunity and inflammation and risk of NHL using a panel of 9412 single-nucleotide polymorphisms (SNPs) from 1253 genes in a study of 458 patients with NHL and 484 frequency-matched controls. We modeled haplotypes and risk of NHL, as well as the main effects for all independent SNPs from a gene in multivariate logistic regression models; we separately report results for nonsynonymous (ns) SNPs. In gene-level analyses, the strongest findings (P < or = .001) were for CREB1, FGG, MAP3K5, RIPK3, LSP1, TRAF1, DUSP2, and ITGB3. In nsSNP analyses, the strongest findings (P < or = .01) were for ITGB3 L59P (odds ratio [OR] = 0.66; 95% confidence interval [CI] 0.52-0.85), TLR6 V427A (OR = 5.20; CI 1.77-15.3), SELPLG M264V (OR = 3.20; CI 1.48-6.91), UNC84B G671S (OR = 1.50; CI 1.12-2.00), B3GNT3 H328R (OR = 0.74; CI 0.59-0.93), and BAT2 V1883L (OR = 0.64; CI 0.45-0.90). Our results suggest that genetic variation in genes associated with immune response (TRAF1, RIPK3, BAT2, and TLR6), mitogen-activated protein kinase (MAPK) signaling (MAP3K5, DUSP2, and CREB1), lymphocyte trafficking and migration (B3GNT3, SELPLG, and LSP1), and coagulation pathways (FGG and ITGB3) may be important in the etiology of NHL, and should be prioritized in replication studies.
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Affiliation(s)
- James R Cerhan
- Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
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Jakubowska A, Gronwald J, Menkiszak J, Górski B, Huzarski T, Byrski T, Edler L, Lubinski J, Scott RJ, Hamann U. Integrin beta3 Leu33Pro polymorphism increases BRCA1-associated ovarian cancer risk. J Med Genet 2007; 44:408-11. [PMID: 17220212 PMCID: PMC2740893 DOI: 10.1136/jmg.2006.047498] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
Integrins are heterodimeric transmembrane glycoproteins that function as key adhesion and cell signalling receptors. A functional polymorphism in the integrin beta3 subunit encoded by the ITGB3 gene, Leu33Pro, has been shown to modify a variety of traits of beta3-expressing cells. To analyse the role of this functional polymorphism in modifying BRCA1-associated ovarian and breast cancer risks, a case-control study was performed among Polish BRCA1 mutation carriers including 319 breast cancer cases, 146 ovarian cancer cases and 290 controls unaffected by breast and ovarian cancer, in situ breast cancer or any other kind of cancer. Genotyping analysis was performed using PCR-based restriction fragment length polymorphism analysis. Odds ratios were calculated using univariate and multivariate logistic regression, taking into account a series of confounding variables, including the presence of related study subjects, that potentially could have biased any association. The results revealed that the ITGB3_Leu33Pro polymorphism was associated with a 2.5-fold increased risk of ovarian cancer, whereas no association with breast cancer risk was found. Thus, it appears that the ITGB3_Leu33Pro polymorphism may potentially increase the risk of ovarian cancer in Polish women with an inherited BRCA1 mutation.
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Langsenlehner U, Renner W, Yazdani-Biuki B, Eder T, Wascher TC, Paulweber B, Clar H, Hofmann G, Samonigg H, Krippl P. Integrin alpha-2 and beta-3 gene polymorphisms and breast cancer risk. Breast Cancer Res Treat 2006; 97:67-72. [PMID: 16317580 DOI: 10.1007/s10549-005-9089-4] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Integrins are cell surface receptors, which mediate cell-to-cell and cell-to-extracellular matrix adhesion. Some of them, e.g. alpha(V)beta(3), alpha(IIb)beta(3) and alpha(2)beta(1), have been suggested as key players for cancer development and tumor metastasis. Two polymorphisms in the gene for the alpha(2) component, ITGA2 807C>T and 1648G>A, have been associated with the cell-surface density of integrin alpha(2)beta(1). The 176T>C polymorphism in the ITGB3 gene, encoding the beta(3) subunit of integrins alpha(IIb)beta(3) and alpha(V)beta(3), modifies a variety of traits of beta(3) expressing cells. To analyze the role of ITGA2 and ITGB3 polymorphisms for breast cancer risk and prognosis, we performed a case-control study including 500 female breast cancer patients and 500 healthy female age-matched control subjects. All study participants were of Caucasian origin (Austria, Middle-Europe). The ITGA2 1648_AA genotype was significantly associated with breast cancer (odds ratio 3.12; 95% confidence interval 1.11-8.77). Carriers of the most common ITGA2 haplotype (807C_1648G, 'wildtype') were at decreased risk for breast cancer (odds ratio 0.72; 95% confidence interval 0.53-0.98). A histological grade of 3 or 4 was found more often in ITGA2 807TT subjects (p=0.039 compared to CC+CT genotypes) and carriers of an ITGA2 1648A allele (p=0.017 compared to GG genotype). Carriers of the ITGA2 807C_1648G haplotype were less likely to have a histological grade 3 or 4 compared to non-carriers (p=0.003). The ITGB3 176T>C polymorphisms was not associated with breast cancer susceptibility. In a Cox-regression analysis, carriers of the homozygous ITGB3 176-CC genotype had a higher risk for metastasis (relative risk 2.3; 95% CI 1.3-4.2; p=0.005). We conclude that functional polymorphisms in integrin genes ITGA2 and ITGB3 influence the development and progression of breast cancer, respectively. The precise mechanism remains to be determined, but likely involves dysregulated signaling pathways.
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Affiliation(s)
- Uwe Langsenlehner
- Department of Internal Medicine, Division of Oncology, Medical University Graz, Graz, Austria
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Vijayan KV, Liu Y, Souza S, Thiagarajan P, Bray PF. Fibrinogen and prothrombin binding is enhanced to the Pro33 isoform of purified integrin alphaIIbbeta3. J Thromb Haemost 2006; 4:905-6. [PMID: 16634766 DOI: 10.1111/j.1538-7836.2006.01850.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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O'Halloran AM, Curtin R, O'Connor F, Dooley M, Fitzgerald A, O'Brien JK, Fitzgerald DJ, Shields DC. The impact of genetic variation in the region of the GPIIIa gene, on Pl expression bias and GPIIb/IIIa receptor density in platelets. Br J Haematol 2006; 132:494-502. [PMID: 16412022 DOI: 10.1111/j.1365-2141.2005.05897.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Some studies have suggested that genetic variability in the glycoprotein (GP) IIIa gene modulates expression of platelet GPIIb/IIIa (alpha(2b)beta(3)). We sought to determine as to whether combinations of genetic variants within the GPIIIa gene (haplotypes) influenced the expression of GPIIIa RNA and protein levels in human platelets. Three promoter polymorphisms, Pl(A1/A2) genotype and platelet receptor densities were determined in 207 acute coronary syndrome (ACS) patients. Allele-specific quantitative reverse transcription-polymerase chain reaction of platelet RNA from Pl(A1/A2) heterozygotes identified a greater expression of Pl(A2) bearing transcripts among heterozygotes. Among the patients studied, the ratio of Pl(A1)/Pl(A2) RNA expression was significantly influenced by promoter haplotype (P < 0.01). However, this effect reflected carriership of rare not common haplotypes (P = 0.2). There was a threefold variation between subjects in the number of GPIIb/IIIa receptors expressed per platelet, although no association between receptor density and the Pl(A2) (P = 0.93) or promoter polymorphisms was demonstrated (-468A, P = 0.52; -425C, P = 0.59; -400A, P = 0.52). Among common haplotypes, Pl(A1)/Pl(A2) RNA expression was negatively correlated with adjusted GPIIb/IIIa receptor density (P = 0.04). The overall trend towards higher expression of Pl(A2) bearing message in Pl(A1/A2) heterozygotes, and the existence of rare haplotypes with more pronounced changes indicate the existence of cis-acting genetic factors that remain to be identified.
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Affiliation(s)
- Aisling M O'Halloran
- Department of Clinical Pharmacology, Royal College of Surgeons in Ireland, Dublin, Ireland
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Fontana P, Reny JL. Pharmacogénétique et médicaments antiplaquettaires. Rev Med Interne 2005; 26:725-32. [PMID: 16154027 DOI: 10.1016/j.revmed.2005.02.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2004] [Accepted: 02/01/2005] [Indexed: 11/21/2022]
Abstract
PURPOSE The observation of inherited drug response variability gave rise to the field of pharmacogenetics. Pharmacogenetic research on drug targets, particularly platelet enzymes and receptors, is more recent and is becoming an emerging field. CURRENT KNOWLEDGE AND KEY POINTS In the Framingham study, the heritability of platelet aggregation response ranges from 44 to 62%, depending on the agonists used. The gene coding for GPIIIa, a sub-unit of the fibrinogen receptor GPIIbIIIa, is one of the most extensively studied gene in relation with aggregation tests and antiplatelet drugs. The GPIIIa PLA1/PLA2 polymorphism has been associated with clopidogrel and orbofiban platelet response. However, data are more controversial concerning the association with aspirin response. Recently, Cox-1 and GPIa (part of the GPIaIIa collagen receptor) genetic variations have also been pointed out as possible candidates to explain part of the variability of the response to antiplatelet agents. Finally, the H1/H2 polymorphism of the platelet ADP receptor P2Y12 gene has been associated with ADP-induced platelet aggregation response and peripheral arterial disease. This polymorphism may modulate the effect of P2Y12 antagonists like clopidogrel and its clinical implication is currently under study. FUTURE PROSPECTS AND PROJECTS Gene-expression profiling and proteomics may allow the identification of new candidate genes whose variations may be associated with the heritability of platelet aggregation response. In the next future, phenotypic or genotypic studies could be available to tailor the prescription of antiplatelet drugs.
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Affiliation(s)
- P Fontana
- Service d'angiologie et d'hémostase, département de médecine interne, faculté de médecine, hôpital cantonal universitaire, 24, rue Micheli-du-Crest, 1211 Genève 14, Suisse.
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Porto I, Leone AM, Nanni L, Sciahbasi A, De Vita M, Lanza GA, Andreotti F. Interplay of platelet polymorphisms, risk factors, and von [corrected] Willebrand factor [corrected] in determining collagen-adenosine diphosphate PFA-100 results in patients with coronary artery disease. Blood Coagul Fibrinolysis 2005; 16:97-104. [PMID: 15741796 DOI: 10.1097/01.mbc.0000161562.28646.94] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Platelets play a pivotal role in thrombus formation in patients with coronary artery disease (CAD), since the high shear generated in the presence of severe coronary stenoses can increase platelet reactivity (PR) and trigger thrombogenesis. Several reports have suggested a functional effect of human platelet antigen (HPA)-1 and HPA-2 gene polymorphisms on PR. However, the true determinants of high-shear PR in CAD patients taking their usual medications are still incompletely understood. In 104 patients with stable CAD we analyzed the possible clinical, biochemical and genetic factors affecting high-shear PR, measured by the ex vivo platelet function analyzer (PFA-100) collagen-adenosine diphosphate method. In univariate analysis, a lower PR was associated with decreased plasma von Willebrand factor-ristocetin cofactor activity, increased blood levels of triglycerides, female sex, use of thienopyridines, lower platelet count, and HPA-1b carriership. All variables, except HPA-1b, remained associated with lower PR in multivariate analysis. However, the introduction in the model of the HPA-1 and HPA-2 genotypes as interaction terms led to a significant improvement in the prediction of PR, although the quantitative effect was small (about 3% improvement, P=0.046).Thus, in CAD patients, there seems to be only a mild effect of the platelet glycoprotein HPA-1 and HPA-2 polymorphisms on collagen-adenosine diphosphate-stimulated PR after the effect of well-established clinical and biochemical determinants are considered.
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Affiliation(s)
- Italo Porto
- Department of Cardiology, John Radcliffe Hospital, Oxford, UK.
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Mikkelsson J, Perola M, Karhunen PJ. Genetics of platelet glycoprotein receptors: risk of thrombotic events and pharmacogenetic implications. Clin Appl Thromb Hemost 2005; 11:113-25. [PMID: 15821818 DOI: 10.1177/107602960501100201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Platelet aggregation and coronary thrombosis have a central role in the development of acute coronary syndromes and myocardial infarction (MI). Therapies aimed at inhibiting platelet aggregation have shown great benefit in individuals with coronary disease or with multiple risk factors for coronary disease. Genetic variation in platelet surface receptors mediating thrombus formation has been suggested to be associated with platelet hyperreactivity, with increased risk of MI and possibly with the benefit received from various antithrombotic drug treatments. This review focuses on discrepancies and their likely explanations in studies on platelet glycoprotein genetics. Current knowledge on important issues concerning coronary event phenotypes and pharmacogenetics is analyzed. Possible future applicability of these data to patient treatment is also discussed.
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Affiliation(s)
- Jussi Mikkelsson
- Tampere University Hospital, Research Unit and Medical School, University of Tampere, Tampere University Hospital, and National Public Health Institute, Helsinki, Finland.
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Raz P, Lohmann CH, Turner J, Wang L, Poythress N, Blanchard C, Boyan BD, Schwartz Z. 1alpha,25(OH)2D3 regulation of integrin expression is substrate dependent. J Biomed Mater Res A 2005; 71:217-25. [PMID: 15386491 DOI: 10.1002/jbm.a.30134] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Osteoblasts are attachment-dependent cells that interact with their surface through integrin-mediated mechanisms. Their differentiation is regulated by 1,25-dihydroxyvitamin D3 [1alpha,25(OH)(2)D(3)] and is affected by substrate chemistry and microtopography, suggesting that 1alpha,25(OH)(2)D(3) may regulate integrin expression in a surface-specific manner. To test this hypothesis, osteoblast-like human MG63 cells were grown on tissue culture plastic and on grit-blasted and acid-etched titanium disks with a complex microtopography to induce osteoblast differentiation. Expression of alpha(2), alpha(5), alpha(v), beta(1), and beta(3) integrins were quantified by real-time polymerase chain reaction (PCR) as a function of time in culture and treatment with 1alpha,25(OH)(2)D(3). Results were correlated with expression of osteocalcin, a marker of a differentiated osteoblast. Osteocalcin mRNA increased with time and 1alpha,25(OH)(2)D(3) treatment and these changes were greater in cultures on the titanium disks. Integrin expression varied with time in culture and this was also surface dependent. At each time point, beta(1) and alpha(2) mRNAs were greater on titanium than on plastic, whereas alpha(5) expression was reduced and alpha(v),beta(3) expression was unaffected. 1alpha,25(OH)(2)D(3) increased beta(1) mRNA on both surfaces at all time points, but it increased alpha(2) expression only in 8-d cultures. 1alpha,25(OH)(2)D(3) caused reduced alpha(5) expression only in cultures grown on plastic for 8 d, and had no effect on either alpha(v) or beta(3) expression regardless of surface. These results show that integrin expression in human osteoblast-like cells is differentially modulated by 1alpha,25(OH)(2)D(3) in a time-dependent manner that is sensitive to the surface on which the cells are grown.
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Affiliation(s)
- P Raz
- Department of Periodontics, Hebrew University Hadassah, Jerusalem, Israel
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Affiliation(s)
- H Deckmyn
- Laboratory for Thrombosis Research, IRC, KU Leuven Campus Kortrijk, Kortrijk, Belgium.
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Wang-Gohrke S, Chang-Claude J. Integrin ?3 Leu33Pro polymorphism and breast cancer risk: a population-based case-control study in Germany. Breast Cancer Res Treat 2004; 88:231-7. [PMID: 15609125 DOI: 10.1007/s10549-004-0782-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
A functional polymorphism at codon 33 (leucine-to-proline, Leu33Pro)/nucleotide 1565 (T-to-C, T1565C) of the integrin beta3 has been hypothesized to increase the risk of breast cancer and its metastasis. Three studies have been conducted up to date and the results were contradictory. We used a large population-based age-matched case-control study in German Caucasian women by the age of 50 years to assess breast cancer risk associated with this polymorphism, taking into consideration of possible interaction with other risk factors, and to examine if it affects clinical presentation. Overall, the odds ratios (OR) for breast cancer were not increased in women carrying either allele. However, we observed a differential effect of the Leu33Pro polymorphism by age group when patients were stratified by 45 years of age (p=0.055). Being a carrier of the 33proline allele was found to be associated with a 32% increased risk (95% Cl=1.0-1.8) for breast cancer compared to the wild-type leucine homozygotes among women age 45 or younger but not in older women. Furthermore, we observed significant dose effect of the 33proline allele (p=0.04), with 30% risk increase per allele (95% Cl=1.0-1.7). Significant evidence was also found for a positive association between 33proline carrier status and increasing axillary node involvement (p=0.048) but neither size nor grading of tumor in this study. Our data suggest that inheritance of the integrin beta3 Leu33Pro polymorphism may increase the breast cancer risk by age 45 in the German population.
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Affiliation(s)
- Shan Wang-Gohrke
- Department of Obstetrics and Gynecology, University of Ulm, Prittwitzstrasse 43, 89075, Ulm, Germany.
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Boekholdt SM, Peters RJG, de Maat MPM, Zwinderman AH, van Der Wall EE, Reitsma PH, Jukema JW, Kastelein JJP. Interaction between a genetic variant of the platelet fibrinogen receptor and fibrinogen levels in determining the risk of cardiovascular events. Am Heart J 2004; 147:181-6. [PMID: 14691438 DOI: 10.1016/j.ahj.2003.07.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND The PlA1A2 polymorphism of glycoprotein IIIa (GPIIIa), which affects postoccupancy signaling by the platelet fibrinogen receptor IIbIIIa, has been investigated as a potential genetic risk factor for cardiovascular events in numerous studies, without consistent results. We investigated whether the effect of this genetic variant of the platelet fibrinogen receptor on the risk of cardiovascular events is affected by fibrinogen plasma levels. METHODS The GPIIIa PlA1A2 polymorphism and fibrinogen levels were determined in 455 men with angiographically documented coronary atherosclerosis. RESULTS Neither carriership of the rare PlA2 allele nor fibrinogen plasma levels affected the time to cardiovascular event, as assessed in a proportional hazards model. However, there was a significant interaction between PlA2 carriership and fibrinogen plasma levels (P =.002). Carriership of the variant PlA2 allele significantly affected event-free survival only in individuals within the highest fibrinogen quartile (hazard ratio, 2.7; 95% CI, 1.1 to 7.1; P =.03). CONCLUSIONS We observed a statistically significant interaction between a genetic variant of the platelet fibrinogen receptor and fibrinogen levels in determining the risk of cardiovascular events. This interaction may account for the inconsistent results of genetic association studies investigating this genotype as a genetic risk factor in thrombotic cardiovascular events.
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Abstract
The propensity for both arterial and venous thrombotic disorders involves a genetic predetermination that operates In concert with environmental factors or triggers. Appropriate clinical assessment and therapeutic recommendations for patients with thrombosis requires a thorough knowledge of genetic variables that influence this propensity. This review focuses on the pathophysiology, natural history, and molecular biology of defined thrombophilic risk factors relevant to the care of patients with thrombotic disorders.
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Affiliation(s)
- Robert D. McBane
- Division of Cardiovascular Medicine, Section of Hematology Research, Mayo Clinic and Foundation for Education and Research, Rochester, Minnesota
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Bojesen SE, Tybjaerg-Hansen A, Nordestgaard BG. Integrin beta3 Leu33Pro homozygosity and risk of cancer. J Natl Cancer Inst 2003; 95:1150-7. [PMID: 12902444 DOI: 10.1093/jnci/djg005] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Increased tumor cell expression of integrins containing the beta3 subunit is associated with increased progression to invasive tumors, whereas inhibition of beta3 integrin expression and/or function may reduce tumor growth and metastasis. The Leu33Pro polymorphism of the beta3 subunit modulates the function of alpha(IIb)beta3 integrin. We examined whether this polymorphism influences cancer risk. METHODS Using participants (n = 9242) from the Copenhagen City Heart Study with 24 years of follow-up and endpoints from the Danish Cancer Registry, we assessed the risk of all cancers and of 27 cancer types in individuals who carry the Leu33Pro polymorphism (heterozygotes and homozygotes) relative to those without the polymorphism (non-carriers). Relative risks (RRs) of cancer and 95% confidence intervals (CIs) were calculated by Cox proportional hazards regression analysis. Differences in cumulative cancer incidence (per 10 000 person-years) were tested using log-rank statistics. Statistical tests were two-sided. RESULTS Among the participants, 70.0% were non-carriers, 27.3% were heterozygotes, and 2.7% were homozygotes. We detected 1296 participants with a first cancer. Cumulative incidences in non-carriers, heterozygotes, and homozygotes were 81, 83, and 112, respectively (homozygotes versus non-carriers, P =.02). The age-adjusted RR of all cancers in homozygotes relative to non-carriers was 1.4 (95% CI = 1.1 to 1.9). Incidences in non-carriers, heterozygotes, and homozygotes were 3, 4, and 16 for ovarian cancer; 19, 24, and 36 for breast cancer; and 2, 3, and 7 for melanoma (homozygotes versus non-carriers; P =.002, P =.06, and P =.03, respectively). The age-adjusted RR in homozygotes relative to non-carriers was 4.7 (95% CI = 1.6 to 14) for ovarian cancer, 1.9 (95% CI = 1.0 to 3.7) for breast cancer, and 3.5 (95% CI = 1.1 to 12) for melanoma. Adjustment for other cancer risk factors did not alter these results. Heterozygotes did not differ from non-carriers with respect to cancer risk. CONCLUSION Individuals homozygous for the Leu33Pro polymorphism of the beta3 integrin subunit have an increased cancer risk.
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Affiliation(s)
- Stig E Bojesen
- Department of Clinical Biochemistry, Herlev University Hospital, Herlev, Denmark
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Abstract
An acute coronary syndrome (ACS) is the clinical manifestation of a thrombotic event occurring within a coronary artery narrowed by atherosclerosis. This atherothrombotic event is thought to occur following destabilizing changes within the atherosclerotic plaque, rendering it a surface on which thrombus can develop. The development and progression of this thrombus are determined by deleterious perturbations in the hemostatic equilibrium within the local environment of the plaque that favor thrombosis. Major risk factors for the development of atherosclerotic disease have been clearly established and are targets of aggressive modification in an effort to impede the development or slow the progression of disease. While conferring an increased risk for plaque development, these and other risk factors also establish a prothrombotic milieu within the microenvironment of the atherosclerotic plaque that favors thrombosis. This review seeks to address these traditional and emerging risk factors from the context of their pathologic effects on local hemostatic balance. Aggressive risk factor modification not only reduces atherosclerotic disease development and progression, but also ameliorates the prothrombotic state, and ultimately serves to reduce atherothrombotic events.
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Affiliation(s)
- Frederick L Ruberg
- Evans Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA
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Li R, Mitra N, Gratkowski H, Vilaire G, Litvinov R, Nagasami C, Weisel JW, Lear JD, DeGrado WF, Bennett JS. Activation of integrin alphaIIbbeta3 by modulation of transmembrane helix associations. Science 2003; 300:795-8. [PMID: 12730600 DOI: 10.1126/science.1079441] [Citation(s) in RCA: 234] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Transmembrane helices of integrin alpha and beta subunits have been implicated in the regulation of integrin activity. Two mutations, glycine-708 to asparagine-708 (G708N)and methionine-701 to asparagine-701, in the transmembrane helix of the beta3 subunit enabled integrin alphaIIbbeta3 to constitutively bind soluble fibrinogen. Further characterization of the G708N mutant revealed that it induced alphaIIbbeta3 clustering and constitutive phosphorylation of focal adhesion kinase. This mutation also enhanced the tendency of the transmembrane helix to form homotrimers. These results suggest that homomeric associations involving transmembrane domains provide a driving force for integrin activation. They also suggest a structural basis for the coincidence of integrin activation and clustering.
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Affiliation(s)
- Renhao Li
- Department of Biochemistry and Biophysics, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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Vijayan KV, Liu Y, Dong JF, Bray PF. Enhanced activation of mitogen-activated protein kinase and myosin light chain kinase by the Pro33 polymorphism of integrin beta 3. J Biol Chem 2003; 278:3860-7. [PMID: 12460991 DOI: 10.1074/jbc.m208680200] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Integrin beta(3) is polymorphic at residue 33 (Leu(33) or Pro(33)), and the Pro(33) variant exhibits increased outside-in signaling to focal adhesion kinase and greater actin reorganization. Because focal adhesion kinase activation and an intact cytoskeleton are critical links for integrin-mediated signaling to MAPK, we explored the role of integrin alpha(IIb)beta(3) in this signaling using Chinese hamster ovary and human kidney 293 cell lines expressing either the Leu(33) or Pro(33) isoform of beta(3). Compared with Leu(33) cells, Pro(33) cells demonstrated substantially greater activation of ERK2 (but not MAPK family members JNK and p38) upon adhesion to immobilized fibrinogen (but not fibronectin) and upon integrin cross-linking. ERK2 activation was mediated through MAPK kinase and required phosphoinositide 3-kinase signaling and an intact actin cytoskeleton. Human platelets and Chinese hamster ovary cells expressing the Pro(33) isoform showed enhanced activation of the ERK2 substrate myosin light chain kinase (MLCK) upon adhering to fibrinogen. Furthermore, compared with platelets and cells expressing the Leu(33) isoform, the Pro(33) variant showed greater alpha-granule release, clot retraction, and adhesion to fibrinogen under shear stress, and these functional differences were abolished by MLCK and MAPK kinase inhibition. Post-integrin occupancy signaling through MAPK and MLCK after alpha(IIb)beta(3) cross-linking may explain in part the increased adhesive properties of the Pro(33) variant of integrin beta(3).
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Affiliation(s)
- K Vinod Vijayan
- Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA
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Pontiggia L, Lassila R, Pederiva S, Schmid HR, Burger M, Beer JH. Increased platelet-collagen interaction associated with double homozygosity for receptor polymorphisms of platelet GPIa and GPIIIa. Arterioscler Thromb Vasc Biol 2002; 22:2093-8. [PMID: 12482840 DOI: 10.1161/01.atv.0000042230.26207.d2] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
OBJECTIVE There is considerable controversy regarding the clinical role of the single-nucleotide polymorphisms (SNPs) of the platelet glycoprotein receptor GPIa C807T and the Pl(A1/A2) of GPIIIa as cardiovascular risk factors. We hypothesized that two combined SNPs in their homozygous prothrombotic forms could clarify their pathophysiological impact. METHODS AND RESULTS We identified a family with a striking history of premature cardiovascular events and a high frequency of the prothrombotic form of the two SNPs. From this family, the platelets of a healthy, 27-year-old propositus with this double homozygosity were compared with three matched male neutral gene variant controls. The propositus had shortened PFA-100 closure times and an increased platelet aggregation response to collagen. Platelet deposition to collagen was augmented under the blood flow conditions of a high shear rate model (1600 s(-1)). Platelet adhesion on collagen monomers was induced in a static system, leading to the promotion of subsequent procoagulant activity. CONCLUSIONS The combined homozygous prothrombotic SNPs of GPIa and GPIIIa are associated with an increased platelet-collagen interaction and procoagulant activity that can be readily demonstrated in several independent systems. Our patient may serve as a useful model for the functional consequences of two combined, potentially procoagulant, platelet SNPs.
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Affiliation(s)
- Luca Pontiggia
- Department of Medicine, Laboratory for Thrombosis Research, Kantonsspital Baden, Switzerland
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46
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Weber AA, Jacobs C, Meila D, Weber S, Zotz RB, Scharf RE, Kelm M, Strauer BE, Schrör K. No evidence for an influence of the human platelet antigen-1 polymorphism on the antiplatelet effects of glycoprotein IIb/IIIa inhibitors. PHARMACOGENETICS 2002; 12:581-3. [PMID: 12360110 DOI: 10.1097/00008571-200210000-00011] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
This study investigated the hypothesis that the human platelet antigen-1 (HPA-1) polymorphism may influence the antiplatelet effects of glycoprotein (GP)IIb/IIIa inhibitors. Adenosine diphosphate (30 micro mol)-induced fibrinogen binding was measured by flow cytometry. Abciximab (0.03-3 micro g/ml), tirofiban (0.3-30 nmol/l) or eptifibatide (0.01-1 micro g/ml) were incubated for 15 min with the samples prior to stimulation. IC(50) values for the inhibition of fibrinogen binding were determined from each experiment. All subjects were genotyped by GALIOS and automated fluorescence correlation spectroscopy. Although a marked variability in the inhibitory effects of all three GPIIb/IIIa inhibitors was confirmed, there were no significant differences between the genotypes with respect to the inhibition of fibrinogen binding. Thus, the present study does not provide evidence for an effect of HPA-1 polymorphism on the inter-individual variability in the platelet inhibitory effects of the three GPIIb/IIIa inhibitors approved for clinical use.
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Affiliation(s)
- Artur-Aron Weber
- Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum Düsseldorf, Düsseldorf, Germany
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Abstract
The PFA-100 (platelet function analyzer) is a relatively new tool for the investigation of primary hemostasis. Recent studies have shown its utility as a screening tool for investigating possible von Willebrand disorder (VWD) and various platelet disorders. More recently, the PFA-100 has been shown to be valuable in monitoring desmopressin acetate (DDAVP) therapy in both VWD and platelet disorders. The PFA-100 has also been evaluated in many other studies for its utility in assessing drug effects, for potential monitoring of antiplatelet medication (including aspirin), or for evaluation of overall primary hemostasis in various clinical disorders or during surgical procedures. This article reviews current findings and highlights the benefits and limitations of the clinical utility of the PFA-100. Ultimately, the greatest strengths of the PFA-100 are its simplicity of use and excellent sensitivity to particular hemostatic disturbances such as VWD, platelet disorders, and platelet-affecting medication. However, because it is thus a global test system, this also creates a significant limitation because the PFA-100 is not specific for, nor predictive of, any particular disorder. However, used appropriately, the PFA-100 can be considered a worthwhile addition to any hemostasis laboratory involved in the diagnosis or therapeutic monitoring of bleeding disorders and potentially of antiplatelet medication. This review should be valuable to both hemostasis scientists and clinical specialists.
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Affiliation(s)
- Emmanuel J Favaloro
- Diagnostic Haemostasis Laboratory, Department of Hematology, Institute of Clinical Pathology and Medical Research, Westmead Hospital, Western Sydney Area Health Service, Westmead, NSW, 2145, Australia.
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Kunicki TJ, Nugent DJ. The influence of platelet glycoprotein polymorphisms on receptor function and risk for thrombosis. Vox Sang 2002; 83 Suppl 1:85-90. [PMID: 12617110 DOI: 10.1111/j.1423-0410.2002.tb05274.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
With regard to hemostasis and thrombosis, collagens are among the most important physiologic components of the extracellular matrix in their role as platelet activators. Differences in the rate of platelet activation markedly influence normal hemostasis and the pathological outcome of thrombosis. Thus, collagen receptors, such as the integrin alpha2beta1 and indirectly, GPIb alpha, represent a relatively unexploited target of pharmacological control and are only recently becoming appreciated as potential factors in the generic risk for thrombosis. In general, the importance platelet glycoprotein polymorphisms as genetic risk factors for arterial thrombosis is a new area of human genomics that needs to be carefully addressed. Discrepancies in the degree to which they are reported to contribute to risk for clinical thrombosis will only be resolved once there is a universal standard for clinical study design. Most of the clinical studies differ by patient population size, ethnicity, bias in the selection of patients and controls, plurality in clinical endpoints and variation of environmental factors. Despite these differences, there is substantial evidence that the integrin beta3 PlA2 haplotype, the GPIb alpha Met145 haplotype, the GPIb alpha -5C haplotype and the integrin alpha2 haplotype 1 (807T) each contribute to the risk for and morbidity of thrombotic disease. There may remain dispute as to the extent of their contribution. However, well-designed, large, prospective, genetic and epidemiologic studies are needed to clarify the role of these and other platelet receptor polymorphisms. Most importantly, the cumulative effects of multiple platelet and plasma glycoproteins SNPs to thrombotic risk must be evaluated concurrently. Additional in vitro studies of the functional relevance underlying these polymorphisms are needed to provide a sound biological explanation for the results of clinical correlations. The opportunity now exists to make significant inroads into the development of strategies for the prevention of thrombotic disease.
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Weber AA, Meila D, Jacobs C, Weber S, Kelm M, Strauer BE, Zotz RB, Scharf RE, Schrör K. Low incidence of paradoxical platelet activation by glycoprotein IIb/IIIa inhibitors. Thromb Res 2002; 106:25-9. [PMID: 12165285 DOI: 10.1016/s0049-3848(02)00083-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The human platelet antigen-1 (HPA-1, Pl(A)) polymorphism has been proposed to influence the inhibitory actions of abciximab. Thus, we hypothesized that this polymorphism might also be the cause for paradoxical activation of platelets by GPIIb/IIIa inhibitors. The effects of abciximab (1-10 microg/ml), tirofiban (3-30 nM), or eptifibatide (0.3-3 microg/ml) on basal and ADP (3 microM)-induced CD62P externalization were measured in n=62 healthy blood donors and n=177 patients with stable coronary artery disease. All subjects were genotyped for the human platelet antigen-1 (HPA-1, Pl(A)) polymorphism by GALIOS(R) and fluorescence correlation spectroscopy. Although a significant platelet hyperreactivity was observed in the patients, the HPA-1 genotype did not influence basal or ADP-induced CD62P expression. A moderate (twofold) stimulation of CD62P expression by abciximab but not by tirofiban or eptifibatide was observed in one patient. Interestingly, this patient carried the HPA-1 b/b genotype. In no other subject any activation of platelets by GP IIb/IIIa inhibitors was observed and there were no statistically significant differences between HPA-1 genotypes with respect to the effects of GP IIb/IIIa inhibitors on basal or ADP-stimulated CD62P expression. It is concluded that paradoxical platelet activation by abciximab is a rare (<2%) phenomenon. HPA-1 b/b genotype might be a contributing factor but clearly does not predict platelet activation by GP IIb/IIIa inhibitors.
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Affiliation(s)
- Artur-Aron Weber
- Institut für Pharmakologie und Klinische Pharmakologie, Heinrich-Heine-Universität, Universitätsklinikum Düsseldorf, Moorenstr. 5, D-40225, Düsseldorf, Germany.
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O'Connor FF, Shields DC, Fitzgerald A, Cannon CP, Braunwald E, Fitzgerald DJ. Genetic variation in glycoprotein IIb/IIIa (GPIIb/IIIa) as a determinant of the responses to an oral GPIIb/IIIa antagonist in patients with unstable coronary syndromes. Blood 2001; 98:3256-60. [PMID: 11719362 DOI: 10.1182/blood.v98.12.3256] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
This study examined the influence of the Pl(A) polymorphism of glycoprotein IIIa (GPIIIa) in determining the response to an oral GPIIb/IIIa antagonist, orbofiban, in patients with unstable coronary syndromes. Genotyping for the Pl(A) polymorphism was performed in 1014 patients recruited into the OPUS-TIMI-16 (orbofiban in patients with unstable coronary syndromes-thrombolysis in myocardial infarction 16) trial, in which patients were randomized to low- or high-dose orbofiban or placebo for 1 year. The primary end point (n = 165) was a composite of death, myocardial infarction (MI), recurrent ischemia requiring rehospitalization, urgent revascularization, and stroke. Overall, orbofiban failed to reduce ischemic events when compared with placebo, but increased the rate of bleeding. In the whole population, Pl(A2) carriers had a significant increase in MI (n = 33) during follow up, with a relative risk (RR) of 2.71 (95% CI, 1.37 to 5.38; P =.004). There was a significant interaction between treatment (placebo and orbofiban) and the Pl(A) polymorphism for bleeding (n = 187; P =.05). Thus, while orbofiban increased bleeding in noncarriers (RR = 1.87, 1.29 to 2.71; P <.001) in a dose-dependent fashion, it did not increase bleeding events in Pl(A2) carriers (RR = 0.87, 0.46 to 1.64). There was no interaction between treatment (placebo and orbofiban) and the Pl(A) polymorphism for the primary end point (P =.10). However, in the patients receiving orbifiban there was a higher risk of a primary event (RR = 1.55, 1.03 to 2.34; P =.04) and MI (RR 4.27, 1.82 to 10.03; P <.001) in Pl(A2) carriers compared with noncarriers. In contrast, there was no evidence that Pl(A2) influenced the rate of recurrent events in placebo-treated patients. In patients presenting with an acute coronary syndrome, the Pl(A) polymorphism of GPIIb/IIIa may explain some of the variance in the response to an oral GPIIb/IIIa antagonist.
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Affiliation(s)
- F F O'Connor
- Department of Clinical Pharmacology, and Surgen Ltd, Royal College of Surgeons in Ireland
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