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      Association between insulin receptor substrate-1 polymorphisms and high platelet reactivity with clopidogrel therapy in coronary artery disease patients with type 2 diabetes mellitus

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          Abstract

          Background

          The mechanisms leading to the high on-treatment platelet reactivity in diabetes patients are not fully elucidated. The genetic factors may be associated with the diminished antiplatelet efficacy of dual antiplatelet therapy. We investigated the possible association between insulin receptor substrate-1 (IRS-1) polymorphisms and high platelet reactivity in coronary artery disease (CAD) patients with type 2 diabetes mellitus (T2DM).

          Methods

          A total of 674 CAD patients with T2DM were enrolled in this study. Platelet aggregation and platelet activation were assessed with light transmission aggregometry and flow cytometry analysis, respectively. Participants were divided into high platelet reactivity (HPR) group and non-HPR group according to their maximal platelet aggregation. Genotypes were identified by polymerase chain reaction and direct sequencing of genomic DNA. The association between IRS-1 genetic variants and platelet function was assessed.

          Results

          There were 233 participants in the HPR group and 441 participants in the non-HPR group. G allele frequencies of rs13431554 were 27.7 % for the HPR group and 18.6 % for the non-HPR group (p < 0.001). Adenosine diphosphate and arachidonic acid induced platelet aggregation were significantly higher in G allele carriers compared with non-carriers (56.8 ± 16.2 vs 52.0 ± 17.9 %, p < 0.01, 28.9 ± 18.6 vs 25.2 ± 17.8 %, p < 0.01, respectively). We observed that P-selectin expression and PAC-1 binding were higher in G allele carriers compared with non-carriers (40.8 ± 12.4 vs 36.2 ± 13.8, p = 0.01; 43.7 ± 15.9 vs 38.7 ± 19.9, p = 0.03, respectively).

          Conclusion

          The G allele of rs13431554 in the IRS-1 gene was associated with a hyperreactive platelet phenotype in the CAD patients with T2DM.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s12933-016-0362-0) contains supplementary material, which is available to authorized users.

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          Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial.

          J Stamler, O Vaccaro, J Neaton … (1993)
          To assess predictors of CVD mortality among men with and without diabetes and to assess the independent effect of diabetes on the risk of CVD death. Participants in this cohort study were screened from 1973 to 1975; vital status has been ascertained over an average of 12 yr of follow-up (range 11-13 yr). Participants were 347,978 men aged 35-57 yr, screened in 20 centers for MRFIT. The outcome measure was CVD mortality. Among 5163 men who reported taking medication for diabetes, 1092 deaths (603 CVD deaths) occurred in an average of 12 yr of follow-up. Among 342,815 men not taking medication for diabetes, 20,867 deaths were identified, 8965 ascribed to CVD. Absolute risk of CVD death was much higher for diabetic than nondiabetic men of every age stratum, ethnic background, and risk factor level--overall three times higher, with adjustment for age, race, income, serum cholesterol level, sBP, and reported number of cigarettes/day (P < 0.0001). For men both with and without diabetes, serum cholesterol level, sBP, and cigarette smoking were significant predictors of CVD mortality. For diabetic men with higher values for each risk factor and their combinations, absolute risk of CVD death increased more steeply than for nondiabetic men, so that absolute excess risk for diabetic men was progressively greater than for nondiabetic men with higher risk factor levels. These findings emphasize the importance of rigorous sustained intervention in people with diabetes to control blood pressure, lower serum cholesterol, and abolish cigarette smoking, and the importance of considering nutritional-hygienic approaches on a mass scale to prevent diabetes.
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            Genetic determinants of response to clopidogrel and cardiovascular events.

            Tabassome Simon, Céline Verstuyft, Murielle Mary-Krause … (2009)
            Pharmacogenetic determinants of the response of patients to clopidogrel contribute to variability in the biologic antiplatelet activity of the drug. The effect of these determinants on clinical outcomes after an acute myocardial infarction is unknown. We consecutively enrolled 2208 patients presenting with an acute myocardial infarction in a nationwide French registry and receiving clopidogrel therapy. We then assessed the relation of allelic variants of genes modulating clopidogrel absorption (ABCB1), metabolic activation (CYP3A5 and CYP2C19), and biologic activity (P2RY12 and ITGB3) to the risk of death from any cause, nonfatal stroke, or myocardial infarction during 1 year of follow-up. Death occurred in 225 patients, and nonfatal myocardial infarction or stroke in 94 patients, during the follow-up period. None of the selected single-nucleotide polymorphisms (SNPs) in CYP3A5, P2RY12, or ITGB3 were associated with a risk of an adverse outcome. Patients with two variant alleles of ABCB1 (TT at nucleotide 3435) had a higher rate of cardiovascular events at 1 year than those with the ABCB1 wild-type genotype (CC at nucleotide 3435) (15.5% vs. 10.7%; adjusted hazard ratio, 1.72; 95% confidence interval [CI], 1.20 to 2.47). Patients carrying any two CYP2C19 loss-of-function alleles (*2, *3, *4, or *5), had a higher event rate than patients with none (21.5% vs. 13.3%; adjusted hazard ratio, 1.98; 95% CI, 1.10 to 3.58). Among the 1535 patients who underwent percutaneous coronary intervention during hospitalization, the rate of cardiovascular events among patients with two CYP2C19 loss-of-function alleles was 3.58 times the rate among those with none (95% CI, 1.71 to 7.51). Among patients with an acute myocardial infarction who were receiving clopidogrel, those carrying CYP2C19 loss-of-function alleles had a higher rate of subsequent cardiovascular events than those who were not. This effect was particularly marked among the patients undergoing percutaneous coronary intervention. (ClinicalTrials.gov number, NCT00673036.) 2009 Massachusetts Medical Society
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              Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study.

              Jean-Philippe Collet, Jean-Sébastien Hulot, Anna Peña … (2009)
              Clopidogrel and low-dose aspirin have become the mainstay oral antiplatelet regimen to prevent recurrent ischaemic events after acute coronary syndromes or stent placement. The frequent genetic functional variant 681 G>A (*2) of cytochrome P450 2C19 (CYP2C19) is an important contributor to the wide variability between individuals of the antiplatelet effect of clopidogrel. We assessed whether the CYP2C19*2 polymorphism affected long-term prognosis of patients who were chronically treated with clopidogrel. Between April 1, 1996, and April 1, 2008, 259 young patients (aged <45 years) who survived a first myocardial infarction and were exposed to clopidogrel treatment for at least a month, were enrolled in a multicentre registry and underwent CYP2C19*2 determination. The primary endpoint was a composite of death, myocardial infarction, and urgent coronary revascularisation occurring during exposure to clopidogrel. Follow-up was every 6 months. The key secondary endpoint was stent thrombosis proven by angiography. Median clopidogrel exposure time was 1.07 years (IQR 0.28-3.0). Baseline characteristics were balanced between carriers (heterozygous *1/*2, n=64; homozygous *2/*2, n=9) and non-carriers (n=186) of CYP2C19*2 variant. The primary endpoint occurred more frequently in carriers than in non-carriers (15 vs 11 events; hazard ratio [HR] 3.69 [95% CI 1.69-8.05], p=0.0005), as did stent thrombosis (eight vs four events; HR 6.02 [1.81-20.04], p=0.0009). The detrimental effect of the CYP2C19*2 genetic variant persisted from 6 months after clopidogrel initiation up to the end of follow-up (HR 3.00 [1.27-7.10], p=0.009). After multivariable analysis, the CYP2C19*2 genetic variant was the only independent predictor of cardiovascular events (HR 4.04 [1.81-9.02], p=0.0006). The CYP2C19*2 genetic variant is a major determinant of prognosis in young patients who are receiving clopidogrel treatment after myocardial infarction.
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                Author and article information

                Contributors
                Dingyu Zhang: xiaolei217@sina.cn
                Xiaolin Zhang: xiaolindianyu75@sina.com
                Dan Liu: ayakim@163.com
                Tengfei Liu: alialick@163.com
                Wenzhi Cai: cutetaylor@126.com
                Chenghui Yan: zhangleishenyang@sina.com
                Yaling Han: hanyaling@263.net
                Journal
                Journal ID (nlm-ta): Cardiovasc Diabetol
                Journal ID (iso-abbrev): Cardiovasc Diabetol
                Title: Cardiovascular Diabetology
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1475-2840
                Publication date (Electronic): 22 March 2016
                Publication date PMC-release: 22 March 2016
                Publication date Collection: 2016
                Volume: 15
                Electronic Location Identifier: 50
                Affiliations
                Cardiovascular Research Institute and Department of Cardiology, Shenyang Northern Hospital, 83 Wenhua Road, Shenyang, 110840 China
                Article
                Publisher ID: 362
                DOI: 10.1186/s12933-016-0362-0
                PMC ID: 4804508
                PubMed ID: 27005817
                SO-VID: 33c3594b-b903-4188-9e61-36fec702951b
                Copyright © © Zhang et al. 2016
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 28 October 2015
                Date accepted : 3 March 2016
                Funding
                Funded by: the National Research Key Project of the Twelfth Five-Year Plan of Republic of China
                Award ID: No.2011BAI11B07
                Award Recipient :
                Funded by: Major High-tech Clinical Army Projects
                Award ID: No. 2010GXJS001
                Award Recipient :
                Funded by: the National Young Science Foundation of China
                Award ID: 81100135
                Award Recipient :
                Funded by: key Project of National 12th Five-Year Research Program of China
                Award ID: 2012ZX09303016-002
                Award Recipient :
                Funded by: National Basic Research Program of China
                Award ID: 973 Program 2012CB517804
                Award Recipient :
                Categories
                Subject: Original Investigation
                Custom metadata
                issue-copyright-statement © The Author(s) 2016

                ScienceOpen disciplines: Endocrinology & Diabetes
                Keywords: insulin receptor substrate-1,single nucleotide polymorphism,high platelet reactivity,clopidogrel,coronary artery disease,type 2 diabetes mellitus
                Data availability:
                ScienceOpen disciplines: Endocrinology & Diabetes
                Keywords: insulin receptor substrate-1, single nucleotide polymorphism, high platelet reactivity, clopidogrel, coronary artery disease, type 2 diabetes mellitus

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