Variants in clopidogrel-relevant genes and early neurological deterioration in ischemic stroke patients receiving clopidogrel_West China Medical Journal

Authors：

QING Ting ¹ ,  YI Xingyang ^1,2 , WANG Chun ² , ZENG Tao ² , LUO Hua ¹ , LI Zuoxiao ¹ , LIN Jing ³ , ZHOU Qiang ³

1. Department of Neurology, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P. R. China;
2. Department of Neurology, People’s Hospital of Deyang City, Deyang, Sichuan 618000, P. R. China;
3. Department of Neurology, the Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325200, P. R. China;

Corresponding author：

YI Xingyang, Email: yixingyang64@126.com

Keywords：

Ischemic stroke; early neurological deterioration; clopidogrel; genetic polymorphism; generalized multifactor dimensionality reduction

DOI：

10.7507/1002-0179.202112086

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Objective To evaluate the associations of 16 variants in clopidogrel-relevant genes with early neurological deterioration (END) in acute ischemic stroke (AIS) patients receiving clopidogrel treatment. Methods AIS patients admitted to the Department of Neurology of three hospitals between June 2014 and January 2015 were included. The 16 variants in clopidogrel-relevant genes were examined using mass spectrometry. Gene-gene interactions were analyzed by generalized multifactor dimensionality reduction (GMDR) methods. The primary outcome was END within the 10 days of admission. Results A total of 375 patients with AIS were included. Among the 375 patients, 95 (25.33%) patients developed END within the first 10 days of admission. Among the 16 variants, only CYP2C19*2 rs4244285 AG+AA was associated with END using single-locus analytical approach (P<0.001). GMDR analysis revealed that there was a synergistic effect of gene-gene interactions among CYP2C19*2 rs4244285, P2Y12 rs16863323, and GPⅢa rs2317676 on risk for END (P=0.019). Cox regression analysis showed that the high-risk interactive genotype was independent predictor for END [hazard ratio=2.184, 95% confidence interval (1.472, 3.238), P=0.004]. Conclusions END is very common in patients with AIS. Interactions among CYP2C19*2 rs4244285, P2Y12 rs16863323, and GPⅢa rs2317676 may confer a higher risk for END. It may be very important to modify clopidogrel therapy for the patients carrying the high-risk interactive genotype.

Citation： QING Ting, YI Xingyang, WANG Chun, ZENG Tao, LUO Hua, LI Zuoxiao, LIN Jing, ZHOU Qiang. Variants in clopidogrel-relevant genes and early neurological deterioration in ischemic stroke patients receiving clopidogrel. West China Medical Journal, 2022, 37(6): 830-837. doi: 10.7507/1002-0179.202112086 Copy

1.	Yi X, Han Z, Zhou Q, et al. 20-hydroxyeicosatetraenoic acid as a predictor of neurological deterioration in acute minor ischemic stroke. Stroke, 2016, 47(12): 3045-3047.
2.	Vahidy FS, Hicks WJ 2nd, Acosta I, et al. Neurofluctuation in patients with subcortical ischemic stroke. Neurology, 2014, 83(5): 398-405.
3.	周锦涛, 易兴阳, 林静, 等. 环氧二十碳三烯酸受 EPHX2 基因调控与急性缺血性小卒中后早期神经功能恶化发生相关. 中华神经科杂志, 2021, 54(5): 441-448.
4.	Yang JY, Gao Y. Clinical relevance of serum omentin-1 levels as a biomarker of prognosis in patients with acute cerebral infarction. Brain Behav, 2020, 10(7): e01678.
5.	CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet, 1996, 348(9038): 1329-1339.
6.	Yin T, Miyata T. Pharmacogenomics of clopidogrel: evidence and perspectives. Thromb Res, 2011, 128(4): 307-316.
7.	Wiśniewski A, Filipska K. The phenomenon of clopidogrel high on-treatment platelet reactivity in ischemic stroke subjects: a comprehensive review. Int J Mol Sci, 2020, 21(17): 6408.
8.	Rho GJ, Shin WR, Kong TS, et al. Significance of clopidogrel resistance related to the stent-assisted angisoplasty in patients with atherosclerotic cerebrovascular disease. J Korean Neurosurg Soc, 2011, 50(1): 40-44.
9.	Yi X, Wang Y, Lin J, et al. Interaction of CYP2C19, P2Y12, and GPⅢa variants associates with efficacy of clopidogrel and adverse events on patients with ischemic stroke. Clin Appl Thromb Hemost, 2017, 23(7): 761-768.
10.	Han SW, Kim SH, Lee JY, et al. A new subtype classification of ischemic stroke based on treatment and etiologic mechanism. Eur Neurol, 2007, 57(2): 96-102.
11.	Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke, 2014, 45(7): 2160-2236.
12.	王拥军, 王春雪, 缪中荣. 中国缺血性脑卒中和短暂性脑缺血发作二级预防指南 2014. 中华神经科杂志, 2015, 48(4): 258-273.
13.	Wang Y, Wang Y, Zhao X, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med, 2013, 369(1): 11-19.
14.	Lin J, Han Z, Wang C, et al. Dual therapy with clopidogrel and aspirin prevents early neurological deterioration in ischemic stroke patients carrying CYP2C19*2 reduced-function alleles. Eur J Clin Pharmacol, 2018, 74(9): 1131-1140.
15.	孙加琳, 李静, 郭切, 等. 细胞色素 P4502C19 基因多态性对脑卒中并发 2 型糖尿病患者氯吡格雷反应性的影响. 中国临床药理学杂志, 2021, 37(13): 1638-1640.
16.	刘洋, 樊双义. 氯吡格雷抵抗: 基因多态性和药物相互作用. 国际脑血管病杂志, 2017, 25(9): 844-852.
17.	Baturina O, Andreev D, Fedina L, et al. Influence of clinically significant genes on antiplatelet effect of clopidogrel and clinical outcomes in patients with acute coronary syndrome and atrial fibrillation. Pharmacology, 2022: 1-11.
18.	Umemura T, Senda J, Fukami Y, et al. Impact of albuminuria on early neurological deterioration and lesion volume expansion in lenticulostriate small infarcts. Stroke, 2014, 45(2): 587-590.
19.	罗丹阳, 刘信东, 柳华, 等. 急性缺血性脑卒中早期神经功能恶化危险因素及其交互效应分析. 西部医学, 2021, 33(6): 874-878.
20.	Nam KW, Kang MK, Jeong HY, et al. Triglyceride-glucose index is associated with early neurological deterioration in single subcortical infarction: early prognosis in single subcortical infarctions. Int J Stroke, 2021, 16(8): 944-952.
21.	Lou XY, Chen GB, Yan L, et al. A generalized combinatorial approach for detecting gene-by-gene and gene-by-environment interactions with application to nicotine dependence. Am J Hum Genet, 2007, 80(6): 1125-1137.
22.	Martínez-Quintana E, Tugores A. Clopidogrel: a multifaceted affair. Clin Pharmacol, 2015, 55(1): 1-9.
23.	轩继中, 程兆云, 赵子牛, 等. 抗血小板药物基因检测技术在冠状动脉旁路移植术后个体化用药中的临床应用. 中国动脉硬化杂志, 2018, 26(9): 920-924.
24.	夏春勇, 张作文, 贺小艳, 等. 缺血性脑卒中患者 CYP2C19 基因多态性与个体化用药的相关性. 中国临床药理学与治疗学, 2021, 26(3): 318-323.
25.	刘艺, 陶婷, 孙增先. 氯吡格雷抵抗的危险因素. 国际脑血管病杂志, 2021, 29(7): 521-525.
26.	Alhazzani A, Venkatachalapathy P, Padhilahouse S, et al. Biomarkers for antiplatelet therapies in acute ischemic stroke: a clinical review. Front Neurol, 2021, 12: 667234.
27.	Simon T, Verstuyft C, Mary-Krause M, et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med, 2009, 360(4): 363-375.
28.	董梅, 赵仕琪, 李震中. 氯吡格雷治疗后血小板高反应性的影响因素研究进展. 脑与神经疾病杂志, 2020, 38(3): 185-188.
29.	Fontana P, Dupont A, Gandrille S, et al. Adenosine diphosphate-induced platelet aggregation is associated with P2Y12 gene sequence variations in healthy subjects. Circulation, 2003, 108(8): 989-995.
30.	Fujisaki T, Kuno T, Ando T, et al. Potent P2Y12 inhibitors versus clopidogrel in elderly patients with acute coronary syndrome: systematic review and meta-analysis. Am Heart J, 2021, 237: 34-44.
31.	Li JL, Fu Y, Qin SB, et al. Association between P2RY12 gene polymorphisms and adverse clinical events in coronary artery disease patients treated with clopidogrel: a systematic review and meta-analysis. Gene, 2018, 657: 69-80.

1. Yi X, Han Z, Zhou Q, et al. 20-hydroxyeicosatetraenoic acid as a predictor of neurological deterioration in acute minor ischemic stroke. Stroke, 2016, 47(12): 3045-3047.
2. Vahidy FS, Hicks WJ 2nd, Acosta I, et al. Neurofluctuation in patients with subcortical ischemic stroke. Neurology, 2014, 83(5): 398-405.
3. 周锦涛, 易兴阳, 林静, 等. 环氧二十碳三烯酸受 EPHX2 基因调控与急性缺血性小卒中后早期神经功能恶化发生相关. 中华神经科杂志, 2021, 54(5): 441-448.
4. Yang JY, Gao Y. Clinical relevance of serum omentin-1 levels as a biomarker of prognosis in patients with acute cerebral infarction. Brain Behav, 2020, 10(7): e01678.
5. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet, 1996, 348(9038): 1329-1339.
6. Yin T, Miyata T. Pharmacogenomics of clopidogrel: evidence and perspectives. Thromb Res, 2011, 128(4): 307-316.
7. Wiśniewski A, Filipska K. The phenomenon of clopidogrel high on-treatment platelet reactivity in ischemic stroke subjects: a comprehensive review. Int J Mol Sci, 2020, 21(17): 6408.
8. Rho GJ, Shin WR, Kong TS, et al. Significance of clopidogrel resistance related to the stent-assisted angisoplasty in patients with atherosclerotic cerebrovascular disease. J Korean Neurosurg Soc, 2011, 50(1): 40-44.
9. Yi X, Wang Y, Lin J, et al. Interaction of CYP2C19, P2Y12, and GPⅢa variants associates with efficacy of clopidogrel and adverse events on patients with ischemic stroke. Clin Appl Thromb Hemost, 2017, 23(7): 761-768.
10. Han SW, Kim SH, Lee JY, et al. A new subtype classification of ischemic stroke based on treatment and etiologic mechanism. Eur Neurol, 2007, 57(2): 96-102.
11. Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke, 2014, 45(7): 2160-2236.
12. 王拥军, 王春雪, 缪中荣. 中国缺血性脑卒中和短暂性脑缺血发作二级预防指南 2014. 中华神经科杂志, 2015, 48(4): 258-273.
13. Wang Y, Wang Y, Zhao X, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med, 2013, 369(1): 11-19.
14. Lin J, Han Z, Wang C, et al. Dual therapy with clopidogrel and aspirin prevents early neurological deterioration in ischemic stroke patients carrying CYP2C19*2 reduced-function alleles. Eur J Clin Pharmacol, 2018, 74(9): 1131-1140.
15. 孙加琳, 李静, 郭切, 等. 细胞色素 P4502C19 基因多态性对脑卒中并发 2 型糖尿病患者氯吡格雷反应性的影响. 中国临床药理学杂志, 2021, 37(13): 1638-1640.
16. 刘洋, 樊双义. 氯吡格雷抵抗: 基因多态性和药物相互作用. 国际脑血管病杂志, 2017, 25(9): 844-852.
17. Baturina O, Andreev D, Fedina L, et al. Influence of clinically significant genes on antiplatelet effect of clopidogrel and clinical outcomes in patients with acute coronary syndrome and atrial fibrillation. Pharmacology, 2022: 1-11.
18. Umemura T, Senda J, Fukami Y, et al. Impact of albuminuria on early neurological deterioration and lesion volume expansion in lenticulostriate small infarcts. Stroke, 2014, 45(2): 587-590.
19. 罗丹阳, 刘信东, 柳华, 等. 急性缺血性脑卒中早期神经功能恶化危险因素及其交互效应分析. 西部医学, 2021, 33(6): 874-878.
20. Nam KW, Kang MK, Jeong HY, et al. Triglyceride-glucose index is associated with early neurological deterioration in single subcortical infarction: early prognosis in single subcortical infarctions. Int J Stroke, 2021, 16(8): 944-952.
21. Lou XY, Chen GB, Yan L, et al. A generalized combinatorial approach for detecting gene-by-gene and gene-by-environment interactions with application to nicotine dependence. Am J Hum Genet, 2007, 80(6): 1125-1137.
22. Martínez-Quintana E, Tugores A. Clopidogrel: a multifaceted affair. Clin Pharmacol, 2015, 55(1): 1-9.
23. 轩继中, 程兆云, 赵子牛, 等. 抗血小板药物基因检测技术在冠状动脉旁路移植术后个体化用药中的临床应用. 中国动脉硬化杂志, 2018, 26(9): 920-924.
24. 夏春勇, 张作文, 贺小艳, 等. 缺血性脑卒中患者 CYP2C19 基因多态性与个体化用药的相关性. 中国临床药理学与治疗学, 2021, 26(3): 318-323.
25. 刘艺, 陶婷, 孙增先. 氯吡格雷抵抗的危险因素. 国际脑血管病杂志, 2021, 29(7): 521-525.
26. Alhazzani A, Venkatachalapathy P, Padhilahouse S, et al. Biomarkers for antiplatelet therapies in acute ischemic stroke: a clinical review. Front Neurol, 2021, 12: 667234.
27. Simon T, Verstuyft C, Mary-Krause M, et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med, 2009, 360(4): 363-375.
28. 董梅, 赵仕琪, 李震中. 氯吡格雷治疗后血小板高反应性的影响因素研究进展. 脑与神经疾病杂志, 2020, 38(3): 185-188.
29. Fontana P, Dupont A, Gandrille S, et al. Adenosine diphosphate-induced platelet aggregation is associated with P2Y12 gene sequence variations in healthy subjects. Circulation, 2003, 108(8): 989-995.
30. Fujisaki T, Kuno T, Ando T, et al. Potent P2Y12 inhibitors versus clopidogrel in elderly patients with acute coronary syndrome: systematic review and meta-analysis. Am Heart J, 2021, 237: 34-44.
31. Li JL, Fu Y, Qin SB, et al. Association between P2RY12 gene polymorphisms and adverse clinical events in coronary artery disease patients treated with clopidogrel: a systematic review and meta-analysis. Gene, 2018, 657: 69-80.

West China Medical Journal

Variants in clopidogrel-relevant genes and early neurological deterioration in ischemic stroke patients receiving clopidogrel

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