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

Video：

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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.	周錦濤, 易興陽, 林靜, 等. 環氧二十碳三烯酸受 EPHX2 基因調控與急性缺血性小卒中后早期神經功能惡化發生相關. 中華神經科雜志, 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.	Wi?niewski 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.	王擁軍, 王春雪, 繆中榮. 中國缺血性腦卒中和短暫性腦缺血發作二級預防指南 2014. 中華神經科雜志, 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.	孫加琳, 李靜, 郭切, 等. 細胞色素 P4502C19 基因多態性對腦卒中并發 2 型糖尿病患者氯吡格雷反應性的影響. 中國臨床藥理學雜志, 2021, 37(13): 1638-1640.
16.	劉洋, 樊雙義. 氯吡格雷抵抗: 基因多態性和藥物相互作用. 國際腦血管病雜志, 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.	羅丹陽, 劉信東, 柳華, 等. 急性缺血性腦卒中早期神經功能惡化危險因素及其交互效應分析. 西部醫學, 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.	軒繼中, 程兆云, 趙子牛, 等. 抗血小板藥物基因檢測技術在冠狀動脈旁路移植術后個體化用藥中的臨床應用. 中國動脈硬化雜志, 2018, 26(9): 920-924.
24.	夏春勇, 張作文, 賀小艷, 等. 缺血性腦卒中患者 CYP2C19 基因多態性與個體化用藥的相關性. 中國臨床藥理學與治療學, 2021, 26(3): 318-323.
25.	劉藝, 陶婷, 孫增先. 氯吡格雷抵抗的危險因素. 國際腦血管病雜志, 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, 趙仕琪, 李震中. 氯吡格雷治療后血小板高反應性的影響因素研究進展. 腦與神經疾病雜志, 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. 周錦濤, 易興陽, 林靜, 等. 環氧二十碳三烯酸受 EPHX2 基因調控與急性缺血性小卒中后早期神經功能惡化發生相關. 中華神經科雜志, 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. Wi?niewski 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. 王擁軍, 王春雪, 繆中榮. 中國缺血性腦卒中和短暫性腦缺血發作二級預防指南 2014. 中華神經科雜志, 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. 孫加琳, 李靜, 郭切, 等. 細胞色素 P4502C19 基因多態性對腦卒中并發 2 型糖尿病患者氯吡格雷反應性的影響. 中國臨床藥理學雜志, 2021, 37(13): 1638-1640.
16. 劉洋, 樊雙義. 氯吡格雷抵抗: 基因多態性和藥物相互作用. 國際腦血管病雜志, 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. 羅丹陽, 劉信東, 柳華, 等. 急性缺血性腦卒中早期神經功能惡化危險因素及其交互效應分析. 西部醫學, 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. 軒繼中, 程兆云, 趙子牛, 等. 抗血小板藥物基因檢測技術在冠狀動脈旁路移植術后個體化用藥中的臨床應用. 中國動脈硬化雜志, 2018, 26(9): 920-924.
24. 夏春勇, 張作文, 賀小艷, 等. 缺血性腦卒中患者 CYP2C19 基因多態性與個體化用藥的相關性. 中國臨床藥理學與治療學, 2021, 26(3): 318-323.
25. 劉藝, 陶婷, 孫增先. 氯吡格雷抵抗的危險因素. 國際腦血管病雜志, 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, 趙仕琪, 李震中. 氯吡格雷治療后血小板高反應性的影響因素研究進展. 腦與神經疾病雜志, 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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