BTK、PLCG2、CYP3A4、TP53基因多态性及TPO浓度与伊布替尼出血风险的相关性

doi:10.12092/j.issn.1009-2501.2026.07.004

摘要/Abstract

摘要：

目的: 探讨布鲁顿酪氨酸激酶（Bruton’s tyrosine kinase，BTK）、磷脂酶Cγ2（phospholipase C gamma 2，PLCG2）、细胞色素P450 3A4（CYP3A4）及肿瘤蛋白p53（tumor protein p53，TP53）基因常见单核苷酸多态性（single nucleotide polymorphism，SNP）与血浆血小板生成素（thrombopoietin，TPO）浓度及伊布替尼治疗相关出血事件之间的关联，为个体化风险管理提供依据。方法: 回顾性纳入2022年1月至2024年2月于安徽医科大学第一附属医院接受伊布替尼治疗的34例B细胞非霍奇金淋巴瘤患者。通过基质辅助激光解吸电离飞行时间质谱（MALDI-TOF MS）对选定的4个基因共17个SNP位点进行基因分型。采用酶联免疫吸附法（ELISA）测定血浆TPO浓度。依据CTCAE 5.0标准评估治疗相关出血不良反应。统计分析采用χ²检验、Fisher精确检验、独立样本t检验及Spearman相关分析。结果: 34例患者中，24例（70.6%）出现不良反应，其中出血（1～2级）最为常见（15例，44.1%）。遗传分析显示，所有检测的SNP位点的基因型分布在出血组与未出血组间均无显著差异（所有P>0.05）。然而，出血患者的血浆TPO浓度显著高于未出血患者（540.6 ± 94.6 pg/mL vs. 483.7±60.5 pg/mL，P=0.041）。进一步分析未发现上述SNP位点多态性与TPO浓度存在显著关联（所有P>0.05）。结论: 在本研究队列样本中，所考察的BTK、PLCG2、CYP3A4及TP53基因常见多态性并非伊布替尼相关出血风险的主要决定因素。血浆TPO浓度升高与出血事件显著相关，提示其或可作为预测伊布替尼治疗出血风险的潜在生物标志物，该标志物仍需在更大规模前瞻性研究中验证。

关键词: 伊布替尼, 出血, 单核苷酸多态性, 血小板生成素, 相关性研究

Abstract:

AIM: To explore the association between common single nucleotide polymorphisms (SNPs) in Bruton's tyrosine kinase (BTK), phospholipase Cγ2 (phospholipase C gamma 2, PLCG2), CYP3A4 (cytochrome), and tumor protein p53 (TP53) genes, plasma thrombopoietin (TPO) concentration, and ibrutinib treatment-related bleeding events, and to provide reference for individualized risk management. METHODS: A retrospective analysis was conducted on 34 patients with B-cell non-Hodgkin lymphoma who received ibrutinib treatment at the First Affiliated Hospital of Anhui Medical University from January 2022 to February 2024. Genotyping of 17 selected SNP sites across the four genes was performed using matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). Plasma TPO concentration was measured by enzyme-linked immunosorbent assay (ELISA). Treatment-related bleeding adverse reactions were assessed according to CTCAE 5.0 criteria. Statistical analyses included the χ² test, Fisher's exact test, independent samples t-test, and Spearman correlation analysis. RESULTS: Among the 34 patients, 24 (70.6%) experienced adverse reactions, with bleeding (grades 1-2) being the most common (15 cases, 44.1%). Genetic analysis revealed no significant differences in genotype distribution for all detected SNP loci (including TP53 rs1042522, CYP3A4 rs2246709, etc.) between the bleeding and non-bleeding groups (all P>0.05). However, plasma TPO concentration was significantly higher in patients with bleeding compared to those without bleeding (540.6 ± 94.6 pg/mL vs. 483.7±60.5 pg/mL, P=0.041). Further analysis found no significant association between the polymorphisms at the studied SNP site and TPO concentration (all P> 0.05). CONCLUSION: The common polymorphisms in the BTK, PLCG2, CYP3A4, and TP53 genes were not major determinants of ibrutinib-associated bleeding risk. Elevated plasma TPO concentration was significantly correlated with bleeding events, suggesting it may serve as a potential biomarker for predicting bleeding risk during ibrutinib therapy. This marker requires validation in larger-scale prospective studies.

Key words: ibrutinib, bleeding, single nucleotide polymorphism, thrombopoietin, correlation study

中图分类号:

R979.1
R969

钱磊, 韩功伟, 阮晓敏, 李余芳, 刘沁华, 夏泉. BTK、PLCG2、CYP3A4、TP53基因多态性及TPO浓度与伊布替尼出血风险的相关性[J]. 中国临床药理学与治疗学, 2026, 31(7): 892-898.

Lei QIAN, Gongwei HAN, Xiaomin RUAN, Yufang LI, Qinhua LIU, Quan XIA. Correlation between BTK, PLCG2, CYP3A4, and TP53 gene polymorphisms, and TPO concentration, and bleeding risk associated with ibrutinib[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2026, 31(7): 892-898.

图/表 5

参考文献 18

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Item	Overall (n=34)	Bleeding Group (n=15)	Non-Bleeding Group (n=19)	P-value
Gender/n(%)				0.608
Male	22(64.7)	9(60.0)	13(68.4)
Female	12(35.3)	6(40.0)	6(31.6)
Age/years	61.1±7.2	59.9±5.6	62.0±7.8	0.325
Diagnosis/n(%)				0.645
CLL/SLL	21(61.8)	10(66.7)	11(57.9)
WM	7(20.6)	2(13.3)	5(26.3)
MCL	6(17.6)	3(20.0)	3(15.8)
Ibrutinib daily dose/n(%)				1.000
420 mg	29(85.3)	13(86.7)	16(84.2)
560 mg	4(11.8)	2(13.3)	2(10.5)
280 mg	1(2.9)	0(0.0)	1(5.3)
Hypertension history/n(%)				0.231
Yes	8(23.5)	5(33.3)	3(15.8)
No	26(76.5)	10(66.7)	16(84.2)
Cardiac disease history/n(%)				0.439
Yes	1(2.9)	1(6.7)	0(0.0)
No	33(97.1)	14(93.3)	19(100.0)
Family history of tumors/n(%)				0.439
Yes	1(2.9)	1(6.7)	0(0.0)
No	33(97.1)	14(93.3)	19(100.0)
Adverse reactions/n(%)
Overall	24(70.6)
Bleeding (Grade 1-2)	15(44.1)
Hypertension	5(14.7)
Atrial fibrillation	5(14.7)
Rash	2(5.9)

Item	Overall (n=34)	Bleeding Group (n=15)	Non-Bleeding Group (n=19)	P-value
Gender/n(%)				0.608
Male	22(64.7)	9(60.0)	13(68.4)
Female	12(35.3)	6(40.0)	6(31.6)
Age/years	61.1±7.2	59.9±5.6	62.0±7.8	0.325
Diagnosis/n(%)				0.645
CLL/SLL	21(61.8)	10(66.7)	11(57.9)
WM	7(20.6)	2(13.3)	5(26.3)
MCL	6(17.6)	3(20.0)	3(15.8)
Ibrutinib daily dose/n(%)				1.000
420 mg	29(85.3)	13(86.7)	16(84.2)
560 mg	4(11.8)	2(13.3)	2(10.5)
280 mg	1(2.9)	0(0.0)	1(5.3)
Hypertension history/n(%)				0.231
Yes	8(23.5)	5(33.3)	3(15.8)
No	26(76.5)	10(66.7)	16(84.2)
Cardiac disease history/n(%)				0.439
Yes	1(2.9)	1(6.7)	0(0.0)
No	33(97.1)	14(93.3)	19(100.0)
Family history of tumors/n(%)				0.439
Yes	1(2.9)	1(6.7)	0(0.0)
No	33(97.1)	14(93.3)	19(100.0)
Adverse reactions/n(%)
Overall	24(70.6)
Bleeding (Grade 1-2)	15(44.1)
Hypertension	5(14.7)
Atrial fibrillation	5(14.7)
Rash	2(5.9)

Gene	SNP-ID	HWE Equilibrium Test
BTK	rs1057519825	NA
	rs1603004481	NA
PLCG2	rs1057519831	NA
	rs397514562	NA
	rs763369976	NA
	rs774452862	NA
	rs72824905	NA
CYP3A4	rs72552798	NA
	rs4986913	NA
	rs12721634	NA
	rs1449865051	NA
	rs28371759	0.945
	rs57409622	NA
	rs113667357	NA
	rs2246709	0.215
	rs4646440	0.147
TP53	rs1042522	0.015

Gene	SNP-ID	HWE Equilibrium Test
BTK	rs1057519825	NA
	rs1603004481	NA
PLCG2	rs1057519831	NA
	rs397514562	NA
	rs763369976	NA
	rs774452862	NA
	rs72824905	NA
CYP3A4	rs72552798	NA
	rs4986913	NA
	rs12721634	NA
	rs1449865051	NA
	rs28371759	0.945
	rs57409622	NA
	rs113667357	NA
	rs2246709	0.215
	rs4646440	0.147
TP53	rs1042522	0.015

Gene	SNP ID	Genotype	Bleeding group (n=15)	Non- bleeding group (n=19)	P- value
CYP3A4	rs2246709	GG+AG	9	14	0.490
		AA	6	5
	rs4646440	AG+AA	9	9	0.527
		GG	6	10
	rs28371759	AG	0	1	1.000
		AA	15	18
TP53	rs1042522	CC+CG	12	14	1.000
		GG	3	5