CN114164263A - Mapk4基因多态性作为预测甲氨蝶呤临床疗效的基因标志物及检测试剂盒 - Google Patents

Mapk4基因多态性作为预测甲氨蝶呤临床疗效的基因标志物及检测试剂盒 Download PDF

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CN114164263A
CN114164263A CN202011496584.8A CN202011496584A CN114164263A CN 114164263 A CN114164263 A CN 114164263A CN 202011496584 A CN202011496584 A CN 202011496584A CN 114164263 A CN114164263 A CN 114164263A
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mapk4
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颜克香
徐金华
张学军
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Huashan Hospital of Fudan University
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Abstract

本发明属生物技术领域，涉及银屑病药物疗效检测基因标志物及检测试剂盒，具体涉及MAPK4 SNP位点rs12961853 CC基因型作为预测甲氨蝶呤治疗银屑病的临床疗效的基因标志物；进一步提供了用于检测MAPK4 SNP位点rs12961853基因型与MTX治疗银屑病临床疗效的关系的检测试剂盒，针对携带MAPK4 SNP位点rs12961853基因型与否的银屑病患者用MTX治疗干预的有效率的发生情况，预测评估MTX治疗银屑病的临床疗效，有助于指导临床实践制定适合的MTX治疗干预方案，为提高MTX的临床疗效提供基础。

Description

MAPK4基因多态性作为预测甲氨蝶呤临床疗效的基因标志物 及检测试剂盒
技术领域
本发明属于生物技术领域，涉及银屑病药物疗效检测试剂盒，具体涉及一种一种用于预测甲氨蝶呤(MTX)治疗银屑病临床疗效的检测试剂盒，该试剂盒通过检测银屑病患者MAPK4的SNP位点，预测MTX的临床疗效。本发明可用于临床制定适合的MTX治疗干预方案，为提高MTX的临床疗效提供基础。
背景技术
现有技术公开了银屑病为常见的慢性炎症性疾病，可累及皮肤、指甲、关节、肾脏、心血管等多个脏器。由于该疾患发病率高、病程长、易复发、难根治，给患者带来严重的身心损害和经济负担。目前临床实践中常采用的药物干预中，如常使用的阿维A有效率只有20％左右，而且会引起血脂增高，增加患者心血管疾病的风险，有甚者还会出现肝肾功能的损害；生物制剂的临床有效率虽然高在50％-80％左右，但由于价格昂贵，致使大多数患者无力承担；甲氨蝶呤(MTX)为目前较常采用的较经济、有效的治疗银屑病的药物，但由于其存在有骨髓抑制和肝纤维化影响的风险，严重限制了MTX在银屑病治疗中的广泛应用。因此，寻找能用于预测MTX的临床疗效和毒副作用的生物标记，有利于提高临床疗效和降低毒副作用，该课题已成为本领域技术人员关注的热点。
研究显示，银屑病是一定遗传背景下由免疫细胞与角质形成细胞相互作用共同介导的慢性炎症性疾病，临床表现为边界清楚的白色鳞屑性斑块，特征性的组织病理表现与表皮分化异常密切相关。MAPK是信号从细胞表面传导到细胞核内部的重要传递者。丝裂原活化蛋白激酶(mitogen-activated protein kinase，MAPK)是一组能被不同的细胞外刺激，如细胞因子、神经递质、激素、细胞应激及细胞黏附等激活的丝氨酸-苏氨酸蛋白激酶。MAPK4是丝裂原活化蛋白激酶中的一员，在银屑病发病中的作用机制以及MAPK4基因多态性与MTX临床疗效间的关系等尚未见相关报道。
MTX在1972年被FDA批准治疗银屑病，其结构类似叶酸，与二氢叶酸还原酶不可逆地结合，发挥抗增殖活性，诱导凋亡和增加腺苷浓度，具有抗炎和免疫调节作用。有研究发现叶酸代谢通路相关的酶的基因多态性与MTX治疗类风湿性关节炎的临床疗效和毒副作用的相关：如MTHFR1298A＞C(rs1801131)，ATIC347C＞G(rs2372536)，RFC-180G＞A(rs1051266)，SLC19A1A＞G(rs2838956)and SLC19A1G＞A(rs7499)与MTX的临床疗效相关；而RFC-180G＞A(rs1051266)基因多态性与MTX的毒性相关。
基于现有技术的基础与现状，本申请的发明人拟通过研究MAPK4 SNP位点rs12961853基因型与MTX治疗银屑病临床疗效的关系，提供MAPK4 SNP位点rs12961853CC基因型作为预测MTX治疗银屑病的临床疗效的基因标志物，以及用于制备预测甲氨蝶呤治疗银屑病临床疗效的检测试剂盒。
发明内容
本发明的目的是基于现有技术的现状，提供新的预测MTX临床疗效的基因标志物，本发明通过研究携带MAPK4 SNP位点rs12961853 TT和CT基因型的银屑病患者用MTX治疗有效率，提出了MAPK4 SNP位点rs12961853 CC基因型可作为预测MTX治疗银屑病的临床疗效的基因标志物；
本发明的进一步目的是提供用于预测甲氨蝶呤治疗银屑病临床疗效的检测试剂盒。本发明中，通过研究MAPK4 SNP位点rs12961853基因型与MTX治疗银屑病临床疗效的关系，如携带MAPK4 SNP位点rs12961853 CC基因型与否的银屑病患者用MTX治疗的有效率的发生情况用于预测MTX治疗银屑病的临床疗效的评估，有助于指导临床实践制定适合的MTX治疗干预方案。
本发明中，检测了310例银屑病患者MAPK4 SNP位点rs12961853的基因型与MTX治疗银屑病临床疗效间的关系，分型成功309例，结果显示：1)携带MAPK4 SNP rs12961853 TT和CT基因型的患者在治疗第8周PASI50的改善率(61.2％和55.4％)显著高于携带CC基因型患者(40.0％)，差异有统计学意义，p＝0.0333；2)携带MAPK4 SNP rs12961853 TT和CT基因型的患者在治疗第12周PASI75的改善率(51.7％和48.9％)显著高于携带CC基因型患者(23.7％)，差异有统计学意义，p＝0.0158。
本发明经试验结果证实，检测银屑病患者MAPK4 SNP位点rs12961853的基因型，可用作预测MTX治疗银屑病的临床疗效。
本发明进一步实验结果显示，未经基因检测MTX治疗银屑病的临床疗效为46.5％，针对携带MAPK4 SNP位点rs12961853TT和CT基因型的银屑病患者采用MTX治疗干预，其有效率可提高至50.2％，结果表明，携带MAPK4 SNP位点rs12961853 CC基因型的银屑病患者采用MTX治疗干预有效率低，仅29.1％。
本发明提供了新的预测MTX临床疗效的基因标志物，尤其涉及MAPK4 SNP位点rs12961853 CC基因型可作为预测MTX治疗银屑病的临床疗效的基因标志物；
本发明进一步提供了用于预测甲氨蝶呤治疗银屑病临床疗效的检测试剂盒，针对携带MAPK4 SNP位点rs12961853 TT和CT基因型否的银屑病患者采用MTX治疗干预其治疗有效率高；本发明可用于预测MTX治疗银屑病的临床疗效的评估，有助于指导临床实践制定适合的MTX治疗干预方案。
本发明所述的MAPK4基因的基因图谱，可按下述查找：
https://www.ncbi.nlm.nih.gov/genome/gdv/browser/genome/？id＝GCF_ 000001405.39。
具体实施方式
实施例1：MAPK4基因多态性与MTX治疗银屑病的临床疗效的相关性
材料与方法：
1)银屑病患者：选定2015年1月到2019年6月到华山医院皮肤科银屑病专病门诊就诊的银屑病患者为观察对象；
2)用药干预方法：治疗第1周和第2周每周单次口服MTX7.5mg，第3周到第4周每周单次口服10mg，第5周到第12周每周单次口服12.5mg；
3)纳入标准
(1)年龄18-60岁；
(2)诊断为寻常型、关节病型、红皮病型和脓疱型银屑病的患者，体表受累面积(BSA)＞10％或或银屑病面积与严重程度指数(PASI)＞10；
(3)填写完整流行病学调查表，签署知情同意书者。
4)排除标准
(1)其他特殊类型的寻常型银屑病患者(点滴型、反向型)；
(2)年龄<18岁、妊娠、哺乳期妇女，或6个月内计划生育者及伴侣；
(3)已知对本研究所用药物过敏、及含有相关药物成分过敏的患者；
(4)2w内未使用过除保湿剂外的治疗银屑病其他外用药物，4w内未使用过治疗银屑病的系统用药等其他治疗方案的患者；
(5)造血系统、循环系统、呼吸系统、消化系统、免疫系统等其他原发性疾病患者，原发或继发免疫缺陷、肝脏纤维化或慢性肝病、结核患者，其他感染性疾病及精神疾病患者等；
(6)正在接受其他免疫抑制剂治疗及近期接种或计划接种疫苗患者；
5)定期随访指标：血尿常规，肝肾功能，肝纤维化，血脂，血糖，糖化血红蛋白。
6)提取患者DNA，利用sequenom平台对310例患者的MYLKSNP rs12961853位点进行基因分型，按12w是否达到PASI75分别定义为有效组和无效组；
结果显示，MTX治疗3个月使46.5％的银屑病患者获得PASI75的改善；携带MAPK4SNP rs12961853 TT和CT基因型的患者在治疗第8周PASI50的改善率(61.2％和55.4％)显著高于携带CC基因型患者(40.0％)，差异有统计学意义，p＝0.0333；2)携带MAPK4 SNPrs12961853 TT和CT基因型的患者在治疗第12周PASI75的改善率(51.7％和48.9％)显著高于携带CC基因型患者(29.1％)，差异有统计学意义，p＝0.0158。310例银屑病患者的一般信息及临床疗效如表1所示。
表1
total CC CT TT p-value
Patients n(％) 310 55 139 116
Outcomes at Week8
Achievement，No.(％)
PASI50 170(54.8) 22(40.0) 77(55.4) 71(61.2) 0.0333
PASI75 78(25.2) 10(18.2) 34(24.5) 34(29.3) 0.2837
PASI90 23(7.4) 4(7.3) 9(6.5) 10(8.6) 0.8082
PASI，mean±SD 6.5±5.5 7.1±5.8 6.5±5.8 6.3±5.1 0.703
Mean PASI change from baseline 49.6±33.5 43.1±32.5 48.4±35.3 54.2±31.5 0.0789
BSA(％)，mean±SD 15.6±18.2 16.8±17.4 14.5±17.7 16.4±19.1 0.5059
Mean BSA change from baseline，mean±SD 42.2±47.9 35.7±33.7 40.4±56.7 47.3±41.5 0.0606
Outcomes at Week12
Achievement，No.(％)
PASI50 220(71.0) 31(56.4) 102(73.4) 87(75.0) 0.0302
PASI75 144(46.5) 16(29.1) 68(48.9) 60(51.7) 0.0158
PASI90 63(20.3) 7(12.7) 30(21.6) 26(22.4) 0.2998
PASI.mean±SD 4.8±4.9 5.9±5.3 4.6±5.2 4.4±4.3 0.1576
Mean PASI change from baseline 62.5±33.12 54.1±30.7 62.6±36.2 66.4±29.7 0.02
BSA(％)，mean±SD 10.5±16.0 13.3±15.7 9.5±16.3 10.4±15.8 0.0539
Mean BSA change from baseline，mean±SD 60.5±41.7 47.1±38.9 61.9±44.7 65.1±38.0 0.0097
。

Claims (5)

1.MAPK4 SNP位点rs12961853在用于制备预测甲氨蝶呤临床疗效的基因标志物中的用途。
2.MAPK4 SNP位点rs12961853在用于制备预测甲氨蝶呤治疗银屑病的临床疗效的基因标志物中的用途。
3.按权利要求1或2所述的用途，其特征在于，所述的用途中，针对携带MAPK4 SNP位点rs12961853 CC基因型的银屑病患者观察其采用甲氨蝶呤治疗干预的有效率，以及预测甲氨蝶呤治疗干预的疗效。
4.MAPK4 SNP位点rs12961853在用于制备预测甲氨蝶呤治疗银屑病临床疗效的检测试剂盒中的用途。
5.按权利要求4所述的用途，其特征在于，所述的检测试剂盒通过检测MAPK4 SNP位点rs12961853基因型与甲氨蝶呤治疗银屑病临床疗效的关系，针对携带MAPK4 SNP位点rs12961853基因型与否，观察其采用甲氨蝶呤治疗干预的有效率的发生情况，以及预测评估甲氨蝶呤治疗银屑病的临床疗效。
CN202011496584.8A 2020-09-11 2020-12-17 Mapk4基因多态性作为预测甲氨蝶呤临床疗效的基因标志物及检测试剂盒 Pending CN114164263A (zh)

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