CN114107474B - Anxa6多态性位点作为基因标志物以及和甲氨蝶呤联合的银屑病试剂盒 - Google Patents
Anxa6多态性位点作为基因标志物以及和甲氨蝶呤联合的银屑病试剂盒 Download PDFInfo
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Abstract
本发明属于生物技术领域，涉及银屑病药物疗效的基因标志物和检测试剂盒。本发明提供了位点rs11960458在制备治疗银屑病药物中的应用，所述的rs11960458的基因型为CC或者TT。本发明还涉及一种新的用于预测甲氨蝶呤(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ANXA6的SNP位点，预测MTX的临床疗效。本发明可以协助临床医生为银屑病患者分类，选择MTX治疗干预方案，为提高MTX的临床疗效提供基础。
Description
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，具体涉及一种新的用于预测甲氨蝶呤(MTX)治疗银屑病临床疗效的检测试剂盒，该试剂盒可以检测银屑病患者ANXA6的SNP位点，指导银屑病患者的分类，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，且部分患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，寻找一个生物标记预测MTX的临床疗效，有利于提高临床疗效，该课题成为越来越多的本领域科学家和医生关注的热点。
MTX在1972年被FDA批准治疗银屑病，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。既往的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)andSLC19A1G＞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。很少研究关注疾病易感基因位点与MTX临床疗效间的关系。
AnnexinA6(ANXA6)基因结构上属于高度保守的磷脂膜结合蛋白家族，是存在于动物体内的一类钙结合蛋白，于Ca2+结合后可进一步与磷脂结合，因而称为钙依赖(调节)膜磷脂结合蛋白。ANXA6基因位于染色体5q33.1，全长大约60kb，包含26个外显子，编码一个68kDa的可变连接分离蛋白。中间被不同长度的碱基序列分割开，与ANXA1和ANXA2的序列高度相似。由于外显子21上的选择性剪切方式不同，导致六个氨基酸的改变，丛而形成ANXA6的两个亚型(ANXA6-1和ANXA6-2)。ANXA6表达在多数哺乳动物的骨骼肌，肺脏，脾脏，心脏，淋巴结中。在内皮细胞、有激素分泌功能的上皮细胞、巨噬细胞中大量表达，而在小肠、甲状旁腺以及结肠中却未检测到ANXA6。
ANXA6参与T细胞活化和分化，其表达在T细胞和B细胞分化过程中上调。ANXA6还可以同时结合细胞膜和表皮生长因子/Ras/丝裂原活化蛋白激酶通路的相关蛋白，提供了膜结合多种细胞因子相互作用的载体，丛而发挥调节蛋白的功能。ANXA6磷酸化的具体功能目前尚未明确，但有可能是增加其对Ca2+的敏感性，丛而增加结合细胞膜的能力。ANXA6可以通过磷酸化形式(被一种非受体酪氨酸激酶p56Lck磷酸化)，在T细胞受体激活过程中发挥作用。在大多数的细胞和组织，Ca2+增加可以促进ANXA6易位到细胞膜和内体腔。在晚内体中，低密度脂蛋白或者胆固醇的增加可以刺激ANXA6的膜结合的亲和力。T细胞受体的结构重排可能是银屑病的发病机制。而且，ANXA6基因也可以通过调节EGF受体的信号传导通路，提高角质形成细胞的存活率，并且加速角质形成细胞的增殖，这与银屑病角质形成细胞过度增殖或分化障碍密切吻合。ANXA6基因也有可能是通过下调生长因子受体(EGFR)的不同阶段(早期和晚期)，在银屑病的发病过程中发挥作用。ANXA6基因多态性与银屑病的易感性相关，但能否作为预测甲氨蝶呤临床疗效的基因标志物目前还未见相关报道。
发明内容
本发明的目的是提供新的预测MTX的基因标志物及其应用。
本发明的进一步目的是提供治疗银屑病的药物试剂盒，包括用于预测甲氨蝶呤适用性的检测试剂盒。
本发明通过研究携带ANXA6 SNP位点rs11960458 CC和TT基因型的银屑病患者用MTX治疗3个月PASI75改善率明显优于CT型患者，提出了ANXA6 SNP位点rs11960458 CC和TT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。
本发明提供了位点rs11960458在制备治疗银屑病药物中的应用。
较好的，所述的rs11960458的基因型为CC或者TT。
较好的，所述的rs11960458位点作为银屑病药物试剂盒中的基因标志物。
较好的，所述的银屑病药物试剂盒含有甲氨蝶呤，或者甲氨蝶呤的类似物、活性成分及其衍生物。
较好的，所述的应用包括如下步骤：
从样品中分离含有位点rs11960458的部分；
识别位点rs11960458；
确定位点rs11960458的基因型。
较好的，所述的应用还包括如下步骤：根据位点rs11960458基因型的检测结果，确定所述的基因型是否为CC或者TT。
较好的，所述的应用包括将下述成分组合：
基因型为CC或者TT的rs11960458位点；
含有甲氨蝶呤的活性成分；
所述的组合用于制备银屑病药物试剂盒。
本申请的发明人拟通过研究ANXA6基因SNP位点rs11960458基因型与MTX治疗银屑病临床疗效的关系，提供ANXA6 SNP位点rs11960458 CC和TT基因型作为预测MTX治疗银屑病的临床疗效的基因标志物。本发明中，通过研究ANXA6位点rs11960458基因型与MTX治疗银屑病临床疗效的关系，如携带ANXA6 SNP位点rs11960458 CC和TT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，有助于指导临床医生制定适合的MTX治疗干预方案。
本发明还提供了一种药物试剂盒，所述的药物试剂盒中含有：
检测位点rs11960458的物质；和/或
甲氨蝶呤的活性成分；
所述的位点rs11960458的基因型为CC或者TT。
较好的，所述的检测位点rs11960458的物质包括检测位点rs11960458基因型的引物、探针；或者偶联位点rs11960458识别物的活性物质。
较好的，所述的位点rs11960458作为所述的药物试剂盒的阳性对照，所述的位点rs11960458的基因型为CC或者TT。
较好的，所述的药物试剂盒在预防银屑病中的应用。
本发明还包括ANXA6 SNP位点rs11960458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。
例如，ANXA6 SNP位点rs11960458在用于制备预测甲氨蝶呤临床疗效的检测试剂盒中的用途。
较好的，可以针对携带ANXA6 SNP位点rs11960458 CC和TT基因型的银屑病患者采用甲氨蝶呤治疗干预有效率的情况，预测甲氨蝶呤治疗干预的疗效。
本发明还包括ANXA6 SNP位点rs11960458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。
本发明还包括所述的检测试剂盒通过检测ANXA6 SNP位点rs11960458基因型与甲氨蝶呤治疗银屑病临床疗效的关系，针对携带ANXA6 SNP位点rs11960458CC和TT基因型与否的采用甲氨蝶呤治疗干预的有效率的发生情况，预测评估甲氨蝶呤治疗银屑病的临床疗效。
本发明中，所述的ANXA6基因的基因图谱，可查找如下述：
https://www.ncbi.nlm.nih.gov/genome/gdv/browser/？context＝genome&id＝GCF_000001405.38。
本发明中，银屑病患者病情评分参照PASI(Psoriasis area and severityindex，银屑病面积和严重程度指数)标准，包括皮损面积评分和皮损严重程度评分。
1、评价面积:4个躯体部位分别以0-6分评分:面积:0＝无皮疹；1<10％；2＝10-29％；3＝30-49％；4＝50-69％；5＝70-89％；6＝90-100％；躯干部位:头面＝10％；躯干＝30％；上肢＝20％；下肢＝40％
皮损面积评分:全身分为头颈部、上肢、躯干和下肢4个部位。上述部位占体表面积的百分比分别为10％、20％、30％和40％。4个部位分别进行皮损面积评分，标准如下:
0＝无皮疹、1＝1％-9％、2＝10％-29％、3＝30％-49％、4＝50％-69％、5＝70％-89％、6＝90％-100％。
为了有助于对受累面积进行评估，应注意下述规定:
a.将颈部视为头部的一部分。
b.将腋窝与腹股沟作为躯干的一部分。
c.将臀部作为下肢的一部分。
2、评价临床严重程度:红斑；浸润；鳞屑。每个特点用0-4分评价:0＝无；1＝轻度；2＝中度；3＝重度；4＝极重度。公式计算各躯体部位分值，再累加得到总分，0-72分:
皮损严重程度评分:按照以上4部位评分，每个部位均按以下3个皮损临床特征评分:
红斑(erythema，E):红色或暗红色炎症性斑，压之退色。
浸润(infiltration，I):皮损向四周扩散蔓延的趋势，边界模糊不清，压之有实质感。
表皮脱屑/鳞屑(desquamation，D):指脱落的表皮细胞成片剥落。
皮损严重程度评分如下:
0＝无，此体征经仔细观察不能确认，
1＝轻，此体征能确认但需仔细观察，
2＝中，此体征较明显可立即确认，
3＝重，此体征很明显。
4＝极重，此体征非常明显。
斑块肥厚程度I:0-皮损与正常皮肤平齐；
1-皮损轻微高出于正常皮肤表面；
2-中等度隆起，斑块的边缘为圆或斜坡型；
3-皮损肥厚，隆起明显；
4-皮损高度增厚，隆起极为明显。
红斑E:0-无红斑可见；1-呈淡红色；2-红色；3-深红色；4-红色极深。
鳞屑D:0-表面无可见鳞屑；
1-部分皮损表面上覆有鳞屑，以细微的鳞屑为主；
2-大多数皮损表面完全或不完全覆有鳞屑，鳞屑呈片状；
3-几乎全部皮损表面覆有鳞屑，鳞屑较厚成层；
4-全部皮损表面均覆有鳞屑，鳞屑很厚成层。
渗出、干燥及瘙痒不计入总分。
寻常型银屑病PASI评分公式:
PASI评分＝(E头+I头+D头)×A头×0.1+(E上肢+I上肢+D上肢)×A上肢×0.2+(E躯干+I躯干+D躯干)×A躯干×0.3+(E下肢+I下肢+D下肢)×A下肢×0.4
疗效判定标准:按照银屑病皮损面积及严重程度指数(psoriasis area andseverity index，PASI)评分标准，记录治疗前后的PASI评分，根据PASI评分下降率进行疗效判定。PASI评分下降率二(治疗前PASI评分一治疗后PASI评分)/治疗前PASI评分x100％。
痊愈，PASI评分下降率>90％；
显效，PASI评分下降率为60％一89％；
有效，PASI评分下降率为20％一59％；
无效，PASI评分下降率<20％。
总有效率(痊愈例数+显效例数+有效例数)/，总例数100％。
本发明的实施例中，检测了307例银屑病患者ANXA6 SNP位点rs11960458的基因型与MTX治疗银屑病临床疗效间的关系，结果显示：1)携带ANXA6易感基因CC和TT基因型的患者在治疗第12周PASI75的改善率分别为55.0％和51.1％，显著高于携带CT基因型患者(38.4％)，差异有统计学意义，p＝0.003；2)多元回归分析发现银屑病患者年龄，疾病严重程度(PASI)，体重指数(BMI)和是否伴发关节炎是影响甲氨蝶呤临床疗效的重要临床因素，差异有统计学意义，p<0.05。
本发明检测了307例银屑病患者ANXA6 SNP位点rs11960458的基因型与MTX治疗银屑病临床疗效间的关系。结果显示：携带TNIP1易感基因CC和TT基因型的患者在治疗第12周PASI75的改善率(55.0％和51.1％)显著高于携带TC基因型患者(38.4％)。本发明证实了检测银屑病患者ANXA6 SNP位点rs11960458的基因型，可预测MTX治疗银屑病的临床疗效。
本发明通过多元回归分析分析了307例携带ANXA6 SNP位点rs11960458 CC和TT基因型患者的携带情况及临床因素(银屑病患者年龄，体重指数，疾病严重程度，关节炎的存在)与MTX治疗银屑病临床疗效间的关系。结果显示：1.ANXA6 SNP位点rs11960458 CC和TT基因型与甲氨蝶呤治疗3个月的PASI75改善率密切相关，p＝0.003；2.银屑病患者年龄与甲氨蝶呤治疗3个月的PASI75改善率密切相关，p＝0.000；3.银屑病疾病严重程度与甲氨蝶呤治疗3个月的PASI75改善率密切相关，p＝0.01；4.银屑病患者关节炎的存在与甲氨蝶呤治疗3个月的PASI75改善率密切相关，p＝0.013。
本发明经试验结果证实，检测银屑病患者ANXA6 SNP位点rs11960458的基因型，可用作预测MTX治疗银屑病的临床疗效。
本发明进一步实验把结果显示，未经基因检测MTX治疗银屑病的临床疗效为46.3％，针对携带ANXA6 SNP位点rs11960458CC和TT基因型的银屑病患者采用MTX治疗干预，其有效率可提高至51.1和55.0％。
本发明提供了新的预测MTX临床疗效的基因标志物，尤其是ANXA6 SNP位点rs11960458 CC和TT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ANXA6 SNP位点rs11960458 CC和TT基因型的银屑病患者采用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，有助于指导临床医生制定适合的MTX治疗干预方案。
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，本发明提出了ANXA6 SNP位点rs11960458 CC和TT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；通过研究ANXA6 SNP位点rs11960458基因型与MTX治疗银屑病临床疗效的关系提供了检测试剂盒，针对携带ANXA6 SNP位点rs11960458 CC和TT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，对银屑病患者分类，有助于指导临床医生制定适合的MTX治疗干预方案，为提高MTX的临床疗效提供基础。
具体实施方式
实施例1：ANXA6 SNP位点rs11960458与MTX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307例患者的ANXA6 SNP位点rs11960458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，经生物信息学分析，结果显示，ANXA6基因型在有效组和无效组间有统计学意义；
结果显示：
(1)MTX干预使46.3％的银屑病患者获得PASI75的改善。携带CC和TT基因型患者治疗3个月PASI75改善率分别为55.0％和51.1％，显著高于CT基因型患者(38.4％)(见表1，即Table1)。
(2)多元回归分析发现：ANXA6 SNP位点rs11960458基因型与甲氨蝶呤PASI75改善率相关，p＝0.003；银屑病患者年龄与甲氨蝶呤PASI75改善率相关，p＝0.000；银屑病患者疾病严重程度与甲氨蝶呤PASI75改善率相关，p＝0.01；银屑病患者体重指数与甲氨蝶呤PASI75改善率相关，p＝0.005；银屑病患者关节炎的存在与甲氨蝶呤PASI75改善率相关，p＝0.013(见表2，即Table2)。
表1
| rs11960458 | total | TT | CT | CC |
| Patients n(％) | 307 | 47 | 151 | 109 |
| Male，n(％) | 216(70.3) | 36(76.6) | 108(71.5) | 72(66.1) |
| Age(years)，mean±SD | 48.26±15.05 | 50.3±17.05 | 48.83±14.72 | 46.59±14.58 |
| Age at disease onset，mean±SD | 34.84±15.73 | 35.21±17.17 | 34.80±16.09 | 34.75±14.7 |
| Disease duration，mean±SD | 13.45±10.77 | 15.09±11.31 | 14.01±10.73 | 11.95±10.51 |
| Body mass index(kgm-2)，mean±SD | 24.38±3.48 | 24.83±3.84 | 24.33±3.26 | 24.25±3.63 |
| PASI at baseline，mean±SD | 14.11±7.53 | 13.38±6.79 | 13.71±7.83 | 14.96±7.39 |
| BSA(％)at baseline，mean±SD | 28.82±20.75 | 27.3±19.97 | 28.23±20.75 | 30.29±21.16 |
| Smoking | 100(32.6) | 17(36.2) | 45(29.8) | 38(34.9) |
| Drinking alcohol | 72(23.5) | 7(14.9) | 46(30.5) | 19(17.4) |
| Hypertention[n(％)] | 113(36.8) | 22(46.8) | 57(37.7) | 34(31.2) |
| Diabetes[n(％)] | 58(18.9) | 9(19.1) | 35(23.2) | 14(12.8) |
| arthritis | 162(52.8) | 28(59.6) | 79(52.3) | 55(50.5) |
| Complains of side effects | 109(35.5) | 17(36.2) | 57(37.7) | 35(32.1) |
| MTX dosage | 135.4±21.25 | 131.1±23.76 | 137.6±20.30 | 134.2±21.21 |
| PASI50 at 8 weeks | 168(54.7) | 27(57.4) | 78(51.7) | 63(57.8) |
| PASI75 at 8 weeks | 78(25.4) | 14(29.8) | 32(21.2) | 32(29.4) |
| PASI90 at 8 weeks | 23(7.5) | 5(10.6) | 10(6.6) | 8(7.3) |
| δPASI at 8 weeks | 49.53±33.65 | 48.28±35.08 | 47.87±31.89 | 52.36±35.44 |
| PASI50 at 12 weeks | 218(71.0) | 31(66.0) | 104(68.9) | 83(76.1) |
| PASI75 at 12 weeks | 142(46.3) | 24(51.1) | 58(38.4) | 60(55.0) |
| PASI90 at 12 weeks | 62(20.2) | 9(19.1) | 26(17.2) | 27(24.8) |
| δPASI at 12 weeks | 62.44±33.19 | 61.89±30.89 | 59.48±31.04 | 66.79±36.67 |
表2
本实验表明，同时携带ANXA6 SNP位点rs11960458 CC和TT基因型患者治疗第12周PASI75的改善率(55.0％和51.1％)明显优于CT基因型患者(38.4％)，差异有统计学意义，p<0.05。
以上所述，仅为本申请的具体实施方式，但本申请的保护范围并不局限于此，任何熟悉本领域技术的技术人员在本申请公开的技术范围内，可轻易想到的变化或替换，都应涵盖在本申请的保护范围之内。因此，本申请的保护范围应以所述权利要求的保护范围为准。
Claims (4)
1.位点rs11960458作为基因标志物在用于制备预测甲氨蝶呤MTX治疗银屑病临床疗效的检测试剂盒中的应用；所述的rs11960458的基因型为CC或者TT。
2.如权利要求1所述的应用，其特征在于，所述的检测试剂盒含有甲氨蝶呤MTX。
3.如权利要求1所述的应用，其特征在于，所述的应用包括如下步骤：
从样品中分离含有位点rs11960458的部分；
识别位点rs11960458；
确定位点rs11960458的基因型。
4.如权利要求3所述的应用，其特征在于，所述的应用还包括如下步骤：根据位点rs11960458基因型的检测结果，确定所述的基因型是否为CC或者TT。
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