CN106755291B - 用于筛查克林霉素所致皮肤药物不良反应的人类白细胞抗原基因检测试剂盒 - Google Patents

用于筛查克林霉素所致皮肤药物不良反应的人类白细胞抗原基因检测试剂盒 Download PDF

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CN106755291B
CN106755291B CN201510822101.1A CN201510822101A CN106755291B CN 106755291 B CN106755291 B CN 106755291B CN 201510822101 A CN201510822101 A CN 201510822101A CN 106755291 B CN106755291 B CN 106755291B
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骆肖群
邢清和
杨颖�
陈圣安
杨凡萍
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Abstract

本发明属生物医药技术领域，涉及一种人类白细胞抗原基因‑‑HLA‑B*51:01基因的检测试剂盒，该HLA‑B*51:01基因可作为预测克林霉素所致药疹标记基因本发明提供了上述检测试剂盒对样本的HLA‑B*51:01基因进行分型的应用，包括从获得的患者的外周血中抽取DNA后，用现行的方法检测HLA‑B*51:01基因，如序列特异性寡核苷酸探针(PCR‑SSO)方法。利用本发明提供的HLA‑B*51:01基因检测试剂盒可用于克林霉素使用前筛查及筛选治疗克林霉素所致药疹的靶向药物；前者可指导临床用药，从而减少克林霉素所致药疹的发生；后者主要靶向作用于HLA‑B*51:01分子，从而阻断其在发病中与克林霉素或其代谢产物之间的相互作用。

Description

用于筛查克林霉素所致皮肤药物不良反应的人类白细胞抗原 基因检测试剂盒
技术领域
本发明属于生物医药和试剂检测领域，涉及一种人类白细胞抗原基因检测试剂盒。具体涉及人类白细胞抗原基因——HLA-B*51:01基因，它与克林霉素所致发疹型药疹、荨麻疹、固定性红斑型药疹、多形性红斑等皮肤药物不良反应发病相关。
背景技术
克林霉素属二十种最重要的抗生素之一(J.
Figure BDA0000855802140000011
et al.,Lincomycin,clindamycin and their applications.Appl Microbiol Biotechnol,2004.64:p.455–64.)，是临床上常用药物，在革兰氏阳性菌、厌氧型革兰氏阴性菌、某些原生动物以及真菌感染的治疗方案中有重要地位(Guay D.Update on clindamycin in the management ofbacterial,fungal and protozoal infe ctions.Expert Opin Pharmacother,2007.8(14):p.2401-44.Frankel RI.Clindamycin--efficacy and toxicity.West J Med,1975.122(6):p.526-30.)。但是有研究显示部分患者服用该药后发生不良反应，其中最常发生的不良反应是药疹(http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/050162s085lbl.pdf)。
皮肤药物不良反应即药疹，指药物通过各种途径进入人体后引起的皮肤黏膜炎症反应。轻型药疹中包括发疹型药疹、荨麻疹、固定性红斑型药疹、多形性红斑。目前克林霉素所致药疹的报道中以出疹型药疹居多，发病率从约10％到<1％不等(Geddes AM,et al.,Oon J,Grimshaw GJ:Clinical and bacteriological studies with clindamycin.BrMed J,1970.2:p.703-4.Fass RJ,et al.,Clindamycin in the treatment of seriousanaerobic infections.Ann Intern Med,1973.78:p.853-9.Mazur N,et al.,Clindamycin hypersensitivity appears to be rare.Ann Allergy Asthma Immunol,1999.82:p.443-5.)。也有克林霉素引起的固定性红斑型药疹、荨麻疹、多形性红斑的报道(Mahboob A,et al.,Drugs causing fixed eruptions:a study of 450 cases.Int JDermatol,1998.37(11):p.833-8.Lammintausta K,et al.,Cutaneous adversereactions to clindamycin:results of skin tests and oral exposure.Br JDermatol,2002.146:p.643-648.)。因此，如果能找到克林霉素所致药疹发病的基因标志，将对临床用药起到指导作用。
人类白细胞抗原(Human leukocyte antigen，HLA)基因的表达产物为人类白细胞抗原，后者在免疫反应中担任至关重要的角色。已有研究发现包括卡马西平、阿巴卡韦、别嘌呤醇等在内的数种药物引起的药疹与HLA等位基因相关(Bharadwaj,M.,et al.,Drughypersensitivity and human leukocyte antigens of the major histocompatibilitycomplex.Annu Rev Pharmacol Toxicol,2012.52:p.401-31.Cao,Z.H.,et al.,HLA-B*58:01 allele is associated with augmented risk for both mild and severecutaneous adverse reactions induced by allopurinol in HanChinese.Pharmacogenomics,2012.13(10):p.1193-201.Roujeau,J.C.,et al.,Geneticsusceptibility to toxic epidermal necrolysis.Arch Dermatol,1987.123(9):p.1171-3.)。美国FDA已早在2008年推荐亚洲人群在使用卡马西平前进行HLA-B*15：02基因的筛查(Ferrell PB Jr,Mcleod HL.Carbamazepine,HLA-B*15:02 and risk of Stevens-Johnson Syndrome and toxic epidermal necrolysis:US FDA recommendations[J].Pharmacogenomics,2008,9(10):p.1543-6)，以指导临床用药。
经对现有技术文献的检索发现，至今未见关于HLA-B*51:01基因与克林霉素所致药疹的发病相关，以及可作为基因标记用于筛选该型药疹的相关报道。也未见相关试剂盒的报道。
发明内容
本发明的目的是克服现有技术的缺陷，提供一种人类白细胞抗原基因检测试剂盒，尤其是一种检测检测HLA-B*51:01基因的试剂盒。
本发明还提供了一种上述试剂盒的应用，也就是通过检测HLA-B*51:01基因的存在来评估患者使用克林霉素后是否具有引起药疹的潜在可能。同时可以据此指导临床用药，从而减少克林霉素所致药疹的发生。
一方面，本发明提供了一种人类白细胞抗原基因的检测试剂盒。
所述的人类白细胞抗原基因是HLA-B*51:01基因；
所述的试剂盒中含有检测人类白细胞抗原基因的核酸或者蛋白的试剂。
所述的试剂盒中含有人类白细胞抗原基因的扩增引物；或者标记探针。
或者，所述的试剂盒中含有人类白细胞抗原基因的特异性抗体。
本发明所述克林霉素所致药疹的相关HLA等位基因——HLA-B*51:01基因的核酸序列如SEQ NO.1所示：
(a)序列特征：
*长度：3327碱基对
*类型：核酸
*链型：双链
*拓扑结构：线形
(b)分子类型：基因组DNA(gDNA文库)
(c)假设：否
(d)反义：否
(e)最初来源：人
(f)SEQ ID NO.1核酸序列描述如下：
gatcaggacg aagtcccagg ccccgggcgg ggctctcagg gtctcaggct ccgagagccttgtctgcatt 70
ggggaggcgc agcgttgggg attccccact cccacgagtt tcacttcttc tcccaacctatgtcgggtcc 140
ttcttccagg atactcgtga cgcgtcccca tttcccactc ccattgggtg tcggatatctagagaagcca 210
atcagtgtcg ccggggtccc agttctaaag tccccacgca cccacccgga ctcagaatctcctcagacgc 280
cgagatgcgg gtcacggcgc cccgaaccgt cctcctgctg ctctgggggg cagtggccctgaccgagacc 350
tgggccggtg agtgcggggt cgggagggaa atggcctctg tggggaggag cgaggggaccgcaggcgggg 420
gcgcaggacc tgaggagccg cgccgggagg agggtcgggc gggtctcagc ccctcctcgcccccaggctc 490
ccactccatg aggtatttct acaccgccat gtcccggccc ggccgcgggg agccccgcttcattgcagtg 560
ggctacgtgg acgacaccca gttcgtgagg ttcgacagcg acgccgcgag tccgaggacggagccccggg 630
cgccatggat agagcaggag gggccggagt attgggaccg gaacacacag atcttcaagaccaacacaca 700
gacttaccga gagaacctgc ggatcgcgct ccgctactac aaccagagcg aggccggtgagtgaccccgg 770
cccggggcgc aggtcacgac tccccatccc ccacgtacgg cccgggtcgc cccgagtctccgggtccgag 840
atccgcctcc ctgaggccgc gggacccgcc cagaccctcg accggcgaga gccccaggcgcgtttacccg 910
gtttcatttt cagttgaggc caaaatcccc gcgggttggt cggggcgggg cggggctcgggggacggtgc 980
tgaccgcggg gccggggcca gggtctcaca cttggcagac gatgtatggc tgcgacgtggggccggacgg 1050
gcgcctcctc cgcgggcata accagtacgc ctacgacggc aaagattaca tcgccctgaacgaggacctg 1120
agctcctgga ccgcggcgga caccgcggct cagatcaccc agcgcaagtg ggaggcggcccgtgaggcgg 1190
agcagctgag agcctacctg gagggcctgt gcgtggagtg gctccgcaga cacctggagaacgggaagga 1260
gacgctgcag cgcgcgggta ccaggggcag tggggagcct tccccatctc ctataggtcgccggggatgg 1330
cctcccacga gaagaggagg aaaatgggat cagcgctaga atgtcgccct cccttgaatggagaatggca 1400
tgagttttcc tgagtttcct ctgagggccc cctcttctct ctaggacaat taagggatgacgtctctgag 1470
gaaatggagg ggaagacagt ccctagaata ctgatcaggg gtcccctttg acccctgcagcagccttggg 1540
aaccgtgact tttcctctca ggccttgttc tctgcctcac actcagtgtg tttggggctctgattccagc 1610
acttctgagt cactttacct ccactcagat caggagcaga agtccctgtt ccccgctcagagactcgaac 1680
tttccaatga ataggagatt atcccaggtg cctgcgtcca ggctggtgtc tgggttctgtgccccttccc 1750
cacaccaggt gtcctgtcca ttctcaggct ggtcacatgg gtggtcctag ggtgtcccatgagagatgca 1820
aagcgcctga attttctgac tcttcccatc agacccccca aagacacacg tgacccaccaccccgtctct 1890
gaccatgagg ccaccctgag gtgctgggcc ctgggcttct accctgcgga gatcacactgacctggcagc 1960
gggatggcga ggaccaaact caggacactg agcttgtgga gaccagacca gcaggagatagaaccttcca 2030
gaagtgggca gctgtggtgg tgccttctgg agaagagcag agatacacat gccatgtacagcatgagggg 2100
ctgccgaagc ccctcaccct gagatggggt aaggaggggg atgaggggtc atatctcttctcagggaaag 2170
caggagccct tctggagccc ttcagcaggg tcagggcccc tcgtcttccc ctcctttcccagagccatct 2240
tcccagtcca ccatccccat cgtgggcatt gttgctggcc tggctgtcct agcagttgtggtcatcggag 2310
ctgtggtcgc tactgtgatg tgtaggagga agagctcagg tagggaaggg gtgaggggtggggtctgggt 2380
tttcttgtcc cactgggggt ttcaagcccc aggtagaagt gttccctgcc tcattactgggaagcagcat 2450
ccacacaggg gctaacgcag cctgggaccc tgtgtgccag cacttactct tttgtgcagcacatgtgaca 2520
atgaaggacg gatgtatcac cttgatggtt gtggtgttgg ggtcctgatt tcagcattcatgagtcaggg 2590
gaaggtccct gctaaggaca gaccttagga gggcagttgg tccaggaccc acacttgctttcctcgtgtt 2660
tcctgatcct gccttgggtc tgtagtcata cttctggaaa ttccttttgg gtccaagacgaggaggttcc 2730
tctaagatct catggccctg cttcctccca gtcccctcac aggacatttt cttcccacaggtggaaaagg 2800
agggagctac tctcaggctg cgtgtaagtg gtgggggtgg gagtgtggag gagctcacccaccccataat 2870
tcctcctgtc ccacgtctcc tgcgggctct gaccaggtcc tgtttttgtt ctactccagccagcgacagt 2940
gcccagggct ctgatgtgtc tctcacagct tgaaaaggtg agattcttgg ggtctagagtgggcgggggg 3010
ggcggggagg gggcagaggg gaaaggcctg ggtaatggag attctttgat tgggatgtttcgcgtgtgtc 3080
gtgggctgtt cagagtgtca tcacttacca tgactaacca gaatttgttc atgactgttgttttctgtag 3150
cctgagacag ctgtcttgtg agggactgag atgcaggatt tcttcactcc tcccctttgtgacttcaaga 3220
gcctctggca tctctttctg caaaggcacc tgaatgtgtc tgcgttcctg ttagcataatgtgaggaggt 3290
ggagagacag cccacccttg tgtccactgt gacccct 3327
另一方面，本发明提供了上述检测试剂盒的应用，即对样本的HLA-B*51:01基因进行分型。
例如，如本发明的实施例中所示，采用PCR-SSO法进行HLA-B*51:01基因的分型。
具体而言，对HLA-B*51:01基因的分型的步骤如下：
抽提样本中的DNA；
对HLA的多态区域进行扩增；
在扩增过程中对PCR产物进行同位素或非同位素标记；
将PCR产物与膜上的探针杂交、放射自显影根据信号判断结果。
其中，所述的探针针对PCR扩增产物设计并且固定在膜上。
所述的样本可以是RNA、蛋白、细胞或者血清样本。
最常见的情况下，所述的样本是离体的外周血。
利用HLA-B*51:01基因的分析结果可以判断药疹。
本发明的实验数据证明，HLA-B*51:01基因可作为预测克林霉素所致药疹的标记基因。
试验结果显示，克林霉素所致药疹患者中HLA-B*51:01阳性比例相比于正常对照组(表1)及克林霉素耐受组(表2)之间差异有统计学意义。HLA-B*51:01与克林霉素结合模型见图1(克林霉素与HLA-B*51:01结合模型图)。
本发明的具有实用性的例证：
1)可以利用本发明所介绍的HLA-B*51:01基因作为预测克林霉素所致药疹标记基因。
2)利用本发明提供的HLA-B*51:01基因可用于评价或制备克林霉素使用前筛查试剂盒。
3)利用本发明提供的HLA-B*51:01分子可用于评价或制备克林霉素所致药疹靶向药物。
本发明涉及的是一种人类白细胞抗原基因——HLA-B*51:01基因，它与克林霉素所致药疹发病相关。HLA-B*51:01基因可作为预测克林霉素所致药疹的标记基因。从患者的外周血中抽取DNA后，用现行的方法检测HLA-B*51:01基因，如PCR-SSO(序列特异性寡核苷酸探针)方法。利用本发明提供的HLA-B*51:01基因检测试剂盒可用于克林霉素使用前筛查及筛选治疗克林霉素所致药疹的靶向药物。前者可指导临床用药，从而减少克林霉素所致药疹的发生。后者主要靶向作用于HLA-B*51:01分子，从而阻断其在发病中与克林霉素或其代谢产物之间的相互作用。
附图说明
图1.克林霉素与HLA-B*51:01结合模型图。
具体实施方式
以下结合具体实施例，以进一步说明本发明。应理解，以下实施例仅用于说明本发明而不用于限制本发明的范围。
实施例1：基因的收集和抽提
克林霉素所致药疹患者来自于中国上海复旦大学附属华山医院，在知情同意的前提下参加本课题的研究，采集血液，并签署知情同意书。所有入组患者均通过病史及皮肤病理检查排除病毒疹及毒性红斑等其他诊断。所有患者均在发疹前2个月内静脉或口服使用克林霉素。本实验有两组对照，其一是来自human MHC database(dbMHC)的283位健康人群，除去遗传信息不全的对照组样本后对照组人数为279；另外一组来自中国汉族的26例患者为克林霉素耐受组，均静注克林霉素大于2个月且没有发生任何药物反应；
取样本血液300ul，按试剂盒说明书提取DNA，用紫外分光光度仪检测DNA浓度和纯度。
实施例2：检测HLA基因分型
本发明采用PCR-SSO法(推荐
Figure BDA0000855802140000071
试剂盒-One Lambda,CA,USA)进行HLA基因的分型。其原理是先对HLA的多态区域进行扩增,在扩增过程中对PCR产物进行同位素或非同位素标记,然后针对PCR扩增产物根据碱基配对原则设计系列寡核苷酸探针固定在膜上,最后将PCR产物与膜上的探针杂交、放射自显影根据信号判断结果。根据试剂盒标准步骤进行HLA基因分型。(即将DNA样本、底物、Taq酶、引物混合后混匀，加入扩增板中，按试剂盒说明书中条件扩增，扩增产物进行杂交、染色和读板)。结果分析通过HLA Fusion软件(Onelambda,CA,USA,HLA Fusion3.0)进行。
实施例3：HLA-B*51:01与克林霉素所致药疹相关
统计：利用SPSS20.0计算Odds Ratio(OR)及其95％的可信区间，P值使用Bonferroni校正，选用Fisher精确检验进行统计学分析，统计学的显著性水平设定为P小于0.05。
结果显示：搜集到的克林霉素所致药疹患者12例，克林霉素耐受组26例，克林霉素所致药疹患者中HLA-B*51:01阳性比例相比于正常对照组(如表1所示)及克林霉素耐受组之间差异有统计学意义(如表2所示)；HLA-B*51:01与克林霉素结合模型如图1所示(克林霉素与sHLA-B*51:01结合模型图)。
表1.克林霉素所致药疹组与正常对照组HLA-B*51:01阳性比例
Figure BDA0000855802140000081
*差异有统计学意义(P<0.05)。
表2.克林霉素所致药疹组与克林霉素耐受组HLA-B*51:01阳性比例
Figure BDA0000855802140000091
*差异有统计学意义(P<0.05)。
SEQUENCE LISTING
<110> 复旦大学附属华山医院，复旦大学
<120> 用于筛查克林霉素所致皮肤药物不良反应的人类白细胞抗原基因检测试剂盒
<160> 1
<170> PatentIn version 3.3
<210> 1
<211> 3327
<212> DNA
<213> 人
<400> 1
gatcaggacg aagtcccagg ccccgggcgg ggctctcagg gtctcaggct ccgagagcct 60
tgtctgcatt ggggaggcgc agcgttgggg attccccact cccacgagtt tcacttcttc 120
tcccaaccta tgtcgggtcc ttcttccagg atactcgtga cgcgtcccca tttcccactc 180
ccattgggtg tcggatatct agagaagcca atcagtgtcg ccggggtccc agttctaaag 240
tccccacgca cccacccgga ctcagaatct cctcagacgc cgagatgcgg gtcacggcgc 300
cccgaaccgt cctcctgctg ctctgggggg cagtggccct gaccgagacc tgggccggtg 360
agtgcggggt cgggagggaa atggcctctg tggggaggag cgaggggacc gcaggcgggg 420
gcgcaggacc tgaggagccg cgccgggagg agggtcgggc gggtctcagc ccctcctcgc 480
ccccaggctc ccactccatg aggtatttct acaccgccat gtcccggccc ggccgcgggg 540
agccccgctt cattgcagtg ggctacgtgg acgacaccca gttcgtgagg ttcgacagcg 600
acgccgcgag tccgaggacg gagccccggg cgccatggat agagcaggag gggccggagt 660
attgggaccg gaacacacag atcttcaaga ccaacacaca gacttaccga gagaacctgc 720
ggatcgcgct ccgctactac aaccagagcg aggccggtga gtgaccccgg cccggggcgc 780
aggtcacgac tccccatccc ccacgtacgg cccgggtcgc cccgagtctc cgggtccgag 840
atccgcctcc ctgaggccgc gggacccgcc cagaccctcg accggcgaga gccccaggcg 900
cgtttacccg gtttcatttt cagttgaggc caaaatcccc gcgggttggt cggggcgggg 960
cggggctcgg gggacggtgc tgaccgcggg gccggggcca gggtctcaca cttggcagac 1020
gatgtatggc tgcgacgtgg ggccggacgg gcgcctcctc cgcgggcata accagtacgc 1080
ctacgacggc aaagattaca tcgccctgaa cgaggacctg agctcctgga ccgcggcgga 1140
caccgcggct cagatcaccc agcgcaagtg ggaggcggcc cgtgaggcgg agcagctgag 1200
agcctacctg gagggcctgt gcgtggagtg gctccgcaga cacctggaga acgggaagga 1260
gacgctgcag cgcgcgggta ccaggggcag tggggagcct tccccatctc ctataggtcg 1320
ccggggatgg cctcccacga gaagaggagg aaaatgggat cagcgctaga atgtcgccct 1380
cccttgaatg gagaatggca tgagttttcc tgagtttcct ctgagggccc cctcttctct 1440
ctaggacaat taagggatga cgtctctgag gaaatggagg ggaagacagt ccctagaata 1500
ctgatcaggg gtcccctttg acccctgcag cagccttggg aaccgtgact tttcctctca 1560
ggccttgttc tctgcctcac actcagtgtg tttggggctc tgattccagc acttctgagt 1620
cactttacct ccactcagat caggagcaga agtccctgtt ccccgctcag agactcgaac 1680
tttccaatga ataggagatt atcccaggtg cctgcgtcca ggctggtgtc tgggttctgt 1740
gccccttccc cacaccaggt gtcctgtcca ttctcaggct ggtcacatgg gtggtcctag 1800
ggtgtcccat gagagatgca aagcgcctga attttctgac tcttcccatc agacccccca 1860
aagacacacg tgacccacca ccccgtctct gaccatgagg ccaccctgag gtgctgggcc 1920
ctgggcttct accctgcgga gatcacactg acctggcagc gggatggcga ggaccaaact 1980
caggacactg agcttgtgga gaccagacca gcaggagata gaaccttcca gaagtgggca 2040
gctgtggtgg tgccttctgg agaagagcag agatacacat gccatgtaca gcatgagggg 2100
ctgccgaagc ccctcaccct gagatggggt aaggaggggg atgaggggtc atatctcttc 2160
tcagggaaag caggagccct tctggagccc ttcagcaggg tcagggcccc tcgtcttccc 2220
ctcctttccc agagccatct tcccagtcca ccatccccat cgtgggcatt gttgctggcc 2280
tggctgtcct agcagttgtg gtcatcggag ctgtggtcgc tactgtgatg tgtaggagga 2340
agagctcagg tagggaaggg gtgaggggtg gggtctgggt tttcttgtcc cactgggggt 2400
ttcaagcccc aggtagaagt gttccctgcc tcattactgg gaagcagcat ccacacaggg 2460
gctaacgcag cctgggaccc tgtgtgccag cacttactct tttgtgcagc acatgtgaca 2520
atgaaggacg gatgtatcac cttgatggtt gtggtgttgg ggtcctgatt tcagcattca 2580
tgagtcaggg gaaggtccct gctaaggaca gaccttagga gggcagttgg tccaggaccc 2640
acacttgctt tcctcgtgtt tcctgatcct gccttgggtc tgtagtcata cttctggaaa 2700
ttccttttgg gtccaagacg aggaggttcc tctaagatct catggccctg cttcctccca 2760
gtcccctcac aggacatttt cttcccacag gtggaaaagg agggagctac tctcaggctg 2820
cgtgtaagtg gtgggggtgg gagtgtggag gagctcaccc accccataat tcctcctgtc 2880
ccacgtctcc tgcgggctct gaccaggtcc tgtttttgtt ctactccagc cagcgacagt 2940
gcccagggct ctgatgtgtc tctcacagct tgaaaaggtg agattcttgg ggtctagagt 3000
gggcgggggg ggcggggagg gggcagaggg gaaaggcctg ggtaatggag attctttgat 3060
tgggatgttt cgcgtgtgtc gtgggctgtt cagagtgtca tcacttacca tgactaacca 3120
gaatttgttc atgactgttg ttttctgtag cctgagacag ctgtcttgtg agggactgag 3180
atgcaggatt tcttcactcc tcccctttgt gacttcaaga gcctctggca tctctttctg 3240
caaaggcacc tgaatgtgtc tgcgttcctg ttagcataat gtgaggaggt ggagagacag 3300
cccacccttg tgtccactgt gacccct 3327

Claims (3)

1.检测HLA-B*51:01等位基因的试剂在制备试剂盒中的应用，所述试剂盒的功能为检测或评价人发生应答于克林霉素的皮肤药物不良反应风险。
2.根据权利要求1所述的应用，其特征在于：所述应答于克林霉素的皮肤药物不良反应包括发疹型药疹、荨麻疹、固定性红斑型药疹、多形性红斑。
3.检测HLA-B*51:01等位基因的试剂在制备试剂盒中的应用，所述试剂盒的功能为筛查克林霉素所致皮肤药物不良反应高危者。
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