CN109609616B - Application of HLA-A02: 01 and HLA-C01: 02 in drug eruption caused by tanshinone - Google Patents
Application of HLA-A02: 01 and HLA-C01: 02 in drug eruption caused by tanshinone Download PDFInfo
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Abstract
The invention discloses application of HLA-A02: 01 and HLA-C01: 02 in drug eruption caused by tanshinone. The invention provides application of a substance for detecting whether a human has HLA-A02: 01 allele in preparing a product for detecting or evaluating the risk of a human generating adverse drug reactions in response to tanshinone. The experiment proves that human leukocyte antigen genes HLA-A02: 01 and/or HLA-C01: 02 allele are related to the drug eruption caused by tanshinone. HLA-A02: 01 and/or HLA-C01: 02 allele can be used as marker gene for predicting drug eruption caused by tanshinone.
Description
Technical Field
The invention belongs to the technical field of biology, and particularly relates to application of HLA-A02: 01 and HLA-C01: 02 in drug eruption caused by tanshinone.
Background
The drug eruption refers to the adverse reaction of skin and/or mucosa caused by the drug entering human body through various ways, which is the most common adverse reaction of drugs, and the incidence rate is reported to be 1-3%. With the annual increase of the incidence of drug eruptions in China, the drug eruptions not only cause serious harm to personal health and economic loss, but also become obstacles in public health which hinder the clinical medication safety and the research and development of new drugs, and become a research hotspot at home and abroad. Recent studies at home and abroad have revealed that the occurrence of drug eruptions caused by various drugs is related to the coding gene of individual Human Leukocyte Antigens (HLA), and HLA alleles are the most abundant gene system of human polymorphism. Drug eruptions caused by a plurality of drugs such as abacavir, allopurinol, carbamazepine and methazolamide are sequentially proved to be related to specific HLA alleles. In addition to the severe rash type, the rash-type drug eruptions caused by some drugs are also associated with certain HLA alleles and are mostly distributed in class I alleles. A large sample clinical experiment indicates that screening HLA alleles before administration is of great significance for reducing the occurrence of severe drug eruptions.
The tanshinone (Chinese medicine standard character Z13020110) is collected in the seventeenth volume of a medicine standard Chinese medicine prescription preparation of Ministry of public health, belongs to the national Chinese medicine protection variety (protection variety number ZYB20798060), is approved to be listed in the national basic medicine and national medical insurance medicine catalogue, and the annual sale amount of the tanshinone in the domestic market reaches seven million boxes at present. As an effective and inexpensive antibacterial adjuvant, it is widely used for the treatment of acne, tonsillitis, otitis externa, furuncle, carbuncle, traumatic infection, burn infection, mastitis, cellulitis, pneumonia and osteomyelitis. Besides infection resistance, it has been proved to have various pharmacological effects of antioxidation, cancer cell inhibition, reduction of cardiovascular and cerebrovascular accidents, and the like. However, clinical epidemiological data show that tanshinone is the top-ranked sensitizing drug in China. Retrospective analysis of 1883 cases of drug eruptions over 10 years shows that tanshinone is the only candidate in the ranking list of traditional Chinese medicine/Chinese patent medicine sensitization medicine. Drug eruptions caused by tanshinone are reported in north and south China, all patients definitely take the tanshinone produced by the same manufacturer in different batches and in different years (1996 to 2013), the clinical manifestations are similar eruption type drug eruption characteristics, and part of the drug eruptions are also reported in severe cases such as Stevens-Johnson syndrome. With the sharp increase of the use amount, the curative effect is ensured, and meanwhile, the drug eruption caused by tanshinone also gets more attention, so that the clinical application of the drugs faces the safety challenge.
At present, no reliable means for predicting drug eruption caused by tanshinone exists. In view of its high incidence, its harmfulness and its influence on the development of Chinese medicine, the prediction of its onset undoubtedly has great clinical and economic value.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a new application of HLA-A02: 01 and/or HLA-C01: 02 allele in genetic markers of drug eruptions caused by tanshinone.
The new application provided by the invention is at least one of the following:
1. use of a substance for detecting whether a human has an HLA-A02: 01 and/or HLA-C01: 02 allele for the manufacture of a product for detecting or assessing the risk of a human developing an adverse drug reaction in response to tanshinone;
2. use of a substance for detecting whether a human has an HLA-A02: 01 and/or HLA-C01: 02 allele in the preparation of a product for detecting or assessing the risk of a human developing drug eruptions due to tanshinone;
3. detecting whether a human has HLA-A02: 01 and/or HLA-C01: 02 allele in the application of the substance in preparing a screening product for drug eruption caused by tanshinone;
4. a method of detecting or assessing the risk of a human developing an adverse drug reaction in response to a tanshinone, the method comprising detecting whether the human has an HLA-a 02:01 and/or HLA-C01: 02 allele, wherein a human having an HLA-a 02:01 and/or HLA-C01: 02 allele is at a higher risk of developing an adverse drug reaction using a tanshinone than a human not having an HLA-a 02:01 and/or HLA-C01: 02 allele;
5. a method of detecting or assessing the risk of a human developing a tanshinone drug eruption, the method comprising detecting whether the human has an HLA-a 02:01 and/or HLA-C01: 02 allele. Wherein the risk of tanshinone drug eruption after tanshinone administration by a person having HLA-A02: 01 and/or HLA-C01: 02 alleles is higher than that by a person not having HLA-A02: 01 and/or HLA-C01: 02 alleles;
6. a method of developing a method of treating an adverse drug reaction in response to tanshinone comprising identifying and/or screening a candidate drug using an assay that uses an HLA-a 02:01 and/or HLA-C01: 02 allele as a target;
7. a method for developing a method for treating drug eruptions caused by tanshinone comprising identifying and/or screening candidate drugs using an assay wherein HLA-a 02:01 and/or HLA-C01: 02 alleles are targeted;
8. a product for detecting or assessing the risk of a human developing an adverse drug reaction in response to tanshinone, said product comprising a substance which detects whether a human has an HLA-a 02:01 and/or HLA-C01: 02 allele;
wherein, the substance for detecting whether a human has an HLA-A02: 01 and/or HLA-C01: 02 allele according to any of the methods for detecting the presence of an allele known in the art, such as a reagent, a kit and/or an apparatus for determining the presence of an HLA-A02: 01 and/or HLA-C01: 02 allele by at least one of the following methods: DNA specificity hybridization, PCR-based HLA sequencing typing, and HLA serotyping;
the substance for detecting whether a human has an HLA-A02: 01 and/or HLA-C01: 02 allele may be a reagent, a kit and/or an apparatus used in the method for detecting whether a human has an equivalent genetic marker for an HLA-A02: 01 and/or HLA-C01: 02 allele, the presence of the equivalent genetic marker for an HLA-A02: 01 and/or HLA-C01: 02 allele being indicative of the presence of an HLA-A02: 01 and/or HLA-C01: 02 allele;
the product can be a reagent or a kit, and can also be a combination product of the reagent or the kit and an apparatus;
in the above-mentioned applications, it is possible to detect whether or not a human has an HLA-A02: 01 and/or HLA-C01: 02 allele by using DNA, RNA, protein, cells or serum prepared from peripheral blood of a human to be tested.
The nucleotide sequence of HLA-A02: 01 allele is shown as sequence 1 in the sequence table.
The nucleotide sequence of HLA-C01: 02 allele is shown as sequence 2 in the sequence table.
Practical exemplification of the invention:
1) the HLA-A02: 01 and/or HLA-C01: 02 allele provided by the invention can be used as a medicine rash marker gene for predicting the medicine rash caused by tanshinone.
2) The HLA-A02: 01 and/or HLA-C01: 02 allele provided by the invention can be used for evaluating or preparing a screening kit before tanshinone is used.
3) The HLA-A02: 01 and/or HLA-C01: 02 allele provided by the invention can be used for evaluating or preparing targeted drugs for drug eruptions caused by tanshinone.
The present invention relates to human leukocyte antigen gene HLA-A02: 01 and/or HLA-C01: 02 allele, which is related to the development of drug eruption caused by tanshinone. HLA-A02: 01 and/or HLA-C01: 02 allele can be used as marker gene for predicting drug eruption caused by tanshinone. After the DNA is extracted from the peripheral blood of the patient, the HLA-A02: 01 and/or HLA-C01: 02 alleles are detected by the current method, such as the PCR-SSO (sequence specific oligonucleotide probe) method. The HLA-A02: 01 and/or HLA-C01: 02 allele detection method provided by the invention can be used for screening high-risk people with drug eruptions caused by tanshinone before use and screening targeted drugs for treating the drug eruptions caused by tanshinone. The former can guide clinical medication, thereby reducing the occurrence of drug eruption caused by tanshinone. The latter is mainly targeted to HLA-A02: 01 and/or HLA-C01: 02 molecules, thereby blocking the interaction between the molecules and tanshinone or its metabolites during pathogenesis.
Detailed Description
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
Example 1 HLA-A02: 01 and/or HLA-C01: 02 alleles are genetic markers of risk of drug eruptions due to tanshinone
A sample
The samples are human peripheral blood, including case samples, tanshinone drug-resistant person samples and health control samples.
1. Drug eruption group caused by tanshinone
18 cases of drug eruption patients caused by tanshinone; the mean age of the patients was 30.61 ± 14.57 years, the male to female ratio was 8: 1; the incubation period of tanshinone medicine is 8.83 + -2.64 days (3-14 days).
The clinical manifestations of the patients are mainly eruptive drug eruptions (17/18), which are manifested as erythema multiforme rash spreading diffusely throughout the body, and some patients may be accompanied by fever, abnormal liver function and other system damages. Only one of the patients was diagnosed with Stevens-Johnson syndrome due to oral and conjunctival mucosal lesions with liver dysfunction (1/18). The specific patient clinical information is shown in table 1 below. 300ul of the blood was sampled, DNA was extracted according to the kit instructions, and the DNA concentration and purity were measured by an ultraviolet spectrophotometer.
2. Clinical control group
63 patients who received tanshinone for three months or more and did not have any adverse reaction were used as clinical control group. The mean age of the patients was 24.90 ± 5.74 years, the male to female ratio was 4: 17. 300ul of the blood was sampled, DNA was extracted according to the kit instructions, and the DNA concentration and purity were measured by an ultraviolet spectrophotometer.
3. Group of population control
283 healthy Chinese Han nationality population, all from human MHC database (dbMHC), served as population control group. The tanshinone treatment is not needed.
II, HLA-A02: 01 allele and HLA-C01: 02 allele genotype detection
1. Discovery of alleles HLA-A02: 01 and HLA-C01: 02
The present invention adopts the PCR-SSO method (recommendation)
SSO kit-One Lambda, CA, USA) was used to type HLA genes of 18 patients with drug eruption caused by tanshinone and 63 patients in the tanshinone-resistant group. The principle is that firstly, the polymorphic region of HLA is amplified, the PCR product is labeled with isotope or non-isotope in the amplification process, then a series of oligonucleotide probes are designed according to the base pairing principle for the PCR amplification product and fixed on a membrane, and finally, the PCR product is hybridized with the probes on the membrane, and autoradiography is carried out to judge the result according to the signal. HLA genotyping is carried out according to standard procedures of the kit (i.e., DNA sample, substrate, Taq enzyme and primer are mixed and mixed, added into an amplification plate, amplified according to conditions in the kit specification, and amplified products are hybridized, stained and read plate). Analysis of the results was performed by HLA Fusion software (One lambda, CA, USA, HLA Fusion 3.0).
The results of HLA typing of the tanshinone drug eruption group are shown in Table 1, and it can be seen that the HLA typing of the tanshinone drug eruption group is mainly HLA-A02: 01 and HLA-C01: 02; therefore, the alleles HLA-A02: 01 and HLA-C01: 02 may be used as markers for judging patients with tanshinone drug eruption.
Table 1 shows the basic data and HLA typing results of tanshinone drug eruption group
MPE: rash type drug eruptions; SJS: Stevens-Johnson syndrome;
no statistical difference compared to control group.
2. Relationship between alleles HLA-A02: 01 and HLA-C01: 02 and drug eruption caused by tanshinone
Calculating the HLA-A02: 01 carrying frequency and HLA-C01: 02 carrying frequency of each group (carrying frequency is the number of people carrying the allele in each group of people/the total number of people in the group); and comparing the carrying frequency of HLA-A02: 01 and HLA-C01: 02 of the drug eruption group patients caused by tanshinone with the carrying frequency of related HLA alleles in a clinical control group and a population control group. The Odds Ratio (OR) and its 95% confidence interval were calculated using SPSS16.0, corrected using Haldane's if necessary, statistically analyzed using the chi-square test, and the statistical significance level was set to P less than 0.05.
As a result, as shown in Table 2, the frequency of HLA-A02: 01 and HLA-C01: 02 was significantly higher in the drug eruption group than in the control groups. The OR values of HLA-A02: 01 and HLA-C01: 02 alleles in the drug rash group and the two control groups are more than 1 in different degrees, which indicates that the two alleles are risk factors of drug rash caused by tanshinone.
Table 2 shows the comparison of HLA class I alleles in tanshinone drug eruption group and tolerance group
*P<0.05, with statistical differences. Or (odds ratio): ratio of ratios.
Note that n in the table is the total number of samples in each group. In columns 2-4, the number outside the parentheses is the number of sample persons carrying the allele, and the percentage inside the parentheses is the frequency of carrying the allele (the frequency of carrying is the number of persons carrying the allele/the total number of persons in each group). In columns 5-8, the P value represents the statistical difference between the frequency of HLA-A02: 01 and HLA-C01: 02 in the drug eruption group caused by tanshinone and the clinical control group and the population control group. The OR value represents the ratio of the carrying frequency of HLA-A02: 01 and HLA-C01: 02 in the tanshinone-induced drug eruption group to the two control groups, and the interval between the ratios is 95% of the confidence interval in the parentheses.
As can be seen from the above results,
the persons having HLA-A02: 01 allele were 8.43 times as high in risk of drug eruption after tanshinone administration as those having no HLA-A02: 01 allele, and had confidence intervals at a confidence level of 0.95 of (3.11-22.89).
The persons having HLA-C01: 02 allele were 3.11 times as high in risk of drug eruption after tanshinone administration as those having no HLA-A02: 01 allele, and the confidence interval at the confidence level of 0.95 was (1.17-8.28).
3. Research on independent risk relationship between allele HLA-A02: 01/HLA-C01: 02 and tanshinone drug eruption
The data in Table 2 above were subjected to regression analysis using SPSS16.0 calculation, and the results are shown in Table 3,
TABLE 3 regression analysis of related HLA alleles
*P<0.05, with statistical differences.
As can be seen from Table 3, both HLA-A02: 01 and HLA-C01: 02 alleles were independent risk alleles.
As can be seen from the above-mentioned results,
whether the patient to be detected has drug eruptions or not can be predicted by detecting whether the HLA gene of the patient to be detected which needs to be treated by the tanshinone has the allele HLA-A02: 01, and the risk of the drug eruptions of the patient to be detected which has the allele HLA-A02: 01 is higher than that of the patient to be detected which does not have the allele HLA-A02: 01 after the patient to be detected receives the tanshinone;
or whether the patient to be detected has drug eruptions or not can be predicted by detecting whether the HLA gene of the patient to be detected which needs to be treated by the tanshinone has the allele HLA-C01: 02, and the risk of the drug eruptions of the patient to be detected which has the allele HLA-C01: 02 is higher than that of the patient to be detected which does not have the allele HLA-C01: 02 after the patient to be detected receives the tanshinone;
or whether the patient to be tested has the allele HLA-A02: 01 and HLA-C01: 02 can be detected to predict whether the patient to be tested has the drug eruption, and the risk of the patient to be tested having the allele HLA-A02: 01 and the allele HLA-C01: 02 is higher than the risk of the patient to be tested not having the allele HLA-A02: 01 and the allele HLA-C01: 02 after receiving the tanshinone treatment.
Based on the results of the tests, risk prediction can be aided by the fact that individuals with HLA-A02: 01 and/or HLA-C01: 02, such as individuals treated with tanshinone, may develop drug eruptions, for which alternative treatment with other drugs is recommended. Individuals who do not have HLA-A02: 01 and/or HLA-C01: 02 have a low possibility of developing drug eruptions after tanshinone treatment, and can be selected for use as appropriate.
Sequence listing
<110> Fudan university affiliated Huashan Hospital Fudan university
<120> use of HLA-A02: 01 and HLA-C01: 02 in drug eruption caused by tanshinone
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cgcggggagc cccgcttcat cgcagtgggc tacgtggacg acacgcagtt cgtgcggttc 180
gacagcgacg ccgcgagcca gaggatggag ccgcgggcgc cgtggataga gcaggagggt 240
ccggagtatt gggacgggga gacacggaaa gtgaaggccc actcacagac tcaccgagtg 300
gacctgggga ccctgcgcgg ctactacaac cagagcgagg ccggttctca caccgtccag 360
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Claims (6)
1. Use of a substance for detecting whether a human has an HLA-A02: 01 allele in the manufacture of a product for detecting or assessing the risk of a human developing an adverse drug reaction in response to tanshinone.
2. Use of a substance for determining whether a human has an HLA-A02: 01 allele and a substance for determining whether a human has an HLA-C01: 02 allele for the manufacture of a product for detecting or assessing the risk of an adverse drug reaction in a human in response to a tanshinone.
3. Use of a substance for detecting whether a human has HLA-A02: 01 allele in the preparation of a product for detecting or evaluating the risk of drug eruption caused by tanshinone in a human.
4. Use of a substance for detecting whether a human has an HLA-A02: 01 allele and a substance for detecting whether a human has an HLA-C01: 02 allele for the preparation of a product for detecting or evaluating the risk of drug eruption caused by the occurrence of tanshinone in a human.
5. The application of the substance for detecting whether a human has HLA-A02: 01 allele in preparing a drug rash screening product caused by tanshinone is provided.
6. The application of the substance for detecting whether the human has the HLA-A02: 01 allele and the substance for detecting whether the human has the HLA-C01: 02 allele in preparing the drug eruption screening product caused by tanshinone.
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| WO2014124134A1 (en) * | 2013-02-07 | 2014-08-14 | The General Hospital Corporation | Methods for expansion or depletion of t-regulatory cells |
| KR20170000802A (en) * | 2015-06-24 | 2017-01-03 | 가톨릭대학교 산학협력단 | Composition for preventing or treating osteoarthritis comprising mesenchymal stem cell treated STAT3 inhibitor |
| CN106282328A (en) * | 2015-06-13 | 2017-01-04 | 复旦大学 | A kind of human leukocyte antigen's gene detecting kit and purposes |
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