CN114107475B - TMF1 polymorphism site as gene marker and psoriasis kit combined with methotrexate - Google Patents
TMF1 polymorphism site as gene marker and psoriasis kit combined with methotrexate Download PDFInfo
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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Abstract
The invention belongs to the technical field of biology, and relates to a gene marker and a detection kit for the curative effect of psoriasis drugs. The invention provides application of a locus rs2292199 in preparation of a medicament for treating psoriasis, wherein the genotype of rs2292199 is AG or AA. The invention also relates to a detection kit for predicting the clinical effect of Methotrexate (MTX) on psoriasis, and the kit predicts the clinical effect of MTX by detecting the SNP locus of TMF1 of a psoriasis patient. The invention can assist clinicians in classifying psoriasis patients and select MTX therapeutic intervention schemes, thereby providing a basis for improving the clinical curative effect of MTX.
Description
Technical Field
The invention belongs to the technical field of biology, and relates to a psoriasis drug curative effect detection kit, in particular to a novel detection kit for predicting the clinical curative effect of Methotrexate (MTX) on psoriasis, wherein the detection kit predicts the clinical curative effect of MTX by detecting SNP loci of TMF1 of patients suffering from psoriasis. Can guide a clinician to formulate a proper MTX therapeutic intervention scheme, and provides a basis for improving the clinical curative effect of MTX.
Background
The prior art discloses psoriasis as a common chronic inflammatory disease, and can involve multiple organs such as skin, nails, joints, kidneys, cardiovascular diseases and the like. The disease has high incidence rate, long disease course, easy recurrence and difficult radical cure, and brings serious physical and psychological damage and economic burden to patients. In the prior medical intervention commonly adopted in clinical practice, the effective rate of the commonly used abamectin is only about 20 percent, the blood fat is increased, the risk of cardiovascular diseases of patients is increased, and partial patients can also have the damage of liver and kidney functions; the clinical effective rate of the biological agent is about 50-80%, but most patients cannot bear the biological agent due to the high price; methotrexate (MTX) is a more economical and effective drug for treating psoriasis that is currently more commonly used, but because of the risk of bone marrow depression and hepatic fibrosis, the wide application of MTX in psoriasis treatment is severely limited.
MTX was approved by FDA in 1972 for the treatment of psoriasis, and has a structure similar to folic acid, irreversibly binds to dihydrofolate reductase, exerts antiproliferative activity, induces apoptosis and increases adenosine concentration, and has anti-inflammatory and immunomodulatory effects. Previous studies have found that the genetic polymorphism of enzymes associated with the folate metabolic pathway is related to the clinical efficacy and toxic side effects of MTX in the treatment of rheumatoid arthritis: such as MTHFR1298A＞C(rs1801131), ATIC347C＞G(rs2372536),RFC-180G＞A(rs1051266),SLC19A1A＞G(rs2838956) and SLC19A1G＞A(rs7499), with clinical efficacy of MTX; whereas the RFC-180G > A (rs 1051266) gene polymorphism is associated with MTX toxicity.
Therefore, finding a biomarker to predict clinical efficacy and toxic side effects of MTX is beneficial to improving clinical efficacy and reducing toxic side effects, and the subject becomes a focus of attention of more and more scientists and doctors in the field.
Research shows that psoriasis is a chronic inflammatory disease co-mediated by the interaction of immune cells and keratinocytes under a certain genetic background, clinically presents as a clear-bordered white scale plaque, and the characteristic tissue pathology is closely related to the abnormal differentiation of epidermis. TATA element regulator (TATA ELEMENT modulatory factor, TMF 1) is a potential coactivator of the androgen receptor, mediating STAT3 degradation, playing a key role in two RAB6 dependent reverse trafficking processes: one from endosomes to the golgi apparatus and the other from the golgi apparatus to the estrogen receptor. However, the mechanism research of TMF1 and the related mechanism of psoriasis pathogenesis are not reported at present.
Disclosure of Invention
The invention aims to provide a novel psoriasis-related gene marker and application thereof based on the current state of the art.
It is a further object of the present invention to provide a pharmaceutical kit for the treatment of psoriasis, including a detection kit for predicting the suitability of methotrexate.
The invention firstly discusses the relation between the TMF1 gene polymorphism and the clinical curative effect of MTX, and the improvement rate of PASI75 is obviously better than that of GG type patients after the MTX treatment for 3 months by researching psoriasis patients carrying TMF1 SNP locus rs2292199AG and AA genotype, and the invention provides a gene marker which can be used for predicting the clinical curative effect of MTX on psoriasis by the TMF1 SNP locus rs2292199AG and AA genotype.
The invention provides application of a locus rs2292199 in preparation of a medicament for treating psoriasis.
Preferably, the genotype of rs2292199 is AG or AA.
Preferably, the rs2292199 locus is used as a gene marker in a psoriasis pharmaceutical kit.
Preferably, the psoriasis pharmaceutical kit contains methotrexate, or an analogue, active ingredient or derivative thereof.
Preferably, the application comprises the following steps:
isolating a portion containing site rs2292199 from the sample;
recognition site rs2292199;
The genotype of site rs2292199 is determined.
Preferably, the application further comprises the following steps: and determining whether the genotype is AG or AA according to the detection result of the locus rs2292199 genotype.
Preferably, the application comprises combining the following components:
the locus rs2292199 with the genotype AG or AA;
An active ingredient comprising methotrexate;
The combination is used for preparing a psoriasis pharmaceutical kit.
The inventor of the application aims to provide the SNP locus rs2292199AG and AA genotypes of TMF1 as gene markers for predicting the clinical curative effect of MTX on psoriasis by researching the relation between the SNP locus rs2292199 genotype of the TMF1 gene and the clinical curative effect of MTX on psoriasis. According to the application, through researching the relation between the TMF1 locus rs2292199 genotype and the clinical curative effect of MTX treatment, for example, the occurrence of the effective rate of MTX treatment on psoriasis patients carrying TMF1 SNP locus rs2292199AG and AA genotype or not is used for predicting the evaluation of the clinical curative effect of MTX treatment on psoriasis, a clinician is helped to be guided to formulate a proper MTX treatment intervention scheme.
The invention also provides a pharmaceutical kit, which comprises:
A substance at detection site rs 2292199; and/or
An active ingredient of methotrexate;
The genotype of the locus rs2292199 is AG or AA.
Preferably, the substance of the detection site rs2292199 comprises a primer and a probe for detecting the locus rs2292199 genotype; or an active agent of the conjugate site rs2292199 identifier.
Preferably, the locus rs2292199 is used as a positive control of the pharmaceutical kit, and the genotype of the locus rs2292199 is AG or AA.
Preferably, the pharmaceutical kit is applied to preventing psoriasis.
The invention also comprises the application of the TMF1 SNP locus rs2292199 in preparing a gene marker for predicting the clinical curative effect of methotrexate.
For example, the use of TMF1 SNP locus rs2292199 in the preparation of a detection kit for predicting the clinical efficacy of methotrexate.
Preferably, the curative effect of the methotrexate therapeutic intervention can be predicted according to the condition that the effective rate of the methotrexate therapeutic intervention is adopted by a psoriasis patient carrying TMF1 SNP locus rs2292199AG and AA genotype.
The invention also comprises the application of the TMF1 SNP locus rs2292199 in preparing a gene marker for predicting the clinical curative effect of methotrexate on psoriasis.
The invention also comprises the detection kit, by detecting the relation between the genotype of the TMF1 SNP locus rs2292199 and the clinical curative effect of the methotrexate on the psoriasis, the clinical curative effect of the methotrexate on the psoriasis is predicted and estimated according to the occurrence condition of the effective rate of the methotrexate treatment intervention carried by the genotype of the TMF1 SNP locus rs2292199AG and the AA.
In the invention, the gene map of the TMF1 gene can be searched as follows:
hAAps://www.ncbi.nlm.nih.gov/genome/gdv/browser/？context＝genome&i d＝GCF_000001405.38。
In the present invention, the psoriasis patient condition score refers to the PASI (Psoriasis AREA AND SEVERITY index ) criteria, including the skin lesion area score and the skin lesion severity score.
1. Area of evaluation 4 body parts were scored 0-6 points for area 0 = no rash; 1<10%; 2=10-29%; 3=30-49%; 4=50-69%; 5=70-89%; 6=90-100%; trunk area, head area = 10%; torso = 30%; upper limb = 20%; lower limb = 40%
Skin damage area grading, namely, dividing the whole body into 4 parts of head and neck, upper limbs, trunk and lower limbs. The above parts account for 10%, 20%, 30% and 40% of the body surface area respectively. The skin damage area was scored for each of the 4 sites, with the following criteria:
0=no rash, 1=1% -9%, 2=10% -29%, 3=30% -49%, 4=50% -69%, 5=70% -89%, 6=90% -100%.
To facilitate the assessment of the affected area, the following provisions should be noted:
a. the neck is considered to be part of the head.
B. Armpits and groins are used as part of the torso.
C. Buttocks are taken as a part of the lower limb.
2. Evaluating clinical severity of erythema; soaking; and (5) scaling. Each feature was rated 0-4 score 0 = none; 1 = mild; 2 = medium; 3 = severe; 4 = extremely severe. Calculating the score of each body part according to a formula, and accumulating to obtain the total score, wherein the score is 0-72:
Skin lesion severity score according to the 4-part score above, each part was scored according to the following 3 skin lesion clinical features:
Red spots (erythema, E) are red or dark red inflammatory spots, which are discolored by pressure.
Infiltration (I) the tendency of skin damage to spread around, blurred boundary and a solid texture.
Epidermis desquamation/scaling (desquamation, D) means that the exfoliated epidermis cells exfoliate.
Skin lesion severity scores were as follows:
0 = none, this sign was not confirmed by careful observation,
1=Light, which sign can be confirmed but needs to be carefully observed,
In 2=this sign is more clearly immediately identifiable,
3 = Heavy, this sign is evident.
4 = Extremely heavy, this sign is very pronounced.
Plaque hypertrophy degree I0-skin lesion is flush with normal skin;
1-skin lesions are slightly elevated from normal skin surface;
2-moderately raised, the edge of the plaque being round or sloped;
3-the skin is damaged and fattened, and the bulge is obvious;
the 4-skin loss is highly thickened and the bulge is very obvious.
0-No erythema is visible; 1-pale red; 2-red; 3-dark red; 4-red is extremely deep.
0-No visible scale on the surface;
1-part of the surface of the skin lesion is covered with scales, and the scale is mainly fine;
2-most of the skin lesions are completely or incompletely covered with scales, and the scales are flaky;
3-almost all the surface of the skin damage is covered with scales, and the scales are layered thicker;
4-all the skin damage surfaces are covered with scales, and the scales are layered in a thick way.
Exudation, dryness and itching were not taken into account.
Psoriasis vulgaris PASI scoring formula:
PASI score = (E head+i head+d head) ×a head×0.1+ (E upper limb+i upper limb+d upper limb) ×a upper limb×0.2+ (E trunk+i trunk+d trunk) ×a trunk×0.3+ (E lower limb+i lower limb+d lower limb) ×a lower limb×0.4
Efficacy determination criteria efficacy determination is made by recording the PASI score before and after treatment according to the psoriasis lesion area and severity index (psoriasis AREA AND SEVERITY index, PASI) score criteria, and by determining efficacy according to the rate of decrease in PASI score. The rate of reduction of PASI score is two (pre-treatment PASI score-post-treatment PASI score)/pre-treatment PASI score x 100%.
Recovery, PASI score reduction >90%;
the effect is obvious, and the PASI score reduction rate is 60 percent to 89 percent;
effectively, the PASI score decrease rate was 20% to 59%;
Ineffective, PASI score decrease rate <20%.
The total effective rate (number of recovery cases, number of obvious effect cases and number of effective cases)/(total cases) is 100%.
The gene map of the TMF1 gene can be searched as follows:
hAAps://www.ncbi.nlm.nih.gov/genome/gdv/browser/？context＝genome&a AG＝GCF_000001405.39。
In the invention, the relation between the genotype of the TMF1 SNP locus rs2292199 of 310 psoriasis patients and the clinical curative effect of MTX for treating psoriasis is detected, 309 cases of successful typing are detected, and the result shows that: 1) Patients carrying TMF1 SNP rs2292199AA and AG genotypes had significantly higher improvement rates (59.5% and 55.7%) for PASI50 at week 8 of treatment than patients carrying GG genotype (34.2%), the difference being statistically significant, p=0.0209; 2) Patients carrying TMF1 SNP rs2292199AA and AG genotypes had significantly higher improvement rates (55.0% and 44.3%) for PASI75 at week 12 of treatment than patients carrying GG genotypes (23.7%), the difference being statistically significant, p=0.0025.
The test result proves that the method for detecting the genotype of the TMF1 SNP locus rs2292199 of the psoriasis patient can be used for preparing a kit for predicting the MTX to treat the psoriasis.
The further experiment shows that the clinical curative effect of MTX for treating psoriasis is 46.5% without genetic detection, and the effective rate of MTX therapeutic intervention is improved to 49.4% for psoriasis patients carrying TMF1 SNP locus rs2292199AA and AG genotypes, and the result shows that the effective rate of MTX therapeutic intervention for psoriasis patients carrying TMF1 SNP locus rs2292199AA and AG genotypes is high.
The invention provides a novel gene marker for predicting the clinical curative effect of MTX, in particular to a gene marker which can be used for predicting the clinical curative effect of MTX on psoriasis by using TMF1 SNP locus rs2292199AA and AG genotypes;
The invention further provides a detection kit for predicting the clinical curative effect of methotrexate on psoriasis, and the treatment effective rate of the detection kit is high by adopting MTX treatment to intervene on psoriasis patients carrying TMF1 SNP locus rs2292199AA and AG genotype no; the invention can be used for predicting the evaluation of the clinical curative effect of MTX for treating psoriasis, and is helpful for guiding clinicians to formulate a proper MTX therapeutic intervention scheme.
The invention belongs to the field of biotechnology, and relates to a psoriasis drug curative effect detection gene marker and a detection kit, and the invention provides a TMF1 SNP locus rs2292199AA and AG genotype as gene markers for predicting the clinical curative effect of methotrexate on psoriasis; the detection kit is provided by researching the relation between the genotype of the TMF1 SNP locus rs2292199 and the clinical curative effect of MTX in treating psoriasis, and the clinical curative effect of MTX in treating psoriasis is predicted and estimated according to the occurrence of the effective rate of MTX treatment intervention of a psoriasis patient carrying the genotype of the TMF1 SNP locus rs2292199, so that a clinician is guided to formulate a proper dry pretreatment scheme of MTX treatment, and a foundation is provided for improving the clinical curative effect of MTX.
Detailed Description
Example correlation study of TMF1 Gene polymorphism and clinical efficacy of MTX for treatment of psoriasis
Materials and methods:
1) Psoriasis patient: psoriasis patients from 1 month in 2015 to 6 months in 2019 to the department of dermatology dedicated to psoriasis in Huashan hospital were selected as subjects of observation.
2) The medicine intervention method comprises the following steps: mtx7.5mg was administered singly weekly for weeks 1 and 2, 10mg was administered singly weekly for weeks 3 to 4, and 12.5mg was administered singly weekly for weeks 5 to 12.
3) Inclusion criteria
(1) Age 18-60 years;
(2) Patients diagnosed with psoriasis vulgaris, arthropathy, erythroderma, and pustular, have a body surface afflicted area (BSA) > 10% or a Psoriasis Area and Severity Index (PASI) > 10;
(3) Fill out the complete epidemiological questionnaire and sign the informed consent.
4) Exclusion criteria
(1) Other special types of psoriasis vulgaris patients (drip, reverse);
(2) A family planning person and partner for women of age <18 years, gestation, lactation, or 6 months;
(3) Patients who are allergic to the drugs used in the present study and who have allergies to the relevant drug components are known;
(4) Patients who have not used other external medicines for psoriasis, except for moisturizers, within 2w (2 weeks), and have not used other treatment schemes such as systemic medicines for psoriasis within 4 w;
(5) Patients with other primary diseases such as hematopoietic system, circulatory system, respiratory system, digestive system, and immune system, primary or secondary immunodeficiency, liver fibrosis or chronic liver disease, tuberculosis, other infectious diseases, and mental diseases;
(6) Patients undergoing other immunosuppressive therapy and recent vaccinations or planned vaccinations;
5) Periodic follow-up index: blood urine is normal, liver and kidney functions, liver fibrosis, blood fat, blood sugar and glycosylated hemoglobin.
6) Patient DNA was extracted and SNP rs2292199 loci from 310 patients were genotyped using sequenom platform and defined as active and inactive groups, respectively, as to whether PASI75 was reached at 12 w.
The results show that MTX treatment for 3 months resulted in improvement of PASI75 in 46.5% of psoriatic patients; patients carrying TMF1 SNP rs2292199AA and AG genotypes had significantly higher improvement rates (59.5% and 55.7%) for PASI50 at week 8 of treatment than patients carrying GG genotype (34.2%), the difference being statistically significant, p=0.0209; 2) Patients carrying TMF1 SNP rs2292199AA and AG genotypes had significantly higher improvement rates (55.0% and 44.3%) for PASI75 at week 12 of treatment than patients carrying GG genotypes (23.7%), the difference being statistically significant, p=0.0025. General information and clinical efficacy of 310 psoriasis patients are shown in Table1 (Table 1).
TABLE 1
The foregoing is merely illustrative of the present application, and the present application is not limited thereto, and any changes or substitutions easily contemplated by those skilled in the art within the technical scope of the present application should be included in the scope of the present application. Therefore, the protection scope of the present application shall be subject to the protection scope of the claims.
Claims (4)
1. The application of the locus rs2292199 serving as a gene marker in preparing a detection kit for predicting the clinical curative effect of methotrexate MTX on psoriasis; the genotype of rs2292199 is AG or AA.
2. The use according to claim 1, wherein the detection kit comprises methotrexate MTX.
3. The application of claim 1, wherein the application comprises the steps of:
isolating a portion containing site rs2292199 from the sample;
recognition site rs2292199;
The genotype of site rs2292199 is determined.
4. The application of claim 3, wherein the application further comprises the steps of: and determining whether the genotype is AG or AA according to the detection result of the locus rs2292199 genotype.
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| rs2292199;GenBank;《GenBank》;Fasta sequence * |
| 甲氨蝶呤在皮肤科的临床应用及注意事项;颜克香;《皮肤科学通报》;第38卷(第4期);320-326+4 * |
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