CN109295194B - Psoriasis susceptibility genes LCE3D and TNIP1 and application thereof - Google Patents
Psoriasis susceptibility genes LCE3D and TNIP1 and application thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of biology, relates to psoriasis susceptibility genes and application thereof, and particularly relates to psoriasis susceptibility genes LCE3D and TNIP1 and application thereof in preparation of a detection kit, and provides a novel gene marker for predicting MTX clinical curative effect, in particular to a gene marker for predicting MTX clinical curative effect and toxic and side effects of MTX intervention treatment, wherein the gene marker is LCE3D SNP locus rs41127 4112788AG genotype and TNIP1SNP locus rs10036748TT genotype; the invention also provides a detection kit, which predicts the clinical curative effect and toxic and side effect of MTX by detecting SNP loci of susceptibility genes LCE3D and TNIP1 of psoriasis patients. The method can be further used for predicting the clinical curative effect and toxic and side effect evaluation of MTX treatment psoriasis, and is helpful for guiding a clinician to formulate a proper MTX treatment intervention scheme.
Description
Technical Field
The invention belongs to the technical field of biology, relates to psoriasis susceptibility genes and application thereof, and particularly relates to psoriasis susceptibility genes LCE3D and TNIP1 and application thereof in preparation of a detection kit, wherein the kit predicts clinical curative effect and toxic and side effect of MTX by detecting SNP sites of psoriasis susceptibility genes LCE3D and TNIP 1.
Background
The prior art discloses that psoriasis is a common chronic inflammatory disease and can affect a plurality of organs such as skin, nails, joints, kidneys, cardiovascular diseases and the like; the disease has high incidence, long course of disease, easy recurrence and difficult radical cure, which brings serious physical and mental damage and economic burden to patients. In the pharmaceutical intervention commonly adopted in clinical practice, the effective rate of commonly used abamectin is only about 20 percent, blood fat can be increased, the risk of cardiovascular diseases of patients is increased, and the liver and kidney functions of some patients can be damaged; the clinical effective rate of the related biological preparation is about 50% -80%, but the price is high, so most patients cannot bear the effective rate; methotrexate (MTX) is a more economical and effective medicament for treating psoriasis, but the wide application of MTX in the psoriasis treatment is severely limited due to the risk of bone marrow suppression and hepatic fibrosis. Therefore, finding biomarkers that can predict the clinical efficacy and toxic side effects of MTX is becoming a focus of increasing attention by scientists and physicians in this field.
The research shows that the psoriasis is a chronic inflammatory disease which is mediated by the interaction of immune cells and keratinocytes under a certain genetic background, the clinical manifestation is white squamous plaque with clear boundaries, and the characteristic histopathological manifestation is closely related to the abnormal differentiation of epidermis. It has been shown that the Epidermal Differentiation Complex (EDC) gene is a gene family that is clustered on chromosome 1q21 and is involved in regulating the terminal differentiation of epidermis; the late cornified envelope gene cluster (late cornified envelope gene cluster) is positioned in the EDC gene region, and the coded late cornified envelope protein (LCE) compound plays an important role in the epidermal differentiation process; abnormal keratinized envelope proteins encoded by the LCE gene cluster may affect the stability of the outer membrane of parakeratotic or hyperkeratotic keratinocytes, thereby causing the keratinocytes to aggregate without normal differentiation, and then interfering with the terminal differentiation of the keratinocytes. Researchers have conducted genome-wide association study (GWAS) on Chinese psoriasis and found that LCE1B and LCE3D gene polymorphisms in the LCE gene cluster are associated with psoriasis.
To date, the etiology and pathogenesis of psoriasis has not been fully elucidated, and the classical inflammatory factor kappa B (NF-kappa B) is the major signaling pathway mediating the inflammatory response of psoriasis. Genome-wide association studies (GWAS) have identified TNF α -induced protein3interacting protein1 (TNIP 1) as a psoriasis susceptibility gene that is of great interest for its important role in regulating NF- κ B signaling. TNIP1 is a newly discovered endogenous inflammatory regulator involved not only in the regulation of inflammatory responses but also in the regulation of immune function. Research reports that Single Nucleotide Polymorphism (SNP) of TNIP1 gene is related to psoriasis development of people in Europe, America and China. The down regulation of TNIP1 protein in skin lesions and peripheral blood lymphocytes of patients with ongoing psoriasis is shown by animal experiments, and the down regulation of the level of local TNIP1 protein in the skin of mice can aggravate the IMQ-induced psoriasis-like dermatitis expression of the mice, and the suggestion that the reduction of the expression of TNIP1 can be one of important reasons for the failure of effective inhibition of the psoriasis inflammatory reaction process.
MTX was approved by the FDA for the treatment of psoriasis in 1972, has a structure similar to folic acid, binds irreversibly to dihydrofolate reductase, exerts antiproliferative activity, induces apoptosis and increases adenosine concentration, and has anti-inflammatory and immunomodulatory effects. Researches show that the gene polymorphism of enzymes related to the folic acid metabolic pathway is related to the clinical curative effect and toxic and side effects of MTX for treating rheumatoid arthritis: for example, MTHFR1298A > C (rs1801131), ATIC347C > G (rs2372536), RFC-180G > A (rs1051266), SLC19A1A > G (rs2838956) and SLC19A1G > A (rs7499) are associated with clinical efficacy of MTX; the RFC-180G & gtA (rs1051266) gene polymorphism is related to the toxicity of MTX, and the research attention is drawn to the relationship between the disease susceptibility gene locus and the clinical treatment effect and toxic and side effect of MTX.
Based on the current research situation of the prior art, the inventor of the application intends to provide psoriasis susceptibility genes LCE3D and TNIP1 and application thereof in preparing a detection kit, and predicts the clinical curative effect and toxic and side effect of MTX by detecting SNP sites of the psoriasis susceptibility genes LCE3D and TNIP 1.
Disclosure of Invention
The invention aims to provide a novel gene marker for predicting the clinical curative effect of MTX based on the current situation of the prior art, in particular to psoriasis susceptibility genes LCE3D and TNIP1 and application thereof in preparing a detection kit, and the clinical curative effect and the toxic and side effect of MTX are predicted by detecting SNP sites of the psoriasis susceptibility genes LCE3D and TNIP 1.
The invention researches the relationship between the genotypes of the LCE3D and TNIP1SNP sites rs4112788 and rs10036748 and the curative effect and the toxic and side effect of MTX intervention treatment on psoriasis, and shows that the psoriasis patients carrying the genotypes of the LCE3D SNP site rs 411272788 4112788AG and the TNIP1SNP site rs10036748TT have quick response and high improvement rate of PASI90 but also have increased risk of hepatotoxicity by adopting MTX intervention treatment, and the psoriasis patients carrying the genotypes of the LCE3D SNP site rs41127 4112788AG and the TNIP1SNP site rs10036748TC have high effective rate and do not increase the risk of hepatotoxicity by adopting MTX intervention treatment, and the proposed genotypes of the LCE3D SNP site rs4112788AG and the TNIP1SNP site rs 10036TT genotypes can be used as psoriasis gene markers for predicting the clinical curative effect and the toxic and side effect of MTX treatment on psoriasis.
The invention further aims to provide application of psoriasis susceptibility genes LCE3D and TNIP1 in preparation of a detection kit, and the application is used for predicting clinical curative effect and toxic and side effect of MTX by detecting SNP sites of psoriasis susceptibility genes LCE3D and TNIP 1.
In the invention, the relation between the genotype of LCE3D SNP locus rs4112788 of 90 psoriasis patients and the clinical curative effect of MTX on psoriasis is detected, and the result shows that: 1) patients carrying the LCE3D susceptibility gene AG genotype had 72% improvement in PASI50 at week 8 of treatment, significantly higher than patients carrying the AA/GG genotype (38%/37%), with statistical differences, p < 0.01; 2) the improvement rates of patients carrying the LCE3D susceptibility gene AG genotype in PASI50 and PASI75 at the 12 th week of treatment are 86% and 64% respectively, which are obviously higher than those of patients with AA genotype (50% and 25%) and GG genotype (60% and 31%), the difference has statistical significance, and p is less than 0.05; 3) 50% of patients with psoriasis carry the AG genotype, 9% carry the AA genotype, and 41% carry the GG genotype; 4) the probability of liver function abnormality and liver fiber index abnormality of AG genotype-carrying patients with MTX intervention is 30% and 30%, and the incidence of hepatotoxicity is not statistically different, p is more than 0.05, compared with AA type (25% and 25%) and GG type (37% and 43%).
The invention detects the relationship between the genotype of the TNIP1SNP locus rs10036748 of 90 psoriasis patients and the clinical curative effect and the toxic and side effect of MTX treatment of psoriasis, and the result shows that: 1. the improvement rate of the patient carrying the TNIP1 susceptibility gene TT genotype (76%) at 8 weeks of treatment for PASI50 was significantly higher than that of the patient carrying the TC/TT genotype (43%/33%), and the improvement rate of PASI75 was 64% at 12 weeks of treatment; 2. the risk of liver dysfunction or liver fibrosis of patients carrying TNIP1 susceptibility gene TT genotype treated by MTX is 43% and 45% respectively, which is obviously higher than that of TC/CC genotype patients (22% and 24%, 17% and 0); 3. 43% of patients with psoriasis carry the TT genotype, 49% carry the TC genotype, and 8% carry the CC genotype; the invention proves that the detection of the genotype of the SNP locus rs10036748 of the TNIP1 of the psoriasis patient can predict the clinical curative effect and the toxic and side effect of MTX for treating psoriasis.
The invention analyzes the carrying condition of 43 patients with TNIP1SNP locus rs10036748 genotype carrying LCE3D SNP locus rs4112788AG genotype and the relationship between the carrying condition and the clinical curative effect and the toxic and side effect of MTX treatment psoriasis, and the result shows that: the TNIP1SNP locus rs10036748 genotyping success rate of 1.43 patients carrying the LCE3D SNP locus rs4112788AG genotype, 20 patients carrying the TNIP1rs10036748TC genotype, 50% of the patients carrying the AG genotype, 16 patients carrying the TNIP1rs10036748TT genotype, 40% of the patients carrying the AG genotype, 4 patients carrying the TNIP1rs10036748CC genotype and 10% to 2% of the patients carrying the AG genotype of the LCE3D SNP locus rs4112788AG genotype and the patients carrying the TNIP1SNP locus rs10036748TT genotype are obviously better than the patients carrying the LCE3 4114 SNP locus rs 2788AG genotype and the TNIP1SNP locus rs10036748TC genotype (60% and 20% and p <0.05) at the 8 th week of treatment. 3. The improvement rate (44%) of the patient carrying the LCE3D SNP site rs4112788AG genotype and the TNIP1SNP site rs10036748TT genotype at the same time in the treatment 12 week of PASI90 is obviously better than that of the patient carrying the LCE3D SNP site rs4112788AG genotype and the TNIP1SNP site rs10036748TC genotype at the same time (20%), but the sample size is small, and the statistical significance is not found; 4. the probability (44% and 44%) of liver enzyme abnormality and liver fibrosis serum index abnormality of patients carrying the LCE3D SNP site rs4112788AG genotype and the TNIP1SNP site rs10036748TT genotype at the same time in the treatment 12 week is obviously higher than that of patients carrying the LCE3D SNP site rs4112788AG genotype and the TNIP1SNP site rs10036748TC genotype at the same time (15% and 20%).
The test result proves that the kit can be used for predicting the clinical curative effect and hepatotoxicity of MTX for treating psoriasis by detecting the genotype of LCE3D SNP locus rs4112788 and the genotype of TNIP1SNP locus rs10036748 of psoriasis patients.
Further experimental results show that the clinical curative effect of treating psoriasis by MTX without gene detection is 47%, MTX treatment intervention is adopted for psoriasis patients carrying LCE3D SNP locus rs4112788AG genotype, the effective rate can be improved to 65%, and no risk of increasing hepatotoxicity is seen; the probability of MTX causing liver function abnormality and liver fibrosis index abnormality is 34% and 37% respectively without gene detection, and the probability of liver toxicity occurring by MTX therapeutic intervention for psoriasis patients carrying LCE3D SNP locus rs4112788AG genotype is 30%; meanwhile, the TNIP1SNP locus rs100036748 genotype is detected, MTX therapy intervention is adopted for psoriasis patients carrying LCE3D SNP locus rs4112788AG genotype and TNIP1SNP locus rs100036748TT genotype, the effective rate can be improved to 69%, the PASI90 improvement rate is improved to 44%, but the probability of liver enzyme abnormality and hepatic fibrosis abnormality is increased to 44%, the probability that the liver enzyme abnormality and the hepatic fibrosis abnormality occur is prompted to be closely monitored when MTX therapy is recommended for the partial patients, and liver toxicity of MTX can be reduced by matching liver protection drugs, so that the MTX therapy for the patients has quick response and high cure rate; MTX is adopted for treating and intervening psoriasis patients carrying LCE3D SNP locus rs4112788AG genotype and TNIP1SNP locus rs100036748TC genotype, the effective rate can be improved to 65%, and the probability of liver enzyme abnormality and hepatic fibrosis abnormality is reduced by 15% and 20% respectively. MTX therapy intervention is adopted for psoriasis patients carrying LCE3D SNP locus rs4112788AG genotype and TNIP1SNP locus rs100036748CC genotype, the effective rate is 50%, and therefore MTX therapy for the patients is not recommended;
the experimental detection results show that the detection of the genotypes of the SNP sites rs4112788 and rs10036748 of LCE3D and TNIP1 ensures that the clinical curative effect is improved, and simultaneously, a patient group needing liver protection treatment in MTX interventional therapy can be more definitely determined, so that the economic burden and the toxic and side effects of medicines brought by blindly using liver protection therapists can be effectively avoided.
The invention provides a novel gene marker for predicting the clinical curative effect of MTX, in particular to a gene marker of LCE3D SNP locus rs41127 4112788AG genotype and TNIP1SNP locus rs10036748TT genotype which can be used for predicting the clinical curative effect and the toxic and side effect of MTX intervention treatment of psoriasis;
the invention further provides a detection kit for predicting the clinical curative effect of methotrexate on psoriasis, aiming at the psoriasis patients carrying the genotype of the LCE3D SNP locus rs41127 4112788AG and the genotype of the TNIP1SNP locus rs10036748TC, the treatment efficiency is high by adopting MTX treatment intervention, and the risk of hepatotoxicity is not increased; the MTX therapeutic intervention is adopted for psoriasis patients carrying the LCE3D SNP locus rs4112788AG genotype and the TNIP1SNP locus rs10036748TT genotype, the treatment efficiency is high, the risk of hepatotoxicity is increased, and further, the method is used for predicting the clinical curative effect and toxic and side effect evaluation of the MTX interventional therapy of psoriasis, and is helpful for guiding clinicians to formulate a proper MTX therapeutic intervention scheme.
The gene maps of the two genes can be searched through the following channels:
https://www.ncbi.nlm.nih.gov/genome/gdv/browser/？cfg＝NCID_1_ 17674144_130.14.18.128_9146_1497362468_1541845085；
https://www.ncbi.nlm.nih.gov/genome/gdv/browser/？cfg＝NCID_1_ 17676740_130.14.18.128_9146_1497362669_947243872。
the invention provides psoriasis susceptibility genes LCE3D and TNIP1 and application thereof in preparing a detection kit, and the clinical curative effect and the toxic and side effect of MTX are predicted by detecting SNP loci of the susceptibility genes LCE3D and TNIP1 of a psoriasis patient. The method can be further used for predicting the clinical curative effect and toxic and side effect evaluation of MTX treatment psoriasis, and is helpful for guiding a clinician to formulate a proper MTX treatment intervention scheme.
Detailed Description
Example 1: clinical curative effect and toxic and side effect observation experiment for MTX intervention treatment of psoriasis
The material and the method are as follows:
1) patients with psoriasis: the psoriasis patients who visit the dermatology department clinic for psoriasis in the Huashan hospital from 1 month to 2017 months in 2015 are selected as the observation subjects.
2) The medicine intervention method comprises the following steps: treatment is given as a single oral dose of MTX7.5mg weekly for weeks 1 and 2, 10mg weekly for weeks 3 to 4, and 12.5mg weekly for weeks 5 to 12.
3) Inclusion criteria
(1) Age 18-60 years;
(2) patients diagnosed with vulgaris, arthrosis, erythrodermic, and pustular psoriasis with a body surface area of involvement (BSA) > 10% or a Psoriasis Area and Severity Index (PASI) > 10;
(3) fill in the complete epidemiological questionnaire and sign the informed consent.
4) Exclusion criteria
(1) Other special types of psoriasis vulgaris patients (drip, inverted);
(2) women <18 years of age, pregnant, lactating, or family planning in 6 months;
(3) patients known to be allergic to the drug used in the study, and patients containing allergies to related pharmaceutical ingredients;
(4) patients who have not used other external medicines for treating psoriasis except the humectant in 2w, and patients who have not used other treatment schemes such as systemic medicines for treating psoriasis in 4 w;
(5) patients with other primary diseases such as hemopoietic system, circulatory system, respiratory system, digestive system, and immune system, patients with primary or secondary immunodeficiency, liver fibrosis or chronic liver disease, tuberculosis, and other infectious diseases and mental diseases;
(6) patients undergoing other immunosuppressive treatment and recent or scheduled vaccinations;
5) the regular follow-up index is as follows: hematuria, liver and kidney function, liver fibrosis, blood fat, blood sugar and glycosylated hemoglobin.
The results show that MTX intervention results in an improvement in PASI75 in 47% of psoriasis patients; 30% of patients have adverse reactions such as gastrointestinal discomfort and the like; liver function abnormalities and liver fibrosis index abnormalities occur in 34% of patients and 37% of patients; dyslipidemia is associated with 36% of patients; 37% of patients are accompanied by hypertension; diabetes is associated with 18% of patients. The general information and clinical efficacy of 90 psoriasis patients are shown in table 1.
TABLE 190 general data of psoriasis patients
Example 2 correlation between psoriasis susceptibility genes and MTX clinical efficacy
The material and the method are as follows: extracting DNA of patients, carrying out genotyping on 18 non-HLA loci of 90 patients by using a sequenom platform, respectively defining the loci as an effective group and an ineffective group according to whether 12w reaches PASI75, and displaying that the LCE3D genotype has statistical significance between the effective group and the ineffective group by bioinformatics analysis;
(1) comparison of patient information between MTX treatment-effective and non-effective groups
Improvement in PASI75 achieved at 12 weeks of treatment with MTX was assigned to the effective group, the remainder to the ineffective group, the course of disease (19 ± 12) was significantly longer in the effective group than in the ineffective group (14 ± 11), and the difference was statistically significant p < 0.05; the probability of the LCE3DSNP locus rs4112788AG genotype was significantly higher in the active group (67%) than in the inactive group (31%), with the difference statistically significant p <0.05 (as shown in table 2);
(2) and (3) comparing the information of patients carrying different genotypes of the LCE3DSNP locus rs 4112788.
The experimental result shows that the clinical curative effect of the patient carrying the LCE3DSNP locus rs4112788AG genotype on MTX is 65%, the clinical curative effect is better than that of the patient carrying AA type 25% or GG type 31%, the difference is statistically significant, and p is less than 0.01 (shown in a table 3);
(3) comparison of information of different genotypes of patient at TNIP1SNP locus rs10036748
The experiment shows that the improvement rate of PASI75 of a patient carrying TNIP1SNP locus rs10036748TT genotype after receiving MTX treatment for 12 weeks is 64%, the incidence rate of liver function abnormality and liver fibrosis index abnormality is 43% and 45% respectively, the liver function abnormality and liver fibrosis index abnormality are obviously higher than those of AA genotype (22% and 24%) and GG genotype (17% and 0) patients, and the difference has statistical significance p <0.05 (shown in Table 4);
(5) comparison of patient information simultaneously carrying the genotype of LCE3DSNP locus rs4112788AG and the genotype of TNIP1SNP locus rs10036748
The experiment shows that the improvement rate (94% and 56%) of the patients carrying the LCE3DSNP locus rs41127 4112788AG genotype and the TNIP1SNP locus rs10036748TT genotype at the same time in the treatment of the PASI50 and the PASI75 at the 8 th week is obviously better than that of the patients carrying the LCE3DSNP locus rs41127 4112788AG genotype and the TNIP1SNP locus rs10036748TC genotype at the same time (60% and 20%, and p is less than 0.05), and the difference has statistical significance. The improvement rate (44%) of the patient carrying both the LCE3DSNP locus rs4112788AG genotype and the TNIP1SNP locus rs10036748TT genotype for treating the PASI90 at the 12 th week is obviously better than that of the patient carrying both the LCE3DSNP locus rs4112788AG genotype and the TNIP1SNP locus rs10036748TC genotype (20%), but the sample size is small, so that the statistical significance is not seen. The probability (44% and 44%) of liver enzyme abnormality and liver fibrosis abnormality in the 12 th week of treatment of patients carrying both the LCE3DSNP locus rs4112788AG genotype and the TNIP1SNP locus rs10036748TT genotype is obviously higher than that of patients carrying both the LCE3DSNP locus rs4112788AG genotype and the TNIP1SNP locus rs10036748TC genotype (15% and 20%) (as shown in Table 5).
TABLE 2 comparison of general data and genotypes between MTX treatment-effective and ineffective groups
Table 3 comparison of information from patients carrying LCE3DSNP site rs4112788 with different genotypes
Table 4 comparison of information of patients carrying TNIP1SNP locus rs10036748 with different genotypes
Table 5 comparison of information of patients carrying both LCE3DSNP locus rs4112788AG genotype and TNIP1SNP locus rs10036748 genotype
Claims (4)
- The application of LCE3D SNP locus rs4112788 and TNIP1SNP locus rs10036748 in preparing a detection kit predicts the intervention effect and toxic and side effects of methotrexate by detecting the SNP loci of susceptibility genes LCE3D and TNIP1 of psoriasis patients.
- 2. The use according to claim 1, wherein said use is for predicting the effectiveness of methotrexate intervention in patients with psoriasis who have the genotype at LCE3D SNP site rs4112788AG and TNIP1SNP site rs10036748TC, using methotrexate therapy, without increasing the risk of hepatotoxicity.
- 3. The use as claimed in claim 1, wherein said use is for the treatment of psoriasis patients with the genotype at the SNP site rs41127 4112788AG of LCE3D and the genotype at the SNP site rs10036748TT of TNIP1 with methotrexate with rapid onset of intervention, high recovery rate, increased hepatotoxicity, and prediction of the intervention effect and toxic side effects of methotrexate.
- 4. The use according to claim 1, wherein in said use, said test kit predicts and evaluates the clinical efficacy of methotrexate treatment for psoriasis for the effective rate of intervention with methotrexate treatment and the occurrence of risk of hepatotoxicity carrying the absence or presence of the genotype at LCE3D SNP site rs4112788AG and TNIP1SNP site rs10036748TC by testing the relationship between the genotype at LCE3D SNP site rs4112788 and the genotype at TNIP1SNP site rs10036748TC and the clinical efficacy of methotrexate treatment for psoriasis.
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