CN117363799A - Composition, product and system for predicting effect of interferon drug on treating chronic hepatitis B - Google Patents
Composition, product and system for predicting effect of interferon drug on treating chronic hepatitis B Download PDFInfo
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/70—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving virus or bacteriophage
- C12Q1/701—Specific hybridization probes
- C12Q1/706—Specific hybridization probes for hepatitis
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/156—Polymorphic or mutational markers
Abstract
The invention discloses a composition, a product and a system for predicting the effect of interferon drugs on treating chronic hepatitis B. The composition comprises a reagent for detecting nucleic acid SNP locus information in a biological sample, wherein the SNP locus is selected from at least one of rs7519753, rs12021785, rs12030094, rs12026098 and rs4653644. Aiming at the situation that genetic analysis markers capable of predicting the effect of interferon treatment on chronic hepatitis B are lacking at present, the SNP locus capable of predicting the effect of interferon treatment on chronic hepatitis B is obtained through a large number of samples and two-stage whole genome association analysis, and the SNP locus can be realized through methods of whole genome sequencing, SNP chips, PCR or mass spectrometry, and the like, so that the detection is convenient.
Description
Technical Field
The invention relates to the field of molecular biology, in particular to a composition, a product and a system for predicting the effect of interferon drugs on treating chronic hepatitis B.
Background
Despite the 40 years old of the advent of safe and effective HBV vaccines, chronic b-virus infection remains a public health problem that severely jeopardizes human health. Currently, the first-line drugs against HBV clinically are mainly Interferon (IFN) and nucleotide analogues (nucleic/nucleotide analogues, NAs). Functional cure, i.e., serum HBV DNA and HBsAg clearance, is considered an important therapeutic goal for chronic hepatitis b. A large number of researches show that serum HBsAg clearance is closely related to long-term good prognosis of low incidence of liver cancer of patients with chronic hepatitis B. However, according to existing chronic hepatitis b treatment regimens, only a few patients are able to achieve a functional cure.
Research shows that IFN mainly induces the expression of Interferon-stimulated genes (ISGs) through activating JAK-STAT channels, thereby exerting antiviral and immunoregulatory functions. IFN is mainly used in the form of polyethylene glycol modified long-acting interferon alpha (Peg-IFN alpha). The treatment of chronic hepatitis b by ifnα involves a variety of mechanisms, which have both direct antiviral effects, inhibit cccDNA transcription, promote cccDNA degradation, and kill cells with HBV DNA integration by activating the immune system. The clearance rate of serum HBsAg is about 3% -10% when chronic hepatitis B is treated by Peg-IFN alpha. The clearance of Peg-IFN alpha therapy of HBsAg is even higher than 20% for patients with chronic hepatitis B with pre-treatment serum HBsAg below 200 IU/ml.
Nevertheless, this clearance rate still fails to meet clinical demands, and thus finding a factor that affects the clearance rate of Peg-ifnα for chronic hepatitis b HBsAg has been the focus of research. Previous research and study have demonstrated that viral factors such as viral load, HBV genotype, HBV mutation, etc., and host factors such as age, sex, serum ALT level before treatment, etc., are all related to the clearance rate of Peg-IFN alpha for chronic hepatitis B HBsAg. Many clinical studies have also found that there are also great differences in HBsAg clearance from different regions and from species treated with Peg-ifnα, suggesting that host genetic factors also play an important role.
For Nas drugs, clinical studies have shown that clearance of serum HBsAg is very low, typically less than 1%, following treatment of chronic hepatitis B. There are two major sources of HBsAg, cccDNA and integrated HBV DBA, respectively. NAs inhibits HBV replication mainly by inhibiting HBV reverse transcription, and has limited inhibition effect on cccDNA, and is more incapable of integrating HBV DNA.
Disclosure of Invention
In order to solve at least part of the technical problems in the prior art, the invention provides a composition, a system and application for predicting the curative effect of a drug, and the invention has proved by whole genome association analysis that a host genetic factor SNP rs7519753 can be used for predicting the curative effect of interferon on chronic hepatitis B. Specifically, the present invention includes the following.
In a first aspect of the invention, there is provided a composition for predicting the effect of an interferon drug in treating chronic hepatitis b comprising reagents for detecting nucleic acid SNP site information in a biological sample, the SNP site being selected from at least one of rs7519753, rs12021785, rs12030094, rs12026098 and rs4653644.
In certain embodiments, the composition for predicting the effect of an interferon drug in treating chronic hepatitis b according to the present invention, wherein the interferon drug comprises polyethylene glycol interferon alpha or a combination of polyethylene glycol interferon alpha and other drugs, including nucleoside (nucleotide) analogs, immunomodulatory drugs, and/or direct antiviral drugs.
In certain embodiments, the composition for predicting the effect of interferon drugs in treating chronic hepatitis b according to the present invention, wherein the reagent comprises a primer, a probe or a gene sequencing reagent for detecting SNP site information.
In a second aspect of the invention there is provided a product for predicting the efficacy of a drug comprising a composition according to the invention.
In certain embodiments, the product according to the present invention, wherein the product comprises a detection chip, a detection kit or a detection device.
In a third aspect of the present invention, there is provided a system for predicting the effect of an interferon drug in treating chronic hepatitis b, comprising:
a data acquisition unit configured to be able to acquire information from a subject, the information including information of the following SNP sites: at least one of rs7519753, rs12021785, rs12030094, rs12026098 and rs 4653644; and
and a judging unit configured to judge information of the rs7519753 locus and judge that the interferon drug is effective or that the HBsAg negative conversion rate is high when the locus is CC and CT genotype.
In certain embodiments, the system for predicting the effect of interferon drugs in treating chronic hepatitis b according to the present invention, wherein further comprises a SNP site detection unit configured to be able to communicate with the data acquisition unit and acquire data generated by the SNP site detection unit; the SNP site detection unit includes one of the units for performing the following analysis: polymerase chain reaction PCR, capillary electrophoresis, mass spectrometry, single strand conformational polymorphism SSCP, electrochemical analysis, denaturing HPLC and gel electrophoresis, restriction fragment length polymorphism, single base extension SBE, allele specific primer extension ASPE, restriction enzyme digestion, strand displacement amplification SDA, transcription mediated amplification TMA, ligase chain reaction LCR, nucleic acid sequence based amplification NASBA, primer extension, rolling circle amplification RCA, autonomous sequence replication 3SR, loop mediated isothermal amplification LAMP, nucleic acid sequencing and microarray.
In certain embodiments, a system for predicting the effect of an interferon drug in treating chronic hepatitis b according to the present invention, wherein the SNP site detection unit comprises a unit capable of performing nucleic acid sequencing as follows: maxam-Gilbert sequencing, chain termination methods, shotgun sequencing, bridge PCR, single molecule real-time sequencing, ion semiconductor or ion flow sequencing, sequencing by synthesis, SOLiD sequencing, chain termination or Sanger sequencing, large-scale parallel sequencing MPSS, polymerase clone sequencing, 454 pyrosequencing, DNA nanosphere sequencing, single molecule real-time sequencing, nanopore DNA sequencing, tunneling current DNA sequencing, sequencing by hybridization, mass spectrometry, microfluidic Sanger sequencing, microscope-based sequencing, RNAP sequencing, and in vitro virus high throughput sequencing.
In certain embodiments, the system for predicting the effect of an interferon drug in treating chronic hepatitis b according to the present invention, wherein the information from the subject further comprises subject age, sex, baseline serum ALT, AST, HBsAg, and HBeAg level information.
In certain embodiments, the system for predicting the effect of interferon drugs on chronic hepatitis b according to the present invention, wherein the determination unit is configured to be able to calculate the evaluation value based on information from the subject.
The invention provides a molecular marker for predicting the curative effect of interferon on hepatitis B patients, which comprises rs7519753 or other SNP sites in high linkage disequilibrium with the rs7519753 genetically. By genotyping SNP of a patient with chronic hepatitis B, the treatment effect of interferon on chronic hepatitis B can be predicted, for example, when a patient with chronic hepatitis B with rs7519753 of CC or CT genotype receives interferon treatment, the clearance rate of serum HBsAg is obviously higher than that of a patient with TT genotype.
Drawings
FIG. 1 is a schematic diagram of time-resolved mass-flight spectrometry detection of rs7519753 genotype.
Figure 2 shows quality control of whole genome association analysis.
Fig. 3 shows the results of the whole genome correlation analysis.
Detailed Description
Various exemplary embodiments of the invention will now be described in detail, which should not be considered as limiting the invention, but rather as more detailed descriptions of certain aspects, features and embodiments of the invention.
It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. In addition, for numerical ranges in the present invention, it is understood that the upper and lower limits of the ranges and each intermediate value therebetween are specifically disclosed. Every smaller range between any stated value or stated range, and any other stated value or intermediate value within the stated range, is also encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference for the purpose of disclosing and describing the methods and/or materials associated with the documents. In case of conflict with any incorporated document, the present specification will control.
In the present invention, the terms "reagent" and "detector" are used interchangeably to include any reagent that is capable of displaying the amount of a genetic locus or its mRNA.
Composition for predicting effect of interferon drug on treating chronic hepatitis B
In a first aspect the present invention provides a composition for predicting the effect of an interferon drug in treating chronic hepatitis b, preferably in asian ethnicity, and therefore the present invention provides a composition for predicting the effect of an interferon drug in treating chronic hepatitis b in asian ethnicity or in humans, comprising reagents for detecting nucleic acid SNP locus information in a biological sample, said SNP locus comprising, but not limited to, at least one of rs7519753, rs12021785, rs12030094, rs12026098 and rs4653644. In a preferred embodiment, the SNP site is rs7519753.
In the present invention, the drugs include interferon and nucleoside (nucleotide) analogues, and possibly immunomodulatory and/or direct antiviral drugs. The interferon class of drugs includes the common interferons IFN and polyethylene glycol interferon (also known as long-acting interferon). Immunomodulatory drugs include any immunopotentiator that can be used for immunopotentiation, treatment of immunodeficiency diseases, chronic infections, and as an adjunct treatment for tumors. Direct antiviral drugs (sometimes also referred to as "DAAs") include any drug capable of inhibiting viral replication that is capable of acting directly on viral replication of hepatitis c virus protease, RNA polymerase, and the like, examples of which include, but are not limited to, ribavirin, sofosbuvir (sofosbuvir), semepivir (simeprevir), ledipasvir (ledipasvir), obitavir (ombitasvir), paritevir (paritaprevir), ritonavir (ritonavir), dasibuprevir (dasabatvir), dacarbavir (daclatasvir), atavir (asunaprevir), or combinations thereof.
In certain embodiments, the agent used in the present invention is a polyethylene glycol interferon. Examples of nucleoside (acid) analogs include, but are not limited to, lamivudine (LMV), adefovir Dipivoxil (ADV), entecavir (ETV), telbivudine (LdT), and tenofovir. In certain embodiments, the agent used in the present invention is Adefovir Dipivoxil (ADV). The composition, the system and the prediction method of the invention are not only suitable for single use of the medicaments, but also suitable for combined or combined treatment of the two, such as polyethylene glycol interferon and adefovir dipivoxil for seroconversion of hepatitis B virus antigen or seroconversion of hepatitis B virus surface antigen into negative.
In certain embodiments, the therapeutic effect comprises at least one of the following:
(a') HBsAg turns negative;
(b') reducing, inhibiting, reducing or lowering HBV replication;
(c') enhancing or increasing the interferon response effect, preferably, the interferon response effect comprises an anti-HBV effect;
(d') reducing viral load and/or activity, or sustained virologic response;
(e') reducing the amount and/or activity of HBsAg and/or HBeAg.
In the present invention, "amount and/or activity of HBsAg and/or HBeAg" includes the meaning of at least any one of the amount of HBsAg, the activity of HBsAg, the amount of HBeAg, the activity of HBeAg, which can be measured by methods known in the art. The assay methods include, but are not limited to, chemiluminescent immunoassay, enzyme linked immunosorbent assay, real-time fluorescent quantitative PCR, gene chip technology or immunoblotting, etc.
In the present invention, the type of sample is not limited, and examples thereof include, but are not limited to, a tissue sample or a fluid sample. Tissue samples include somatic cell samples, which include blood or components thereof such as plasma, serum, and the like. The biological sample may be any sample of mammalian origin, preferably a sample of human origin. Examples of the types of biological samples that can be used in the present invention include, but are not limited to, one or more of the following: urine, stool, tears, whole blood, serum, plasma, blood components, bone marrow, cells, tissues, organs, body fluids, saliva, cheek swab, lymph, cerebral spinal fluid, lesion exudates and other fluids produced by the body. The biological sample may also be a frozen, fixed, paraffin embedded or fresh biopsy sample.
In the present invention, the SNP detection method is not particularly limited, and may be measured by at least one of the following methods or a combination of them: polymerase chain reaction PCR, capillary electrophoresis, mass spectrometry, single strand conformational polymorphism SSCP, electrochemical analysis, denaturing HPLC and gel electrophoresis, restriction fragment length polymorphism, single base extension SBE, allele specific primer extension ASPE, restriction enzyme digestion, strand displacement amplification SDA, transcription mediated amplification TMA, ligase chain reaction LCR, nucleic acid sequence based amplification NASBA, primer extension, rolling circle amplification RCA, autonomous sequence replication 3SR, loop mediated isothermal amplification LAMP, nucleic acid sequencing and microarray.
In certain embodiments, the nucleic acid sequencing is selected from the group consisting of: maxam-Gilbert sequencing, chain termination methods, shotgun sequencing, bridge PCR, single molecule real-time sequencing, ion semiconductor or ion flow sequencing, sequencing by synthesis, SOLiD sequencing, chain termination or Sanger sequencing, large-scale parallel sequencing MPSS, polymerase clone sequencing, 454 pyrosequencing, DNA nanosphere sequencing, single molecule real-time sequencing, nanopore DNA sequencing, tunneling current DNA sequencing, sequencing by hybridization, mass spectrometry, microfluidic Sanger sequencing, microscope-based sequencing, RNAP sequencing, and in vitro virus high throughput sequencing.
It will be appreciated that the compositions of the present invention may comprise any suitable reagents that can be used in the detection process described above, including but not limited to, for example, primers, probes or gene sequencing reagents. Although specific nucleotide sequences are not shown in the present invention, primers, probes, etc. for detection can be designed and synthesized by those skilled in the art based on the SNP sites disclosed in the present invention.
The reagent of the present invention may include other components in addition to the above-described reagent. Examples of other ingredients include, but are not limited to, diluents, color developing solutions, stop solutions, wash solutions, and the like. In certain embodiments, any of the above materials may be present separately from the other materials in separate containers (e.g., vials) so long as they are capable of contacting each other at the time of use. In addition, it is preferable that any two or more of the above substances may be mixed to exist as a mixture.
In certain embodiments, the other ingredients may be provided in solution, e.g., in the form of an aqueous solution. Where present in aqueous solution, the concentration or amount of these substances can be readily determined by one skilled in the art according to different needs. For example, for storage purposes, the concentration of the substance may be present in a higher form, and when in operation or in use, the concentration may be reduced to an operating concentration by, for example, diluting a solution of the higher concentration.
The agents of the invention may be further formulated as diagnostic agents for predicting or evaluating the efficacy of interferon antiviral therapies. The diagnostic agent may be in the form of a diagnostic composition, a diagnostic kit, or any other form in which a plurality of agents are used alone in combination.
System for predicting effect of interferon drug on treating chronic hepatitis B
The present invention provides a system for predicting the effect of interferon drugs on chronic hepatitis b, comprising:
a data acquisition unit configured to be able to acquire information from a subject, the information including information of the following SNP sites: at least one of rs7519753, rs12021785, rs12030094, rs12026098 and rs4653644, preferably rs7519753;
and a judging unit configured to judge information of the rs7519753 locus, and judge that the interferon drug is effective or the HBsAg negative conversion rate is high when the locus is CC and CT genotype, and conversely, judge that the interferon drug is not effective or the HBsAg negative conversion rate is low when the information of the rs7519753 locus is not CC and CT genotype.
In a preferred embodiment, the system of the present invention further comprises a SNP site detection unit provided so as to be able to communicate with the data acquisition unit and acquire data generated by the SNP site detection unit; the SNP site detection unit includes one of the units for performing the following detection: polymerase chain reaction PCR, capillary electrophoresis, mass spectrometry, single strand conformational polymorphism SSCP, electrochemical analysis, denaturing HPLC and gel electrophoresis, restriction fragment length polymorphism, single base extension SBE, allele specific primer extension ASPE, restriction enzyme digestion, strand displacement amplification SDA, transcription mediated amplification TMA, ligase chain reaction LCR, nucleic acid sequence based amplification NASBA, primer extension, rolling circle amplification RCA, autonomous sequence replication 3SR, loop mediated isothermal amplification LAMP, nucleic acid sequencing and microarray.
In a preferred embodiment, the SNP site detection units in the system of the invention comprise units capable of performing the following nucleic acid sequencing: maxam-Gilbert sequencing, chain termination methods, shotgun sequencing, bridge PCR, single molecule real-time sequencing, ion semiconductor or ion flow sequencing, sequencing by synthesis, SOLiD sequencing, chain termination or Sanger sequencing, large-scale parallel sequencing MPSS, polymerase clone sequencing, 454 pyrosequencing, DNA nanosphere sequencing, single molecule real-time sequencing, nanopore DNA sequencing, tunneling current DNA sequencing, sequencing by hybridization, mass spectrometry, microfluidic Sanger sequencing, microscope-based sequencing, RNAP sequencing, and in vitro virus high throughput sequencing.
It will be appreciated that the information from the subject may optionally include other clinical information, examples of which include, but are not limited to, subject age, sex, baseline serum ALT, AST, HBsAg, HBeAg level information, and the like.
The system of the present invention further comprises an output unit for outputting a prediction result of whether the interferon drug is effective for chronic hepatitis b, or whether the HBsAg conversion rate is high or low.
In an exemplary embodiment, the system of the present invention is embodied as an electronic device. The electronic device may be in the form of a general purpose computing device. Components of an electronic device may include, but are not limited to: at least one processor, at least one memory, a bus connecting different system components, including the memory and the processor.
The memory of the present invention may include a program/utility having a set (at least one) of program modules including, but not limited to: an operating system, one or more application programs, other program modules, and program data, each or some combination of which may include an implementation of a network environment.
The bus may be one or more of several types of bus structures including a memory bus or memory controller, a peripheral bus, an accelerated graphics port, a processing unit, or a local bus using any of a variety of bus architectures.
The electronic device may also communicate with one or more external devices (e.g., keyboard, pointing device, bluetooth device, etc.), with one or more devices that enable a user to interact with the electronic device, and/or with any device (e.g., router, modem, etc.) that enables the electronic device to communicate with one or more other computing devices.
Such communication may be through an input/output (I/O) interface. And, the electronic device may also communicate with one or more networks such as a Local Area Network (LAN), a Wide Area Network (WAN), and/or a public network, such as the Internet, through a network adapter. The network adapter communicates with other modules of the electronic device via a bus. It should be appreciated that although not shown herein, other hardware and/or software modules may be used in connection with an electronic device, including but not limited to: microcode, device drivers, redundant processing units, external disk drive arrays, RAID systems, tape drives, data backup storage systems, and the like.
Examples
1. Sample and treatment regimen
In order to find SNP loci capable of predicting the efficacy of interferon treatment on chronic hepatitis B, the invention adopts a two-stage whole genome association analysis study (GWAS). The invention belongs to case control researches, and comprises 138 patients with HBsAg turned to negative by polyethylene glycol interferon alpha (Peg-IFN alpha) treatment, and 181 patients with chronic hepatitis B with HBsAg continuously existing by the same treatment scheme. In the first stage of GWAS, 95 patients with chronic hepatitis B (48 patients with HBsAg turning negative and 47 HBsAg lasting positive) are included, the sample is from Beijing Yiyou An Hospital affiliated to the university of first medical science, and all patients receive Peg-IFN alpha single drug therapy or Peg-IFN alpha and ADV combined therapy. The complete genome of 95 patients was sequenced and SNPs associated with HBsAg negative transfer were found by whole genome association analysis.
In the verification stage, 224 chronic hepatitis B patients (90 of which realize HBsAg turning negative and 134 HBsAg continuously positive) who are treated by Peg-IFN alpha are included in the third hospital affiliated to Zhongshan university and the Beijing you an hospital affiliated to the capital medical university. The rs7519753 genotype of the samples was determined using time-resolved mass spectrometry (MALDI-TOF), and the genotyping results are schematically shown in FIG. 1 below.
2. Results
(1) Queue characterization and genome-wide association analysis
Previous studies have shown that factors including age, sex, and baseline serum ALT, AST, HBsAg and HBeAg levels of CHB patients may affect Peg-ifnα therapeutic efficacy. To minimize the bias that these factors may cause, the present invention recruits 48 chronically hepatitis B patients who achieved HBsAg clearance following Peg-IFN alpha treatment. 47 patients who were continuously positive for HBsAg after Peg-IFN alpha treatment were selected by matching age, sex and baseline serum ALT, AST, HBsAg and HBeAg levels. Analysis showed that no significant differences (P > 0.05) were observed between the two groups in gender, age, and distribution of baseline ALT, AST, HBsAg or HBeAg levels, which could avoid false positive results caused by the above factors.
Principal Component Analysis (PCA) showed that the genetic profile of the enrolled individuals and the genetic profile both met asian ethnicity (fig. 2). No significant population separation exists for the two sets of samples, meeting the requirements of whole genome association analysis (fig. 2).
(2) Whole genome association analysis showed that SNP rs7519753 is a significant site of whole genome associated with HBsAg clearance
Whole genome association analysis showed that rs7519753 located on chromosome 1q41 was significantly correlated with HBsAg negative following Peg-ifnα treatment (p=4.85×10 -8 Fig. 3). In the HBsAg to negative group, rs75197The frequency of 53CC and CT genotypes was higher than that of the HBsAg sustained positive group (58.33% vs.6.38%), which means that patients carrying the C allele more easily achieved HBsAg negative after Peg-IFN alpha treatment. The invention also calculates the sensitivity and specificity of the rs7519753C allele as the HBsAg disappearance prediction index in the CHB patients receiving Peg-IFN alpha treatment in the queue, and the sensitivity and the specificity are respectively 0.903 and 0.678 through calculation.
(3) Verification queue confirmed that rs7519753C allele favors negative transfer of HBsAg
To verify the association between rs7519753 and HBsAg to negative, the present invention incorporates two additional cohorts, for a total of 224 patients with chronic hepatitis b receiving Peg-ifnα treatment. The first cohort was from a third hospital affiliated with the university of Zhongshan, and included 40 HBsAg negative-turning samples and 79 HBsAg persistent positive samples (validation cohort 1). The second queue was from the capital university of medical community affiliated Beijing you an hospital, and included 50 samples with HBsAg turned negative and 55 samples with HBsAg consistently positive (validation queue 2). Notably, the samples of verification queue 1 were from south china and the samples of GWAS stage were from north china to verify whether rs7519753 had the same predictive value for patients with chronic hepatitis b in different territories.
The results showed that in both validation queues, the ratio of rs7519753CC and CT genotypes in the HBsAg-to-negative group was significantly higher than in the HBsAg sustained positive group. For validation queue 1, the P value is 0.036 and OR is 1.646. Similarly, for validation queue 2, the P value is 0.027 and OR is 1.861. The meta-analysis is further performed by combining the GWAS phase samples with the validation queue samples. The meta-analysis gave an OR of 2.31 and a P value of 6.71X 10 -8 The OR value refers to the multiple of the occurrence of the C allele to the T genotype negative transfer.
Although illustrated in the examples as rs7519753, one of skill in the art, in addition to by directly determining the genotype of rs7519753, can determine SNPs that are highly linked to rs7519753 for predicting the therapeutic effect of interferon treatment of chronic hepatitis b, including but not limited to rs12021785, rs12030094, rs12026098, and rs4653644, in accordance with the teachings of the present invention. All SNP loci are in linkage disequilibrium with rs7519753 (table 1), and the existing genetic knowledge can speculate that the SNP loci have equal or similar predictive value with rs7519753.
Table 1: linkage disequilibrium between rs7519753 and SNP
| SNP RS_number | R 2 | D’ |
| rs12021785 | 0.984 | 0.968 |
| rs12026098 | 0.984 | 0.958 |
| rs4653644 | 0.984 | 0.958 |
| rs12030094 | 0.978 | 0.937 |
The invention fills the blank that genetic analysis markers capable of predicting the effect of interferon treatment on chronic hepatitis B are not available in clinic at present, and SNP loci capable of predicting the effect of interferon treatment on chronic hepatitis B are obtained through a large number of samples and two-stage whole genome association analysis. When the SNP locus is detected, the detection is realized by methods such as whole genome sequencing, SNP chips, PCR or mass spectrometry, and the like, and the detection is more convenient.
While the invention has been described with reference to exemplary embodiments, it is to be understood that the invention is not limited to the disclosed exemplary embodiments. Various modifications or changes may be made to the exemplary embodiments of the present disclosure without departing from the scope or spirit of the invention. The scope of the claims is to be accorded the broadest interpretation so as to encompass all modifications and equivalent structures and functions.
Claims (10)
1. A composition for predicting the effect of interferon drugs on chronic hepatitis b, comprising a reagent for detecting nucleic acid SNP site information in a biological sample, wherein the SNP site is selected from at least one of rs7519753, rs12021785, rs12030094, rs12026098 and rs4653644.
2. The composition for predicting the effect of an interferon drug to treat chronic hepatitis b according to claim 1, wherein the interferon drug comprises polyethylene glycol interferon alpha or a combination of polyethylene glycol interferon alpha and other drugs including nucleoside (acid) analogues, immunomodulatory drugs and/or direct antiviral drugs.
3. The composition for predicting the effect of interferon drugs on chronic hepatitis b according to claim 2, wherein the reagent comprises a primer, a probe or a gene sequencing reagent for detecting SNP site information.
4. A product for predicting the efficacy of a drug, comprising a composition according to any one of claims 1-3.
5. The product of claim 4, wherein the product comprises a detection chip, a detection kit, or a detection device.
6. A system for predicting the effect of an interferon drug in treating chronic hepatitis b, comprising:
a data acquisition unit configured to be able to acquire information from a subject, the information including information of the following SNP sites: at least one of rs7519753, rs12021785, rs12030094, rs12026098 and rs 4653644; and
and a judging unit configured to judge information of the rs7519753 locus and judge that the interferon drug is effective or that the HBsAg negative conversion rate is high when the locus is CC and CT genotype.
7. The system for predicting the effect of interferon drug on chronic hepatitis b according to claim 6, further comprising a SNP site detection unit provided so as to be capable of communicating with a data acquisition unit and acquiring data generated by the SNP site detection unit; the SNP site detection unit includes one of the units for performing the following analysis: polymerase chain reaction PCR, capillary electrophoresis, mass spectrometry, single strand conformational polymorphism SSCP, electrochemical analysis, denaturing HPLC and gel electrophoresis, restriction fragment length polymorphism, single base extension SBE, allele specific primer extension ASPE, restriction enzyme digestion, strand displacement amplification SDA, transcription mediated amplification TMA, ligase chain reaction LCR, nucleic acid sequence based amplification NASBA, primer extension, rolling circle amplification RCA, autonomous sequence replication 3SR, loop mediated isothermal amplification LAMP, nucleic acid sequencing and microarray.
8. The system for predicting the effect of an interferon drug to treat chronic hepatitis b of claim 7, wherein said SNP site detection unit comprises a unit capable of performing nucleic acid sequencing of: maxam-Gilbert sequencing, chain termination methods, shotgun sequencing, bridge PCR, single molecule real-time sequencing, ion semiconductor or ion flow sequencing, sequencing by synthesis, SOLiD sequencing, chain termination or Sanger sequencing, large-scale parallel sequencing MPSS, polymerase clone sequencing, 454 pyrosequencing, DNA nanosphere sequencing, single molecule real-time sequencing, nanopore DNA sequencing, tunneling current DNA sequencing, sequencing by hybridization, mass spectrometry, microfluidic Sanger sequencing, microscope-based sequencing, RNAP sequencing, and in vitro virus high throughput sequencing.
9. The system for predicting the effect of an interferon drug to treat chronic hepatitis b of claim 7, wherein the information from the subject further comprises subject age, sex, baseline serum ALT, AST, HBsAg and HBeAg level information.
10. The system for predicting the effect of interferon drug on chronic hepatitis b according to claim 9, wherein the judging unit is configured to be able to calculate the evaluation value based on the information from the subject.
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