WO2013078690A1 - Prédisposition à la spondylarthrite ankylosante et procédé de détection d'un polymorphisme mononucléotidique, trousse et utilisation associées - Google Patents

Prédisposition à la spondylarthrite ankylosante et procédé de détection d'un polymorphisme mononucléotidique, trousse et utilisation associées Download PDF

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WO2013078690A1
WO2013078690A1 PCT/CN2011/083410 CN2011083410W WO2013078690A1 WO 2013078690 A1 WO2013078690 A1 WO 2013078690A1 CN 2011083410 W CN2011083410 W CN 2011083410W WO 2013078690 A1 WO2013078690 A1 WO 2013078690A1
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ankylosing spondylitis
base
susceptibility
rsl3198903
dna
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PCT/CN2011/083410
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English (en)
Chinese (zh)
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古洁若
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Gu Jieruo
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Priority to CN201180067466.8A priority Critical patent/CN103502469B/zh
Priority to PCT/CN2011/083410 priority patent/WO2013078690A1/fr
Publication of WO2013078690A1 publication Critical patent/WO2013078690A1/fr

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    • 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
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • 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

Definitions

  • the invention relates to a detection method, a kit and an application thereof for a susceptibility single nucleotide polymorphism (SNP) of ankylosing spondylitis, and belongs to the technical field of medical detection.
  • SNP susceptibility single nucleotide polymorphism
  • Ankylosing spondylitis is a subtype of spondyloarthropathies (SPA). Its main clinical manifestations are central axis manifestations such as inflammatory low back pain, morning stiffness, and restricted spinal activity, or / and concurrent peripheral arthritis, tendon end, ligament attachment point inflammation, to the advanced stage of the disease, there will be spinal rigidity or deformity.
  • Previous studies have suggested that the role of genetic factors plays a more important role in the pathogenesis of AS, and previous twin-based studies have shown that high consistent incidence in monozygotic and fraternal twins suggests genetic factors. The role in the pathogenesis of AS exceeds 90%.
  • HLA-B27 is an important gene that is also thought to be related to the genetic aggregation of AS family.
  • MHC also known as the major histocompatibility complex
  • HLA-B27 is a tightly linked group of genes encoding major histocompatibility antigens on a chromosome of the vertebrate, associated with immune responses, immune regulation, and transplant rejection. Studies have shown that in monozygotic twins, the consistent probability of HLA-B27 is 63%, and the consistent probability of HLA-B27 in twins twins is 23%.
  • HLA-B27-positive first-degree relatives in AS patients are 6-16 times more likely to have a family history of HLA-B27-positive individuals, suggesting that non-HLA-B27 familial factors are present in the disease. Development also plays an important role. This opens up a whole new way of thinking about the mechanism of the occurrence and development of ankylosing spondylitis. Through the whole-genome SNP chip scanning and analysis, we can find the susceptible SNP associated with ankylosing spondylitis and explore the ankylosing spondylitis. Pathogenic or susceptible genes.
  • Single nucleotide polymorphism mainly refers to DNA sequence polymorphism caused by single nucleotide variation at the genomic level, which is the most common type of human heritable variation. , accounting for more than 90% of all known polymorphisms. SNPs are widespread in the human genome, with an average of one in every 500 to 1000 base pairs, with an estimated total of 3 million or more. The polymorphisms exhibited by SNPs involve only a single base variation, which can be caused by a single base transition or transversion, or by the insertion or deletion of a base. In genomic DNA, any base may be mutated, so SNPs may be both within the gene sequence and possibly non-coding sequences outside the gene.
  • cSNP SNP located in the coding region
  • the mutation rate is only 1/5 of the surrounding sequence, but it is of great significance in the study of hereditary diseases. Therefore, the research of cSNP is more concerned.
  • cSNP can be further divided into two types: one is synonymous cSNP (synonymous cSNP), that is, the change of the coding sequence caused by SNP does not affect the amino acid sequence of the translated protein.
  • the mutated base has the same meaning as the unmutated base; the other is a non-synonymous cSNP, which means that the change in the base sequence can change the protein sequence translated by the blueprint, thereby affecting the protein.
  • the function, this change is often the direct cause of changes in biological traits, about half of cSNPs are non-synonymous cSNPs; in addition, SNPs can also be used as genetic markers to help find and identify disease susceptibility genes.
  • Brown et al. performed a full scan and verification of a large sample of AS patients and healthy volunteers based on a self-made intensive SNP chip. It also pointed out that the two genes IL23R and ARTS1 may be new to AS. Sense gene, followed by the research of ARTS1 gene in Korean and Chinese research institutions, the results suggest that ARTS1 is associated with AS; Chinese research institutions have also verified IL-23R, the results No correlation was found between the two, suggesting that there may be differences between different populations. Moreover, although the above-mentioned Brown's research in 2007 used a dense SNP chip, the chip did not perform a full scan of the dense SNP for this genome, but only customized the intensive SNP chip for the location of interest, thus causing the chip.
  • the Illumina HumHap 370 chip has a new generation of Illumina Human lM-duo chips, Illumina Human 610-Quad chip and Illumina OmniExpress chip to provide more dense SNP mark, covering a wider range of areas.
  • Illumina Human lM-duo chips Considering the research background mentioned above, we designed a full-sweep and correlation analysis in the Chinese Han AS patients and healthy volunteers with Illumina Human lM-duo chip, Illumina Human 610-Quad chip and Illumina OmniExpress chip. Genome-wide association analysis (GWAS) to explore whether AS-related susceptibility genes can be found.
  • GWAS Genome-wide association analysis
  • ankylosing spondylitis is a relatively common disease, the course of the disease is lingering, and it is easy to cause disability, it should be an early diagnosis and treatment, especially for young people aged 16-25.
  • SNPs that are closely related to ankylosing spondylitis, and to design methods and kits for detecting the specificity of ankylosing spondylitis.
  • the present invention provides an early and specific method for detecting susceptibility to ankylosing spondylitis in view of the deficiencies of the current detection methods and related kits in the early diagnosis of ankylosing spondylitis. And its kit.
  • SNP rsl3198903 SNP rsl3198903 and tonicity through a dense genome-wide SNP chip for genome-wide association analysis of large samples of ankylosing spondylitis patients and healthy control populations.
  • SNP is an important auxiliary indicator for early diagnosis of ankylosing spondylitis.
  • Rs is the abbreviation of reference SNP ID. After ncbi has classified all submitted SNPs, it will give an rs number, also called reference SNP, and Give specific information about the SNP, including the sequence before and after, location information, distribution frequency, and so on.
  • One of the objects of the present application is to provide a nucleotide fragment of a single nucleotide polymorphism (SNP) for detecting the susceptibility to ankylosing spondylitis, which is at the SNP rsl3198903 site, AS patient base
  • SNP single nucleotide polymorphism
  • One of the objects of the present application is to provide a method for detecting susceptibility to ankylosing spondylitis by the following scheme: obtaining a nucleotide sequence from a sample to be tested, and detecting a base at a position of rsl3198903 When the base is T, the susceptibility to ankylosing spondylitis is significantly increased.
  • sample to be tested includes blood, body fluid or tissue.
  • the method includes the following steps:
  • the method of obtaining the nucleotide sequence from the sample to be tested further comprises real-time PCR, denaturing high-performance liquid chromatography, restriction fragment length polymorphism or ligase detection or gene sequencing.
  • One of the objects of the present application is to provide a method for detecting a susceptibility to a single nucleotide polymorphism of ankylosing spondylitis, the method comprising the steps of:
  • PCR amplification primers for rsl3198903 site were designed using Primer3.0 software;
  • DNA from tissues, cells or blood samples was extracted using the TIANamp Blood DNA kit or NucleoSpin Tissue (MN), quantified by spectrophotometry, agarose gel electrophoresis, and the quality of the qualified DNA was adjusted to 5 ( ig / L, -20 ° C storage standby;
  • reaction conditions are 94 °C for 4 minutes; 94 °C20 seconds, 60 °C for 30 seconds, 72 °C for 1 minute, 30 cycles; 72°C for 3 minutes; 4°C
  • the PCR reaction product was treated with 0.5 U SAP (shrimp alkaline phosphatase) to remove free dNTPs from the system.
  • the reaction system was 7 ⁇ , of which the PCR product was 5 ⁇ , the SAP mixture was 2 ⁇ (SAP 0.5 U, buffer 0.17 ⁇ ), and the reaction procedure was 37. °C 20 minutes; 85 °C 5 minutes; 40 °C ⁇ ; 5.
  • the purified product was detected by conventional DNA sequencing methods for base mutations.
  • One of the objects of the present application is to provide the above-mentioned ankylosing spondylitis susceptibility single nucleotide polymorphism in the preparation of a kit for detecting susceptibility to ankylosing spondylitis, the single nucleotide polymorphism It means that at the rsl3198903 site, the nucleotide changes from C to T.
  • the application includes a kit for detecting a susceptibility to a single nucleotide polymorphism of ankylosing spondylitis, the kit comprising: a PCR reaction primer designed for a region near the base of rsl3198903, a DNA polymerase, Ionic water, dNTP, MgCl 2 , PCR buffer, SAP and resin.
  • the PCR reaction primer comprises a sense strand primer and an antisense strand primer, wherein the sense strand primer is tggcgaagttaatccagctt, and the antisense strand primer is ttccacctcacctttcagga 0.
  • the application comprises obtaining a nucleotide sequence from a sample to be tested, and detecting a base located at a position of rsl3198903, and when the base is T, the susceptibility of ankylosing spondylitis is significantly increased.
  • One of the objects of the present application is to provide the use of the above-described ankylosing spondylitis susceptibility single nucleotide polymorphism in the treatment of mandatory spondylitis.
  • the application includes a risk type when the base at the rsl3198903 site is T, and a protective type in the treatment of ankylosing spondylitis.
  • ankylosing spondylitis-specific single nucleotide polymorphism-associated susceptibility or pathogenicity Because the base at the rsl3198903 site is T.
  • the use comprises an ankylosing spondylitis susceptibility single nucleotide polymorphism (SNP) for the preparation of a medicament for treating ankylosing spondylitis.
  • SNP single nucleotide polymorphism
  • the application includes the intervention of rsl3198903 related to ankylosing spondylitis susceptibility or the function of a causative gene, including translation, transcription and protein synthesis processes, preparation of therapeutic drugs, improvement of abnormal bone metabolism in patients The immune inflammatory response to achieve therapeutic goals.
  • the control population of 4231 healthy volunteers mainly included healthy volunteers without AS symptoms or medical history in three places in China, Guangdong, Anhui and Singapore. These healthy volunteers also agreed to draw blood for the study after being informed. And signed an informed consent form.
  • the basic conditions of the case and healthy volunteers were recorded, including: gender, age and place of origin. 4 ml of whole blood was taken, placed in an EDTA tube, and brought back to the laboratory for DNA extraction.
  • rheumatologists also carefully inquired and recorded the situation of each AS patient and healthy volunteers, especially the AS patients also recorded basic conditions (including: gender, age, age of onset, duration) And clinical phenotype (including: waxy fingers, hip involvement, peripheral arthritis, inflammatory low back pain).
  • the composition of the kit is: Cell Lysis Night, Buffer GS, Buffer GB, Buffer Liquid GD, rinse PW, elution buffer TB, proteinase K, adsorption column CB3, collection tube (2 ml), 1.5 mL sterile collection tube.
  • the study used the Illumina HuamHap 610-Quad SNP chip, the Illumina Human lM-duo chip and the Illumina OmniExpress chip to perform a full-genome SNP scan of the sample.
  • the following are three types of Illumina chips;
  • the chip cartridge can detect four samples in parallel on one chip, which significantly increases the amount of sample output information and reduces errors in experimental operations.
  • the chip is widely used in the content of the HumanHap550 chip, with an additional 100,000 genetic markers.
  • the genome-wide information covered by Human 610-quad is authoritative for both known and recently reported CNV regions.
  • the SNPs of the Illumina HuamHap 610-Quad SNP chip are evenly distributed on the genome at a density of about 5 kb.
  • the Illumina HuamHap 610-Quad SNP chip was designed for specific studies targeting highly polymorphic CNV regions in the genome (fragment replication regions and genomic regions without SNPs).
  • the chip contains more than one million probe information.
  • the chip contains probes for gene SNPs, tagged SNPs, copy number changes (CNV), and other high-value genomic regions, as well as new sites such as: increased disease-associated SNP sites Flexible selection of high-density SNP sites in some genomic coding regions.
  • the chip provides high sample throughput and comprehensive genomic content.
  • the Omni Express accommodates up to 12 samples, and the chip interrogates more than 700,000 variations per sample, with a total of more than 8 million data points on a single chip.
  • the marker on OmniExpress is part of Illumina's HumanOmnil-Quad content, which combines optimized SNP tag combinations from all three phases of the international HapMap program, with the highest data quality and best content, including copy number variation (CNV) ) Comprehensive support for the application.
  • CNV copy number variation
  • the heterozygosity range is statistically analyzed from the mean of the heterozygosity mean (Mean) -3 ⁇ standard deviation (SD) to the mean heterozygosity (Mean) +3 ⁇ standard deviation (SD). Samples not in this interval Will be removed. Not included in further statistics.
  • Factors include gender, age (if there is a statistical difference between the sporadic cases and the healthy volunteers) and the main components of the clustering phenomenon after the above PCA analysis, the results will get the value, when analyzing the data results, we use the software Distribute each The chi-square test is performed on the frequency of alleles in the case and the gene frequency of the healthy volunteer control population, and the chi-square value A is obtained. If the QC is closer to 1, it means that the sample is more effective. If there is an offset, there are two possible situations: one is that the sample is stratified, that is, the population is more discrete; the second is the existence and disease risk. Related SNPs.
  • the estimated SNP for analysis in the three chips is done by the IMPUTE2 software (version number: 2.1.0), which maximizes the chip's coverage of the chromosome.
  • the 3702 healthy volunteers were mainly from the healthy volunteers collected by the Third affiliated Hospital of Sun Yat-sen University and the Cancer Center of Sun Yat-sen University. The population were healthy volunteers without AS symptoms or medical history. These healthy volunteers Also, after being informed, agreed to draw blood for the study and signed an informed consent form.
  • 2.2 Experimental methods and results 2.2.1 DNA extraction
  • the composition of the kit is: Cell lysis night , Buffer GS, Buffer GB, Buffer GD, Rinse PW, Elution Buffer TB, Protease K, Adsorption Column CB3, Collection Tube (2 ml), 1.5 mL sterile collection tube.
  • 2.2.2 Study steps 2.2.2.1 Primer design Primer 3.0 software was used to design the I material.
  • the primer information of SNP rs 13198903 is as follows:
  • the template DNAlul was added to each well in a 384-well plate, and 4 ul of the above reaction system was added.
  • the 384-well plate was centrifuged at 1000 rpm for 1 minute, and after mixing, amplification was carried out according to the following procedure: 94. C 4 minutes pre-denaturation, 94. C 20 seconds, 60 ° C 30 seconds, 72 ° C 1 minute for 30 cycles, 72 ° C 3 minutes, 4 ° C cooling.
  • 2.2.2.3 Sequencing analysis of PCR products The purified products were detected by conventional DNA sequencing methods for base mutations. We sequenced on the ABI PRISM ⁇ 3100 (Applied Biosystems, CA, USA) Genetic Analyzer using the BigDye ⁇ Terminator ⁇ 3 ⁇ 1 kit from Biosystems, Inc. (Applied Biosystems, CA, USA).
  • SNP rs 13198903 showed significant difference between 2205 AS and 3702 healthy volunteer controls, that is, there was a significant correlation with ankylosing spondylitis.
  • the SNP base was risky when T, and protected when C.
  • the subjects in the study were all AS and healthy controls in Examples 1 and 2, and these AS cases were diagnosed by experienced rheumatologists based on clinical findings and imaging findings in 1984. Revised standard AS patients. For each AS patient, blood was drawn for the study and the informed consent was signed after being informed of the study. Finally, a total of 3937 AS patients and 7727 healthy volunteers were included in the study.
  • the composition of the kit is: Cell Lysis Night, Buffer GS, Buffer GB, Buffer GD, Rinse PW, Elution Buffer TB, Proteinase K, Adsorption Column CB3, collection tube (2 ml) and 1.5 mL sterile collection tube.
  • the TIANamp Blood DNA kit is used to extract DNA from human peripheral blood samples.
  • the composition of the kit is: Cell Lysis Night, Buffer GS, Buffer GB, Buffer GD , rinse solution PW, elution buffer TB, proteinase K, adsorption column CB3, collection tube (2 ml), 1.5 mL sterile collection tube. 4.2.3 Experimental steps
  • the template DNAlul was added to each well of the plate to be tested, and 4 ul of the above reaction system was added, and centrifuged at 1000 rpm for 1 minute. After mixing, the amplification was carried out according to the following procedure: 94. C 4 minutes pre-denaturation, 94. C 20 seconds, 56° C 30 seconds, 60° C 1 minute for 30 cycles, 72° C 3 minutes, 4° C cooling.
  • the prepared sample analyte is co-crystallized with the chip substrate, and the crystal is placed in a vacuum tube of the grammar instrument, and then excited by a transient nanosecond (1 (T 9 s) strong laser, which is quick and convenient.
  • T 9 s transient nanosecond
  • test result When the test result is T, it is a risk type, and when the test result is C, it is a protection type.
  • the kit includes: PCR reaction primers designed for the region near the base of rsl3198903, DNA polymerase, deionized water, dNTP, MgCl 2 , PCR buffer, SAP, and resin.
  • the amplification primers and extension primers are shown in the following table: The steps of the detection method are as follows:
  • Primer3.0 software was used to design PCR amplification primers and single base extension primers for the SNP site to be tested;
  • reaction conditions are 94 °C for 4 minutes; 94 °C20 seconds, 60 °C for 30 seconds, 72 °C for 1 minute, 30 cycles; 72 °C for 3 minutes; 4 °C ⁇ ;

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Abstract

La présente invention concerne un procédé de détection d'une prédisposition à la spondylarthrite ankylosante, le procédé comprenant : la détection d'une base sur le site de polymorphisme mononucléotidique rs13198903 d'un échantillon, la prédisposition à la spondylarthrite ankylosante augmentant sensiblement lorsque la base est T. L'invention concerne également une trousse correspondante et son utilisation.
PCT/CN2011/083410 2011-12-03 2011-12-03 Prédisposition à la spondylarthrite ankylosante et procédé de détection d'un polymorphisme mononucléotidique, trousse et utilisation associées WO2013078690A1 (fr)

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CN201180067466.8A CN103502469B (zh) 2011-12-03 2011-12-03 强直性脊柱炎易感性单核苷酸多态性的检测方法、试剂盒及其应用
PCT/CN2011/083410 WO2013078690A1 (fr) 2011-12-03 2011-12-03 Prédisposition à la spondylarthrite ankylosante et procédé de détection d'un polymorphisme mononucléotidique, trousse et utilisation associées

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110459312A (zh) * 2018-05-07 2019-11-15 深圳华大生命科学研究院 类风湿性关节炎易感位点及其应用
CN110628897A (zh) * 2019-10-23 2019-12-31 中国医学科学院北京协和医院 一种kfs致病基因新突变及其应用
CN113025702A (zh) * 2021-03-10 2021-06-25 北京科力丹迪生物医疗科技有限公司 强直性脊柱炎易感基因的早筛方法及试剂盒
CN113637738A (zh) * 2021-08-08 2021-11-12 华中科技大学同济医学院附属协和医院 与冠心病相关的snp位点及其应用

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DATABASE NCBI 21 March 2004 (2004-03-21), retrieved from http://www.ncbi.nlm.nih.gov/projects/SNP/snp ref.cgi?rs=13198903 accession no. s13198903 *
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WU ZHEN ET AL.: "A meta-analysis on interleukin-1 gene cluster polymorphism and genetic susceptibility for ankylosing spondylitis", NATL MED J, vol. 87, no. 7, 13 February 2007 (2007-02-13), CHINA, pages 433 - 437 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110459312A (zh) * 2018-05-07 2019-11-15 深圳华大生命科学研究院 类风湿性关节炎易感位点及其应用
CN110459312B (zh) * 2018-05-07 2024-01-12 深圳华大生命科学研究院 类风湿性关节炎易感位点及其应用
CN110628897A (zh) * 2019-10-23 2019-12-31 中国医学科学院北京协和医院 一种kfs致病基因新突变及其应用
CN110628897B (zh) * 2019-10-23 2022-03-25 中国医学科学院北京协和医院 一种kfs致病基因新突变及其应用
CN113025702A (zh) * 2021-03-10 2021-06-25 北京科力丹迪生物医疗科技有限公司 强直性脊柱炎易感基因的早筛方法及试剂盒
CN113025702B (zh) * 2021-03-10 2022-10-28 北京科力丹迪生物医疗科技有限公司 强直性脊柱炎易感基因的早筛方法及试剂盒
CN113637738A (zh) * 2021-08-08 2021-11-12 华中科技大学同济医学院附属协和医院 与冠心病相关的snp位点及其应用
CN113637738B (zh) * 2021-08-08 2023-07-28 华中科技大学同济医学院附属协和医院 与冠心病相关的snp位点及其应用

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