WO2020153617A1 - Marqueur de polymorphisme mononucléotidique de gène il6 pour prédire le risque de développer une leucopénie induite par un médicament et procédé de prédiction du risque de leucopénie l'utilisant - Google Patents

Marqueur de polymorphisme mononucléotidique de gène il6 pour prédire le risque de développer une leucopénie induite par un médicament et procédé de prédiction du risque de leucopénie l'utilisant Download PDF

Info

Publication number
WO2020153617A1
WO2020153617A1 PCT/KR2019/018715 KR2019018715W WO2020153617A1 WO 2020153617 A1 WO2020153617 A1 WO 2020153617A1 KR 2019018715 W KR2019018715 W KR 2019018715W WO 2020153617 A1 WO2020153617 A1 WO 2020153617A1
Authority
WO
WIPO (PCT)
Prior art keywords
leukopenia
risk
predicting
single nucleotide
nucleotide polymorphism
Prior art date
Application number
PCT/KR2019/018715
Other languages
English (en)
Korean (ko)
Inventor
김주한
Original Assignee
서울대학교 산학협력단
서울대학교병원
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 서울대학교 산학협력단, 서울대학교병원 filed Critical 서울대학교 산학협력단
Publication of WO2020153617A1 publication Critical patent/WO2020153617A1/fr

Links

Images

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
    • C12Q1/68—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
    • 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
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • 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
    • C12Q2600/118—Prognosis of disease development
    • 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
    • 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
    • C12Q2600/158—Expression markers

Definitions

  • the present invention relates to a composition for predicting the risk of leukopenia including a monobasic polymorphic marker in the IL6 gene and a method for predicting the risk of leukopenia using the same.
  • Thiopurine-based drugs such as 6-mercaptopurine, azathiopurine, and thioguanine are widely used in the treatment of patients such as leukemia, Crohn's disease, and ulcerative colitis. It is an immunosuppressive drug.
  • the main problem with the use of cheopurine-based drugs is that even when patients start taking the prescribed doses calculated according to BSA, side effects such as leukopenia or liver toxicity occur in about 6% of patients.
  • Thiopurine-based drug activity is associated with thiopurine s-methyltransferase (TPMT), in which case the TPMT gene has a mutation, TPMT enzyme activity decreases and TGN metabolite increases As a result, serious bone marrow suppression may be reported.
  • TPMT thiopurine s-methyltransferase
  • the U.S. Food and Drug Administration recommends measuring TPMT enzyme activity before using cheopurine-based drugs.
  • the incidence of TPMT mutations in Asians is 2 to 3%, which is found to be significantly lower than in whites (10%), it is questionable whether it is useful to measure the enzyme activity of TPMTs in Asians in advance.
  • previous studies have shown that the NUDT15 mutation, which has been reported to be the genetic cause of leukopenia induced by thiopurine, is observed at a relatively high frequency in 42.5% of Korean leukopenia patients, but the remaining patients are not explained by the NUDT15 mutation. Considering, the understanding of the genetic causes of leukopenia in Asians is still lacking.
  • Patent Document 0001 Korean Registered Patent Publication No. 10-1704143
  • the present inventors conducted a study to develop a marker capable of predicting the risk of developing leukopenia, which is one of the side effects caused by cheopurine-based drugs, and as a result, the significance of specific monobasic polymorphic sites in the IL6 gene and leukopenia
  • the present invention was completed by confirming the correlation.
  • An object of the present invention is to provide a composition for predicting the risk of leukopenia including a monobasic polymorphic marker in the IL6 gene.
  • Another object of the present invention is to provide a kit for predicting the risk of leukopenia, comprising a polynucleotide specifically hybridizing to a polynucleotide comprising the single-basic polymorphic marker site.
  • Another object of the present invention is to provide a method for providing information on predicting the risk of leukopenia including the step of identifying the genotype of the monobasic polymorphic marker.
  • the present invention is a polynucleotide consisting of 10 to 100 consecutive DNA sequences comprising a single nucleotide polymorphism (SNP) region of the 101st nucleotide of SEQ ID NO: 1 or complementary thereof. It provides a composition for predicting the risk of leukopenia, comprising a polynucleotide.
  • SNP single nucleotide polymorphism
  • the present invention includes a polynucleotide composed of 10 to 100 contiguous DNA sequences or a complementary polynucleotide thereof, which specifically hybridizes with the single-nucleotide polymorphic site of the 101 nucleotide of SEQ ID NO: 1.
  • the present invention provides a kit for predicting the risk of leukopenia.
  • the present invention provides a method for providing information on predicting the risk of leukopenia including the step of identifying the genotype of the 101 nucleotide of SEQ ID NO: 1 from sample DNA.
  • the monobasic polymorphic marker in the IL6 gene according to the present invention has a high correlation with the risk of leukopenia induced by drugs, in particular, chipurin-based drugs, and thus, leukemia, Crohn's disease, ulcerative colitis, or Customized patient who can effectively predict or diagnose patients with high susceptibility to leukopenia occurring during chemopurine-based drug treatment in organ transplantation, etc., and achieve optimal treatment effects by administering the appropriate drugs to patients. Treatment can be performed efficiently. Furthermore, the monobasic polymorphic marker according to the present invention can be used in drug development studies for the treatment of drug-induced leukopenia.
  • FIG. 1 is a view showing a process for selecting a patient group to be used as an analysis object in one embodiment of the present invention among leukemia patients using 6-mercaptopurine.
  • FIG. 2 is a diagram showing specific results confirming a correlation between a single nucleotide polymorphism site (rs13306435) on a IL6 gene and a dose percentage decrease (Trend test).
  • FIG. 3 is a diagram showing specific results confirming a correlation between a single nucleotide polymorphism site on the IL6 gene (rs13306435) and G4N (Grade 4 Neutropenia).
  • the present invention comprises a single nucleotide polymorphism (SNP) region of the 101 nucleotide of SEQ ID NO: 1, polynucleotide consisting of 10 to 100 consecutive DNA sequence or a complementary polynucleotide thereof It provides a composition for predicting the risk of leukopenia, comprising.
  • SNP single nucleotide polymorphism
  • 'polymorphism' means a case in which two or more alleles exist in a single locus
  • 'polymorphic site' means a locus in which the allele exists.
  • a single base differs from person to person is referred to as'single nucleotide polymorphism', that is, single nucleotide polymorphism (SNP).
  • the term'allele' refers to several types of a gene present in the same locus of the homologous chromosome. Alleles are also used to indicate polymorphism, for example, SNPs have two types of alleles.
  • the "SEQ ID NO: 1" is a polymorphic sequence comprising a polymorphic site.
  • the polymorphic sequence means a sequence comprising a polymorphic site containing SNP in the polynucleotide sequence.
  • the 101 nucleotide of SEQ ID NO: 1 is present at the IL locus on 7p15.3, and can be represented by rs13306435.
  • the allele of SEQ ID NO: 101, rs13306435, is T.
  • the allele of A at the time of mutation is A. Therefore, since the 101st nucleotide of SEQ ID NO: 1 may be A or T(U), it was described as “w” according to the multi-base description method.
  • the polynucleotide or the complementary polynucleotide thereof according to the present invention may be composed of 10 or more, preferably 10 to 100, more preferably 20 to 80, even more preferably 40 to 60 consecutive bases And is not limited thereto.
  • leukopenia includes those induced by thiopurine-based drugs, for example, when treating leukemia, Crohn's disease, ulcerative colitis, or organ transplant drugs in patients with organ transplants. It may be induced.
  • the cheopurine-based drug includes, but is not limited to, 6-mercaptopurine, azathioprine, or thioguanine.
  • the monobasic polymorphic marker can be used for predicting the risk of leukopenia, a specific base at the site of a monobasic polymorphism as a result of genetic analysis of a group in which leukopenia, a side effect that occurs with the administration of cheopurine-based drugs It is based on the high probability of existence.
  • the monobasic polymorphic marker in the IL6 gene according to the present invention has a high correlation with leukopenia induced by drugs, especially cheopurine-based drugs, and the resulting dose reduction, thereby using leukemia, Crohn's disease, ulcerative colitis Or, it can effectively predict or diagnose patients with high sensitivity to leukopenia, which occurs during chemopurine-based drug treatment, such as organ transplantation, and can achieve optimal treatment effects by administering appropriate drugs to patients. Patient-specific treatment can be efficiently performed. Furthermore, the monobasic polymorphic marker according to the present invention can be used in drug development studies for the treatment of drug-induced leukopenia.
  • the present invention comprises a polynucleotide consisting of 10 to 100 consecutive DNA sequences or a complementary polynucleotide thereof, comprising a single nucleotide polymorphism (SNP) region of the 101 nucleotide of SEQ ID NO: 1
  • a kit for predicting the risk of leukopenia comprising polynucleotides that specifically hybridize.
  • the polynucleotide that specifically hybridizes with the polynucleotide or its complementary polynucleotide is an allele-specific polynucleotide.
  • An allele-specific polynucleotide means to hybridize specifically to each allele. That is, it refers to hybridization so that the base of the polymorphic site present in the polymorphic sequence can be specifically distinguished.
  • It may be a probe or a primer that specifically hybridizes with the polynucleotide or a complementary polynucleotide thereof, but is not limited thereto.
  • the "probe” refers to nucleic acid fragments such as RNA or DNA corresponding to a few bases to hundreds of bases, which are capable of specifically binding other than mRNA, and are labeled to confirm the presence or absence of a specific mRNA and expression level.
  • the probe may be manufactured in the form of an oligonucleotide probe, a single strand DNA probe, a double strand DNA probe, or an RNA probe. The appropriate probe selection and hybridization conditions can be appropriately selected according to techniques known in the art.
  • the "primer” is a nucleic acid sequence having a short free 3-terminal hydroxyl group, capable of forming complementary templates and base pairs, and acting as a starting point for template strand copying. Speak.
  • the primer can initiate DNA synthesis in the presence of four different nucleoside triphosphates and reagents for polymerization (ie, DNA polymerase or reverse transcriptase) at appropriate buffers and temperatures. PCR conditions, sense and antisense primer lengths can be appropriately selected according to techniques known in the art.
  • the kit may be a kit of various types depending on the method using the polynucleotide, and includes, but is not limited to, PCR kit, DNA chip kit, microarray, and the like.
  • the present invention provides a method for providing information on predicting the risk of leukopenia, comprising the step of identifying the genotype of the 101 nucleotide of SEQ ID NO: 1 from sample DNA.
  • the allele of the 101st nucleotide of SEQ ID NO: 1 is TA or AA, it can be predicted that the probability of developing leukopenia is higher than when the allele is TT.
  • leukopenia includes those induced by thiopurine-based drugs, for example, when treating leukemia, Crohn's disease, ulcerative colitis, or organ transplant drugs in patients with organ transplants. It may be induced.
  • the cheopurine-based drug includes, but is not limited to, 6-mercaptopurine, azathioprine, or thioguanine.
  • the method for providing information according to the present invention may further include isolating DNA from a biological sample in order to obtain sample DNA.
  • DNA separation phenol/chloroform extraction method, SDS extraction method, CTAB separation method (Cetyl Trimethyl AmmoniumBromide; Murray et al., Nuc. Res., 4321-4325, 1980) commonly used in the art, or commercially available It can be performed using a DNA extraction kit, but is not limited thereto.
  • the biological sample includes, but is not limited to, blood, saliva, urine, skin cells, mucosal cells, and hair tissue of the subject.
  • Gene sequence analysis may be performed to perform the step of identifying the genotype.
  • any method known in the art can be used, for example, using an automatic base sequencer, pyrosequencing, restriction fragment length polymorphism (PCR-RELP), PCR-SSCP method ( Single strand conformation polymorphism), PCR-SSO method (specific sequence oligonucleotide), PCR-SSO method and dot hybridization method (allele specific oligonucleotide) hybridization method, TaqMan-PCR method, MALDI-TOF/MS method, RCA method (Rolling circle amplification), HRM (high resolution melting) method, primer extension method, Southern blot hybridization method and a known method such as dot hybridization method can be used, but is not limited thereto.
  • PCR-RELP restriction fragment length polymorphism
  • PCR-SSCP method Single strand conformation polymorphism
  • PCR-SSO method specific sequence oligonucleotide
  • NUDT15 Normal Metabolizer (*1/*1) NUDT15 Intermediate Metabolizer (*1/*2, *1/*3, *1/*4, *1/*5, *1/*6, *1/*9) NUDT15 Poor Metabolizer (*3/*3) total TPMT Normal Metabolizer (*1/*1, *1/*1S, *1S/*1S) 188 48 One 237 TPMT Intermediate Metabolizer (*1/*3C, *1S/*3C, *1/*6) 6 One 7 TPMT Poor Metabolizer total 194 49 One 244
  • the initial recommended dose of 6-mercaptopurine is 75 mg/m 2 .
  • the initial dose was adjusted from 75 mg/m 2 to 50 mg/m 2 .
  • the protocol for treatment was determined on a case-by-case basis by the responsible physician for the modification or discontinuation of the drug dose due to adverse events.
  • Past medical records for each patient were reviewed, and information on 6-mercaptopurine, including dose, duration of treatment, and the timing and extent of leukopenia was independently assessed by physicians with unknown genotyping results.
  • 6-Mercaptopurine was prescribed with a schedule of 6-10 repetitions of the same anticancer treatment for one cycle lasting a total of 12 weeks.
  • the first cycle he started taking a prescribed dose of the drug based on the body surface area (BSA), and continued to reduce the dose of 6-mercaptopurine according to adverse events such as leukopenia or hepatotoxicity.
  • BSA body surface area
  • the dose percentage is the ratio of the BSA-based and actual doses in the last cycle of maintenance therapy and is defined as follows.
  • G4N Gram 4 Neutropenia incidence
  • candidate genes were selected by performing multiple covariate linear regression analysis using GVB as a dose percentage and G4N as dependent variables.
  • GVB Genetic Variant Burden
  • the term GVB means the geometric mean of SIFT scores less than 0.7 among SIFT scores, which are indicators of deteriousness of mutation.
  • a multi-covariate linear regression analysis using dose percentage and G4N as dependent variables was performed for all variations of the candidate genes, and three candidate variations shown in Table 2 were selected. Among them, the rs13306435 mutation of the IL6 gene corresponding to the nonsynonymous variant was selected as the final mutation.
  • a single nucleotide polymorphism site was performed by performing a regression analysis among 188 persons selected in Example 1 The effect of (rs13306435) on the dose percentage was statistically confirmed.
  • Correction factors for regression analysis include gender, age at the start of the last cycle, BSA, and genotypes of mutations (0 for wild type, 1 for heterozygous mutant, 1 for homozygous mutant) 2).
  • the dose percentage criteria are 10%, 15%, 25%, 35%, 45%, 60%, 80%, 100%, and the G4N standard is 0%, 4%, 6%. , 8%, 10%, 15%, 20%, 25%.
  • Table 3 shows the results of the regression analysis. Statistically significant (p-value ⁇ 0.05) results are underlined.
  • the p-value of logistic regression was significant at 10%, 15%, 25%, 35%, 45%, and 60% on a dose percentage basis.
  • the p-value of logistic regression was significant at 15%, 20%, and 25% in the G4N criterion.
  • the p-value of linear regression was significant in both criteria.
  • the rs13306435 mutation of the IL6 gene selected as the final candidate in Example 2 was analyzed using Fisher's Exact Test (variant aspect) and Cochran Armitage Trend Test. In Fisher's exact test, the specific single base polymorphism site and leukopenia incidence and odds ratio (OR) were calculated with 95% confidence intervals (CI), and statistical significance was determined to be p ⁇ 0.05.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Engineering & Computer Science (AREA)
  • Analytical Chemistry (AREA)
  • Zoology (AREA)
  • Genetics & Genomics (AREA)
  • Wood Science & Technology (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Physics & Mathematics (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Hospice & Palliative Care (AREA)
  • Oncology (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)

Abstract

La présente invention concerne une composition pour prédire le risque de développement d'une leucopénie comprenant un marqueur de polymorphisme mononucléotidique dans un gène IL6 et un procédé pour prédire le risque de développement de la leucopénie à l'aide de celle-ci. Étant donné que le marqueur de polymorphisme mononucléotidique dans un gène IL6 selon la présente invention présente une corrélation élevée avec le risque de développer une leucopénie induite par des médicaments, en particulier des médicaments à base de thiopurine, des patients présentant une sensibilité élevée à la leucopénie se produisant pendant un traitement médicamenteux à base de thiopurine pour traiter la leucémie, la maladie de Crohn, la rectocolite hémorragique ou une transplantation d'organe etc., peut être efficacement prédite ou diagnostiquée en utilisant le marqueur de polymorphisme mononucléotidique à un stade précoce. Par l'administration d'un médicament approprié pour le patient par l'intermédiaire d'une telle prédiction et d'un diagnostic, il est également possible d'effectuer un traitement spécifique de manière efficace au patient qui peut atteindre un effet de traitement optimal. En outre, le marqueur de polymorphisme mononucléotidique selon la présente invention peut être utilisé dans des études de développement de médicament pour le traitement de la leucopénie induite par un médicament.
PCT/KR2019/018715 2019-01-25 2019-12-30 Marqueur de polymorphisme mononucléotidique de gène il6 pour prédire le risque de développer une leucopénie induite par un médicament et procédé de prédiction du risque de leucopénie l'utilisant WO2020153617A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2019-0010143 2019-01-25
KR20190010143 2019-01-25

Publications (1)

Publication Number Publication Date
WO2020153617A1 true WO2020153617A1 (fr) 2020-07-30

Family

ID=71735779

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2019/018715 WO2020153617A1 (fr) 2019-01-25 2019-12-30 Marqueur de polymorphisme mononucléotidique de gène il6 pour prédire le risque de développer une leucopénie induite par un médicament et procédé de prédiction du risque de leucopénie l'utilisant

Country Status (2)

Country Link
KR (1) KR102304562B1 (fr)
WO (1) WO2020153617A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101704143B1 (ko) * 2014-01-22 2017-02-09 울산대학교 산학협력단 Nudt15 유전자 내의 단일염기다형성 마커를 포함하는 티오퓨린 유도 백혈구 감소증 발병 위험 예측용 조성물
KR101840843B1 (ko) * 2016-02-29 2018-03-21 주식회사 싸이퍼롬 약물 유도 백혈구 감소증 발병 위험 예측용 유전자 단일염기다형성 마커 및 이를 이용한 백혈구 감소증 발병 위험 예측 방법

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101704143B1 (ko) * 2014-01-22 2017-02-09 울산대학교 산학협력단 Nudt15 유전자 내의 단일염기다형성 마커를 포함하는 티오퓨린 유도 백혈구 감소증 발병 위험 예측용 조성물
KR101840843B1 (ko) * 2016-02-29 2018-03-21 주식회사 싸이퍼롬 약물 유도 백혈구 감소증 발병 위험 예측용 유전자 단일염기다형성 마커 및 이를 이용한 백혈구 감소증 발병 위험 예측 방법

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
AD'HIAH, A. H.: "Gene expression and six single nucleotide polymorphisms of interleukin-6 in rheumatoid arthritis: A case-control study in Iraqi patients", ALEXANDRIA JOURNAL OF MEDICINE, vol. 54, 2018, pages 639 - 645, XP055727217 *
MITROKHIN, V.: "Association between interleukin-6/6R gene polymorphisms and coronary artery disease in Russian population: influence of interleukin-6/6R gene polymorphisms on inflammatory markers", JOURNAL OF INFLAMMATION RESEARCH, vol. 10, 2017, pages 15 1 - 160, XP055727216 *
PECHUMER, H.: "Interleukin-6 (ILL-6) levels in febrile children during maximal aplasia after bone marrow transplantation (BMT) are similar to those in children with normal hematopoiesis", ANNALS OF HEMATOLOGY, vol. 70, 1995 *

Also Published As

Publication number Publication date
KR20200092864A (ko) 2020-08-04
KR102304562B1 (ko) 2021-09-24

Similar Documents

Publication Publication Date Title
US10787712B2 (en) Consensus coding sequences of human breast and colorectal cancers
EP3507384B1 (fr) Procédés et compositions pour la prédiction de l'activité d'enzastaurin
Radvanszky et al. Uninterrupted CCTG tracts in the myotonic dystrophy type 2 associated locus
EP2152917B1 (fr) Marqueurs génétiques d'efficacité de l'ilopéridone dans le traitement de symptômes psychotiques
WO2017007275A1 (fr) Composition pour la détermination d'un phénotype nasal
WO2015111852A1 (fr) Composition permettant de prédire le risque de leucopénie induite par une thiopurine, contenant un marqueur de polymorphisme mononucléotidique au sein du gène nudt15
WO2020153617A1 (fr) Marqueur de polymorphisme mononucléotidique de gène il6 pour prédire le risque de développer une leucopénie induite par un médicament et procédé de prédiction du risque de leucopénie l'utilisant
WO2011159004A1 (fr) Snp destiné à prédire la sensibilité à une formulation thérapeutique anticancéreuse ciblée
WO2022191571A1 (fr) Polymorphisme mononucléotidique associé à la résorption de racine apicale externe et utilisation de celui-ci
WO2022154401A1 (fr) Composition pour diagnostiquer ou prédire le syndrome métabolique
KR101840843B1 (ko) 약물 유도 백혈구 감소증 발병 위험 예측용 유전자 단일염기다형성 마커 및 이를 이용한 백혈구 감소증 발병 위험 예측 방법
KR102543907B1 (ko) 치주질환 위험도 평가용 유전자 마커
KR101141185B1 (ko) 치료의 제안된 효능 검출용 마커
WO2017164436A1 (fr) Marqueur de prédiction d'une réponse thérapeutique à un agent anticancéreux chez des patients atteints d'un cancer solide
WO2020204313A1 (fr) Marqueur snp pour diagnostiquer un anévrisme cérébral, comprenant un polymorphisme monobasique du gène gba
WO2020060211A1 (fr) Marqueur génétique permettant de prédire la concentration d'un médicament à base de statine dans le sang
WO2019225803A1 (fr) Association entre un polymorphisme de nucléotide simple de rnf213 et un risque de développer une maladie de moyamoya chez les coréens
WO2018186680A1 (fr) Composition comprenant un ensemble d'amorces pour pcr longue à base d'adn génomique pour le diagnostic de la neurofibromatose
WO2020162663A1 (fr) Marqueur de polymorphisme mononucléotidique pour le diagnostique de la puberté précoce ou son pronostic thérapeutique, et utilisation correspondante
WO2011078495A2 (fr) Procédé de prédiction chimiosensible pour un polymorphisme mononucléotidique (snp)
Patitucci et al. Comparison of different techniques for detecting 17p12 duplication in CMT1A
KR102304555B1 (ko) 약물 유도 백혈구 감소증 발병 위험 예측용 crim1 유전자 단일염기다형성 마커 및 이를 이용한 백혈구 감소증 발병 위험 예측 방법
KR101141546B1 (ko) Ａｎｋｒｄ15, ｈｐｄ, ｐｓｍｄ9, ｗｄｒ66, ｇｐｃ6, ｐａｘ9, ｌｒｒｃ28, ｔｎｓ4, ａｘｌ, 및 ｈｎｒｐｕｌ1 유전자로부터 유래된 단일염기다형을 포함하는 폴리뉴클레오티드, 이를 포함하는 마이크로어레이 및 진단키트, 및 이를 이용한 분석방법
KR102158726B1 (ko) Itpr3 유전자 업스트림의 유전자간 영역을 포함하는 지연성 허혈 진단용 dna 메틸화 마커 조성물
WO2020204312A1 (fr) Marqueur snp pour diagnostiquer un anévrisme cérébral comprenant un polymorphisme nucléotidique unique du gène arhgap32

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19911662

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19911662

Country of ref document: EP

Kind code of ref document: A1