+

WO2011088306A1 - Procédés d'utilisation de variants génétiques pour diagnostiquer la maladie de crohn - Google Patents

Procédés d'utilisation de variants génétiques pour diagnostiquer la maladie de crohn Download PDF

Info

Publication number
WO2011088306A1
WO2011088306A1 PCT/US2011/021282 US2011021282W WO2011088306A1 WO 2011088306 A1 WO2011088306 A1 WO 2011088306A1 US 2011021282 W US2011021282 W US 2011021282W WO 2011088306 A1 WO2011088306 A1 WO 2011088306A1
Authority
WO
WIPO (PCT)
Prior art keywords
disease
nod2
individual
crohn
risk
Prior art date
Application number
PCT/US2011/021282
Other languages
English (en)
Inventor
Jerome I. Rotter
Kent D. Taylor
Stephan R. Targan
Original Assignee
Cedars-Sinai Medical Center
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 Cedars-Sinai Medical Center filed Critical Cedars-Sinai Medical Center
Publication of WO2011088306A1 publication Critical patent/WO2011088306A1/fr

Links

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
    • 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

Definitions

  • the invention relates generally to the field of inflammatory disease, specifically to Crohn's disease.
  • IBD idiopathic inflammatory bowel disease
  • IBD pathogenesis Genetic factors play an important role in IBD pathogenesis, as evidenced by the increased rates of IBD in Ashkenazi Jews, familial aggregation of IBD, and increased concordance for IBD in monozygotic compared to dizygotic twin pairs (3).
  • genetic analyses have linked IBD to specific genetic variants, especially NOD2 (CARD 15) variants on chromosome 16ql2 and the IBD5 haplotype (spanning the organic cation transporters, SLC22A4 and SLC22A5, and other genes) on chromosome 5q31 (3-7).
  • CD and UC are thought to be related disorders that share some genetic susceptibility loci but differ at others.
  • the invention provides a method of diagnosing susceptibility to Crohn's disease in an individual, comprising: obtaining a sample from the individual, assaying the sample to determine the presence or absence of a NOD2 risk variant, and diagnosing susceptibility to Crohn's disease in the individual based on the presence of the NOD2 risk variant.
  • the NOD2 risk variant can be selected from the group consisting of rs2291263, rs2306549, rs8115510, rs7268671 , and rs7866759.
  • the NOD2 risk variants can be located at loci including, but not limited to ITPR2 and PLCB4.
  • Assaying of the sample comprises genotyping for one or more single nucleotide polymorphisms.
  • the sample can be whole blood, plasma, serum, saliva, cheek swab, urine, or stool.
  • the invention provides a method of prognosing Crohn's disease in an individual, comprising: obtaining a sample from the individual, assaying the sample for the presence or absence of one or more genetic risk variants, and prognosing an aggressive form of Crohn's disease based on the presence of one or more NOD2 risk variants.
  • the NOD2 risk variant can be selected from the group consisting of rs2291263, rs2306549, rs81 15510, rs7268671 , and rs7866759.
  • the NOD2 risk variants can be located at loci including, but not limited to ITPR2 and PLCB4.
  • Assaying of the sample comprises genotyping for one or more single nucleotide polymorphisms.
  • the sample can be whole blood, plasma, serum, saliva, cheek swab, urine, or stool.
  • the invention provides method of treating an individual for Crohn's disease, comprising: prognosing an aggressive form of Crohn's disease in the individual based on the presence of one or more NOD2 risk variants, and treating the individual, wherein the one or more NOD2 risk variants are selected from rs2291263, rs2306549, rs8115510, rs7268671 , and rs7866759.
  • the NOD2 risk variants can be located at loci including, but not limited to ITPR2 and PLCB4.
  • Assaying of the sample comprises genotyping for one or more single nucleotide polymorphisms.
  • the sample can be whole blood, plasma, serum, saliva, cheek swab, urine, or stool.
  • FIG. 1 Multidimensional Scaling (MDS) cluster plot used to identify Ashkenazi Jewish subjects.
  • IBD inflammatory bowel disease
  • CD Crohn's disease
  • UC ulcerative colitis
  • IC indeterminate colitis
  • IBS irritable bowel syndrome
  • Risk variant refers to genetic variants, the presence of which correlates with an increase or decrease in susceptibility to Crohn's disease.
  • Risk variants of Crohn's disease include, but are not limited to NOD2 variants at various genetic locus, such as “haplotypes” and/or a set of single nucleotide polymorphisms (SNPs) on a gene or chromatid that are statistically associated.
  • Risk variants can include, but are not limited to rs2291263, rs2306549, rs81 15510, rs7268671 , and rs7866759.
  • Genetic locus can include, but are not limited to ITPR2 and PLCB4.
  • NOD2 risk variant
  • NOD2 means a nucleotide sequence of a NOD2 gene containing one or more changes as compared to the wild-type NOD2 gene or an amino acid sequence of a NOD2 polypeptide containing one or more changes as compared to the wild-type NOD2 polypeptide sequence.
  • NOD2 also known as CARD 15, has been localized to the IBDl locus on chromosome 16 and identified by positional-cloning (4) as well as a positional candidate gene strategy (5).
  • Treatment or “treating,” as used herein refer to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent, slow down and/or lessen the disease even if the treatment is ultimately unsuccessful.
  • Those in need of treatment include those already with Crohn's disease as well as those prone to have Crohn's disease or those in whom Crohn's disease is to be prevented.
  • a therapeutic agent may directly decrease the pathology of IBD, or render the cells of the gastroenterological tract more susceptible to treatment by other therapeutic agents.
  • diagnosis refers to determining the nature or the identity of a condition or disease.
  • a diagnosis may be accompanied by a determination as to the severity of the disease.
  • Diagnosis as it relates to the present invention, relates to the diagnosis of Crohn's disease.
  • prognostic refers to predicting the probable course and outcome of IBD or the likelihood of recovery from IBD.
  • the prognosis can include the presence, the outcome, or the aggressiveness of the disease.
  • biological sample means any biological material obtained from an individual from which nucleic acid molecules can be prepared.
  • examples of a biological sample include, but are not limited to whole blood, plasma, serum, saliva, cheek swab, urine, stool, or other bodily fluid or tissue that contains nucleic acid.
  • novel CD susceptibility loci were identified in a genome-wide association study (GWAS) performed in Ashkenazi subjects selected by genetically derived ethnicity information.
  • GWAS genome-wide association study
  • the inventors replicated some previously described associations between CD and NOD2 risk variants in the Ashkenazi Jewish population ( Figure 2) and identified several other novel NOD2 risk variants as susceptibility genes in CD.
  • These genes act in the intracellular calcium signaling pathway which is important for T cell receptor signaling, and further implicates adaptive immunity in the pathophysiology of CD.
  • the newly discovered NOD2 risk variants that are associated with CD include, but are not limited to rs2291263, rs2306549, rs8115510, rs7268671, and rs7866759.
  • the present invention provides a method of diagnosing susceptibility to Crohn's disease in an individual by determining the presence or absence of a NOD2 risk variant, where the presence of the NOD2 risk variant is indicative of susceptibility to Crohn's disease in the individual.
  • NOD2 risk variants can include, but are not limited to rs2291263, rs2306549, rs81 15510, rs7268671, and rs7866759.
  • the individual is Ashkenazi Jewish.
  • the present invention provides a method of prognosing Crohn's disease in an individual by determining the presence or absence of a NOD2 risk variant, where the presence of the NOD2 risk variant is indicative of a complicated form of Crohn's disease in the individual.
  • NOD2 risk variants can include, but are not limited to rs2291263, rs2306549, rs8115510, rs7268671, and rs7866759.
  • the individual is Ashkenazi Jewish.
  • the present invention provides a method of treating Crohn's disease in an individual by determining the presence of a NOD2 risk variant and treating the individual.
  • NOD2 risk variants can include, but are not limited to rs2291263, rs2306549, rs8115510, rs7268671, and rs7866759.
  • the individual is Ashkenazi Jewish.
  • a variety of methods can be used to determine the presence or absence of a NOD2 risk variant.
  • enzymatic amplification of nucleic acid from an individual may be used to obtain nucleic acid for subsequent analysis.
  • the presence or absence of a NOD2 risk variant may also be determined directly from the individual's nucleic acid without enzymatic amplification.
  • nucleic acid means a polynucleotide such as a single or double-stranded DNA or R A molecule including, for example, genomic DNA, cDNA and mRNA.
  • nucleic acid encompasses nucleic acid molecules of both natural and synthetic origin as well as molecules of linear, circular or branched configuration representing either the sense or antisense strand, or both, of a native nucleic acid molecule.
  • the presence or absence of a NOD2 risk variant may involve amplification of an individual's nucleic acid by the polymerase chain reaction.
  • Use of the polymerase chain reaction for the amplification of nucleic acids is well known in the art (8).
  • a TaqmanB allelic discrimination assay available from Applied Biosystems may be useful for determining the presence or absence of a variant allele.
  • a TaqmanB allelic discrimination assay a specific, fluorescent, dye-labeled probe for each allele is constructed.
  • the probes contain different fluorescent reporter dyes such as FAM and VICTM to differentiate the amplification of each allele.
  • each probe has a quencher dye at one end which quenches fluorescence by fluorescence resonant energy transfer (FRET).
  • FRET fluorescence resonant energy transfer
  • each probe anneals specifically to complementary sequences in the nucleic acid from the individual.
  • the 5' nuclease activity of Taq polymerase is used to cleave only probe that hybridize to the allele.
  • Cleavage separates the reporter dye from the quencher dye, resulting in increased fluorescence by the reporter dye.
  • the fluorescence signal generated by PCR amplification indicates which alleles are present in the sample.
  • Mismatches between a probe and allele reduce the efficiency of both probe hybridization and cleavage by Taq polymerase, resulting in little to no fluorescent signal.
  • Improved specificity in allelic discrimination assays can be achieved by conjugating a DNA minor grove binder (MGB) group to a DNA probe as described, previously (9).
  • Minor grove binders include, but are not limited to, compounds such as dihydrocyclopyrrolo indole tripeptide (DPI).
  • Restriction fragment length polymorphism (RFLP) analysis may also be useful for determining the presence or absence of a particular allele (10-11).
  • restriction fragment length polymorphism analysis is any method for distinguishing genetic polymorphisms using a restriction enzyme, which is an endonuclease that catalyzes the degradation of nucleic acid and recognizes a specific base sequence, generally a palindrome or inverted repeat.
  • restriction enzyme which is an endonuclease that catalyzes the degradation of nucleic acid and recognizes a specific base sequence, generally a palindrome or inverted repeat.
  • Allele-specific oligonucleotide hybridization may also be used to detect a disease- predisposing allele. Allele-specific oligonucleotide hybridization is based on the use of a labeled oligonucleotide probe having a sequence perfectly complementary, for example, to the sequence encompassing a disease-predisposing allele. Under appropriate conditions, the allele-specific probe hybridizes to a nucleic acid containing the disease-predisposing allele but does not hybridize to the one or more other alleles, which have one or more nucleotide mismatches as compared to the probe. If desired, a second allele-specific oligonucleotide probe that matches an alternate allele also can be used.
  • the technique of allele-specific oligonucleotide amplification can be used to selectively amplify, for example, a disease-predisposing allele by using an allele-specific oligonucleotide primer that is perfectly complementary to the nucleotide sequence of the disease-predisposing allele but which has one or more mismatches as compared to other alleles (8).
  • an allele-specific oligonucleotide primer that is perfectly complementary to the nucleotide sequence of the disease-predisposing allele but which has one or more mismatches as compared to other alleles (8).
  • the one or more nucleotide mismatches that distinguish between the disease-predisposing allele and one or more other alleles are preferably located in the center of an allele-specific oligonucleotide primer to be used in allele-specific oligonucleotide hybridization.
  • an allele-specific oligonucleotide primer to be used in PCR amplification preferably contains the one or more nucleotide mismatches that distinguish between the disease-associated and other alleles at the 3 ' end of the primer.
  • HMA heteroduplex mobility assay
  • SSCP single strand conformational, polymorphism
  • This technique can be used to detect mutations based on differences in the secondary structure of single-strand DNA that produce an altered electrophoretic mobility upon non-denaturing gel electrophoresis. Polymorphic fragments are detected by comparison of the electrophoretic pattern of the test fragment to corresponding standard fragments containing known alleles.
  • Denaturing gradient gel electrophoresis also may be used to detect a SNP and/or a haplotype.
  • DGGE Denaturing gradient gel electrophoresis
  • double-stranded DNA is electrophoresed in a gel containing an increasing concentration of denaturant; double- stranded fragments made up of mismatched alleles have segments that melt more rapidly, causing such fragments to migrate differently as compared to perfectly complementary sequences (11).
  • CD subjects of mixed Caucasian ethnicity and 3970 controls from the Cardiovascular Health Study were geno typed, using Illumina technology (Human 610Quad, Human 317Duo or the HumanCNV370-Duo platform). 234,637 SNPs were available for analyses in all datasets. Multidimensional Scaling was used to detect population substructure. Ten principal components were calculated and principal components 1 and 2 were plotted to generate informative cluster plots for ethnicity. Self-reported ethnicity in CD cases was used to confirm the Ashkenazi Jewish "cluster" and select cases and controls ethnically matched by principal components. Association with case/control status was performed using a logistic regression model.
  • the inventors identified 247 Ashkenazi Jewish CD cases and 320 ethnically matched controls by principal components. Genomic inflation was calculated at ⁇ . ⁇ . A Q-Q plot of P values showed a modest increase of significant associations above the expected under the null hypothesis.

Landscapes

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

Abstract

La présente invention concerne le pronostic, le diagnostic, et le traitement de la maladie de Crohn. L'invention concerne également un pronostic, un diagnostic, et un traitement qui sont basés sur la présence d'un ou de plusieurs facteurs de risque génétique comprenant des variants NOD2.
PCT/US2011/021282 2010-01-15 2011-01-14 Procédés d'utilisation de variants génétiques pour diagnostiquer la maladie de crohn WO2011088306A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US29537910P 2010-01-15 2010-01-15
US61/295,379 2010-01-15

Publications (1)

Publication Number Publication Date
WO2011088306A1 true WO2011088306A1 (fr) 2011-07-21

Family

ID=44304665

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2011/021282 WO2011088306A1 (fr) 2010-01-15 2011-01-14 Procédés d'utilisation de variants génétiques pour diagnostiquer la maladie de crohn

Country Status (1)

Country Link
WO (1) WO2011088306A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9580752B2 (en) 2008-12-24 2017-02-28 Cedars-Sinai Medical Center Methods of predicting medically refractive ulcerative colitis (MR-UC) requiring colectomy
WO2017087735A1 (fr) * 2015-11-18 2017-05-26 Millennium Pharmaceuticals, Inc. Procédé de traitement de la maladie de crohn
US10316083B2 (en) 2013-07-19 2019-06-11 Cedars-Sinai Medical Center Signature of TL1A (TNFSF15) signaling pathway
US10633449B2 (en) 2013-03-27 2020-04-28 Cedars-Sinai Medical Center Treatment and reversal of fibrosis and inflammation by inhibition of the TL1A-DR3 signaling pathway
US11186872B2 (en) 2016-03-17 2021-11-30 Cedars-Sinai Medical Center Methods of diagnosing inflammatory bowel disease through RNASET2
US11236393B2 (en) 2008-11-26 2022-02-01 Cedars-Sinai Medical Center Methods of determining responsiveness to anti-TNFα therapy in inflammatory bowel disease

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040077020A1 (en) * 2001-11-30 2004-04-22 Mannick Elizabeth E. Diagnostic microarray for inflammatory bowel disease, crohn's disease and ulcerative colitis
US20070072180A1 (en) * 2002-08-30 2007-03-29 Abreu Maria T Mutations in nod2 are associated with fibrostenosing disease in patients with crohn's disease
US20080200568A1 (en) * 2005-08-30 2008-08-21 Stephanie Chissoe Genes Associated With Type ll Diabetes Mellitus

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040077020A1 (en) * 2001-11-30 2004-04-22 Mannick Elizabeth E. Diagnostic microarray for inflammatory bowel disease, crohn's disease and ulcerative colitis
US20070072180A1 (en) * 2002-08-30 2007-03-29 Abreu Maria T Mutations in nod2 are associated with fibrostenosing disease in patients with crohn's disease
US20080200568A1 (en) * 2005-08-30 2008-08-21 Stephanie Chissoe Genes Associated With Type ll Diabetes Mellitus

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE NCBI [online] 2001, retrieved from http://www.ncbi.nlm.nih.gov/projects/SNP/snp ref.cgi?rs=2291263 Database accession no. rs2291263. *
VAN ES ET AL.: "ITPR2 as a susceptibility gene in sporadic amyotrophic lateral sclerosis: a genome -wide association study.", LANCET NEUROLOGY, vol. 6, 2007, pages 869 - 877, XP022256808, DOI: doi:10.1016/S1474-4422(07)70222-3 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11236393B2 (en) 2008-11-26 2022-02-01 Cedars-Sinai Medical Center Methods of determining responsiveness to anti-TNFα therapy in inflammatory bowel disease
US12084722B2 (en) 2008-11-26 2024-09-10 Cedars-Sinai Medical Center Methods of determining responsiveness to anti-TNFα therapy in inflammatory bowel disease
US9580752B2 (en) 2008-12-24 2017-02-28 Cedars-Sinai Medical Center Methods of predicting medically refractive ulcerative colitis (MR-UC) requiring colectomy
US10633449B2 (en) 2013-03-27 2020-04-28 Cedars-Sinai Medical Center Treatment and reversal of fibrosis and inflammation by inhibition of the TL1A-DR3 signaling pathway
US10316083B2 (en) 2013-07-19 2019-06-11 Cedars-Sinai Medical Center Signature of TL1A (TNFSF15) signaling pathway
US11312768B2 (en) 2013-07-19 2022-04-26 Cedars-Sinai Medical Center Signature of TL1A (TNFSF15) signaling pathway
US12269873B2 (en) 2013-07-19 2025-04-08 Cedars-Sinai Medical Center Signature of TL1A (TNFSF15) signaling pathway
WO2017087735A1 (fr) * 2015-11-18 2017-05-26 Millennium Pharmaceuticals, Inc. Procédé de traitement de la maladie de crohn
US11186872B2 (en) 2016-03-17 2021-11-30 Cedars-Sinai Medical Center Methods of diagnosing inflammatory bowel disease through RNASET2

Similar Documents

Publication Publication Date Title
EP2689036B1 (fr) Méthodes de diagnostic et de traitement des granulomes intestinaux et de la faible densité osseuse dans la maladie intestinale inflammatoire
US20100184050A1 (en) Diagnosis and treatment of inflammatory bowel disease in the puerto rican population
US20110177969A1 (en) The role of il17rd and the il23-1l17 pathway in crohn's disease
US20200270692A1 (en) Predicting age-related macular degeneration with single nucleotide polymorphisms within or near the genes for complement component c2, factor b, plekha1, htra1, prelp, or loc387715
US20100240043A1 (en) Methods of using genetic variants to diagnose and predict inflammatory bowel disease
US20100144903A1 (en) Methods of diagnosis and treatment of crohn's disease
US8153443B2 (en) Characterization of the CBir1 antigenic response for diagnosis and treatment of Crohn's disease
US11542556B2 (en) Single nucleotide polymorphism in HLA-B*15:02 and use thereof
US20100021917A1 (en) Methods of using genes and genetic variants to predict or diagnose inflammatory bowel disease
US20130012602A1 (en) Methods of using znf365 genetic variants to diagnose crohn's disease
WO2011088306A1 (fr) Procédés d'utilisation de variants génétiques pour diagnostiquer la maladie de crohn
US20110117552A1 (en) Methods of using a nod2/card15 haplotype to diagnose crohn's disease
US9305137B1 (en) Methods of identifying the genetic basis of a disease by a combinatorial genomics approach, biological pathway approach, and sequential approach
EP2689034B1 (fr) Rôle de la méthylation de l'interféron gamma dans la maladie intestinale inflammatoire
US20120041082A1 (en) Methods of using smad3 and jak2 genetic variants to diagnose and predict inflammatory bowel disease
US20140017711A1 (en) Methods of diagnosing ulcerative colitis and crohn's disease
WO2009055596A2 (fr) Procédés d'utilisation de variants génétiques permettant de diagnostiquer et de prédire un syndrome métabolique et des traits associés

Legal Events

Date Code Title Description
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11733433

Country of ref document: EP

Kind code of ref document: A1

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载