WO2016133374A1 - Procédé de sélection d'un agent inhibiteur de contractions utérines d'après des informations d'endommagement de protéines sur chaque individu pour prévenir des effets secondaires de l'agent inhibiteur de contractions utérines - Google Patents

Procédé de sélection d'un agent inhibiteur de contractions utérines d'après des informations d'endommagement de protéines sur chaque individu pour prévenir des effets secondaires de l'agent inhibiteur de contractions utérines Download PDF

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WO2016133374A1
WO2016133374A1 PCT/KR2016/001631 KR2016001631W WO2016133374A1 WO 2016133374 A1 WO2016133374 A1 WO 2016133374A1 KR 2016001631 W KR2016001631 W KR 2016001631W WO 2016133374 A1 WO2016133374 A1 WO 2016133374A1
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drug
score
uterine contraction
sequence variation
protein
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Korean (ko)
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김주한
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싸이퍼롬, 인코퍼레이티드
김주한
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    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B50/00—ICT programming tools or database systems specially adapted for bioinformatics
    • G—PHYSICS
    • G09—EDUCATION; CRYPTOGRAPHY; DISPLAY; ADVERTISING; SEALS
    • G09F—DISPLAYING; ADVERTISING; SIGNS; LABELS OR NAME-PLATES; SEALS
    • G09F19/00—Advertising or display means not otherwise provided for
    • G09F19/12—Advertising or display means not otherwise provided for using special optical effects
    • G09F19/18—Advertising or display means not otherwise provided for using special optical effects involving the use of optical projection means, e.g. projection of images on clouds
    • G—PHYSICS
    • G09—EDUCATION; CRYPTOGRAPHY; DISPLAY; ADVERTISING; SEALS
    • G09F—DISPLAYING; ADVERTISING; SIGNS; LABELS OR NAME-PLATES; SEALS
    • G09F19/00—Advertising or display means not otherwise provided for
    • G09F19/22—Advertising or display means on roads, walls or similar surfaces, e.g. illuminated

Definitions

  • the present invention relates to a method for selecting uterine contraction inhibitors based on individual protein damage information using individual genome sequencing to prevent adverse effects.
  • Pharmacogenetics predicts genetic differences in metabolism and reactions of drugs or chemicals in the general population or in individuals. In some individuals, reactions other than the expected drug response to the drug may be present. These drug side effects may be related to the severity of the disease being treated, drug interactions, the patient's age, nutritional status, liver and kidney function, climate, or food. Although it may be due to factors, genetic differences related to drug metabolism, for example, polymorphism of drug enzyme genes, may be affected.
  • ritodrine a type of uterine contraction inhibitor
  • ritodrine is a beta-adrenergic receptor agonist, which is used between 22 and 37 weeks of pregnancy.
  • Ritodrin is a class of beta-adrenergic receptor agonists, as well as calcium channel blockers, oxytonin antagonists, NSAIDs (non-steroidal anti-inflammatory drugs), nitrates, and MgSO4.
  • Progesterone progesterone
  • Ritodrin is known to have side effects such as tachycardia, hypotension, anxiety, chest pain, abnormal ECG, pulmonary edema, hyperglycemia, hypokalemia, arrhythmia and myocardial infarction.
  • treatment with ritodrine should include an appropriate assessment of the patient's cardiovascular status along with cardiopulmonary function monitoring and electrocardiogram monitoring throughout the treatment period. If complications occur, medications should be discontinued immediately and, in some cases, switched to other medications, leading to failure of early analgesia.
  • the pharmacogenomics mentioned above may be used as a method for predicting side effects of drugs before drug administration. It has also been found that drug dynamics are associated with genotypes for ritodrine. Previous studies have shown that the time to deliver after the administration of ritodrine is related to rs1042719 of the ADRB2 (Adrenoceptor, beta 2) gene.
  • ADRB2 Adrenoceptor, beta 2
  • the present invention was devised in view of the above, and after analyzing individual genome sequence variation information and calculating individual protein damage scores from gene sequence variation information related to pharmacodynamics or pharmacokinetics of uterine contraction inhibitors, By calculating the individual drug scores in association with the interaction between the drug and the protein, it is intended to provide a method for predicting the possibility of adverse effects of uterine contraction inhibitors and providing information for selecting the uterine contraction inhibitors.
  • the present invention comprises the steps of determining one or more gene sequence variation information involved in pharmaco-dynamics or pharmaco-kinetics of a uterine contraction inhibitor from personal genome sequence information; Calculating an individual protein damage score using the gene sequence variation information; And correlating the individual protein damage scores with the correlation between the drug and the protein to calculate the individual drug scores, thereby providing a method for providing information for selecting the uterine contraction inhibitor using the personal genome sequence variation.
  • the present invention provides a uterine contraction inhibitor that can be applied to an individual, the database for retrieving or extracting information related to the gene or protein associated with the uterine contraction inhibitor; A communication unit accessible to the database; A first calculation module configured to calculate one or more gene sequence variation information related to pharmacodynamics or pharmacokinetics of the uterine contraction inhibitor based on the information; A second calculation module for calculating an individual protein damage score using the gene sequence variation information; A third calculating module that calculates an individual drug score by associating the individual protein damage score with a correlation between a drug and a protein; And it provides a uterine contraction inhibitor selection system using a personal genome sequence variation comprising a display unit for displaying the calculated value calculated by the calculation module.
  • the present invention comprises the steps of obtaining genetic sequence variation information involved in the pharmacodynamics or pharmacokinetics of the uterine contraction inhibitor from the individual genome sequence information; Calculating an individual protein damage score using the gene sequence variation information; And correlating the individual protein damage score with a correlation between the drug and the protein to calculate the individual drug score, wherein the execution module executes a processor to perform the operation. .
  • Individual uterine contraction inhibitor selection method and system based on the individual genome sequence variation information of the present invention through the sequence analysis of the exon region of the gene encoding various proteins involved in the pharmacodynamics or pharmacokinetics of the uterine contraction inhibitors In other words, the reliability of the uterine contraction inhibitors is high.
  • NGS Next Generation Sequencing
  • ritodrine uterine contraction inhibitors
  • it is useful to determine whether and how to use the uterine contraction inhibitors applied to the individual by predicting the side effects or risks of uterine contraction inhibitors, for example, ritodrine in advance. This may lead to improved success rate of early analgesic suppression therapy by administering an appropriate dose of ritodrine in patients with early analgesia.
  • it may be possible to introduce a new treatment method by increasing the safety of ritodrine administration in a patient group that could not withstand the drug or had to stop the drug due to side effects.
  • 1 is a flow chart showing each step of the method for providing information for the selection of uterine contraction inhibitors using individual genome sequence variation according to an embodiment of the present invention.
  • DB database
  • 3A and 3B are flowcharts illustrating a receiver operating curve (ROC) curve for verification of a method for selecting a uterine contraction inhibitor using a genome sequence variation according to an embodiment of the present invention.
  • ROC receiver operating curve
  • the present invention is based on the discovery that individual drugs can be selected for high-safety drugs and doses / uses in the treatment of uterine contraction inhibitors by analyzing individual genome sequence variation information.
  • the present invention comprises the steps of determining one or more gene sequence variation information involved in pharmaco-dynamics or pharmaco-kinetics of a uterine contraction inhibitor from personal genome sequence information; Calculating an individual protein damage score using the gene sequence variation information; And calculating the individual drug score by associating the individual protein damage score with the correlation between the drug and the protein, thereby providing information for selecting the uterine contraction inhibitor using the personal genome sequence variation.
  • uterine contraction inhibitors include, but are not limited to, all substances that exhibit the same, similar pharmacological activity, such as drugs belonging to the drug class disclosed in Table 1, derivatives thereof, and pharmaceutically acceptable salts thereof.
  • Beta-adrenergic receptors Terbutaline, Ritodrine, Fenoterol, Albuterol Calcium channel blockers Nicardipine, Nifedipine Oxytonin antagonists Atosiban Nonsteroidal Anti-inflammatory Drugs (NSAIDs) Indomethacin, Ketorolac, Sulindac Myosin light chain inhibitor MgSO4 nitrate Nitroglycerin Progesterone Hydroxyprogesterone caproate, Micronized progesterone ethyl alcohol
  • DrugBank http://www.drugbank.ca/
  • KEGG Drug http://www.genome.jp/kegg/drug/
  • PharmGKB https://www.pharmgkb.org/
  • BLK BLK
  • SPTA1 IFT74 RSPH3
  • CYP8B1 ICE1, NKAIN3, AASDH
  • the genes involved in the pharmacokinetics or pharmacokinetics of the uterine contraction inhibitors are BLK, SPTA1, IFT74, RSPH3, CYP8B1, ICE1, NKAIN3, AASDH, FUT6, SLC12A7, CD1A, CYP1A1, CARS2, ZDHHC12, CSPG5, PXG1, , HHATL, SERPINA7, TNKS, PSMD9, ZNF273, FAT4, GALNT10, OR6B1, RBBP8NL, KNDC1, UGT1A10, and ARL13B, and one selected from the group consisting of SLC15A2, SPINK6, C10orf113, and TP53, TP53. , MAD1L1, ASZ1, MAN2B2, CAPN14, BAAT, LAMA4, ADCY3, GRM7, SNAP47, LRIT2, LRRC3C, EFCAB4A, CPOX, and VARS2.
  • the genes / proteins are expressed according to the nomenclature of the HUGO Gene Nomenclature Committee (HGNC) (Gray KA, Daugherty LC, Gordon SM, Seal RL, Wright MW, Bruford EA.genenames.org: the HGNC resources in 2013. Nucleic Acids Res. 2013 Jan; 41 (Database issue): D545-52. Doi: 10.1093 / nar / gks1066. Epub 2012 Nov 17 PMID: 23161694).
  • HGNC HUGO Gene Nomenclature Committee
  • Gene sequence variation used as one information in the present invention refers to a variation or polymorphism of the individual gene sequence.
  • the gene sequence mutation or polymorphism occurs at a gene region, particularly an exon region, which encodes a protein associated with pharmacodynamics or pharmacokinetics of the uterine contraction inhibitor, but is not limited thereto.
  • base sequence variation information used in the present invention means information about the substitution, addition or deletion of the base constituting the exon of the gene. Substitution, addition, or deletion of such bases can occur for a variety of reasons, for example, by structural differences including mutations, truncation, deletions, duplications, inversions and / or translocations of chromosomes.
  • nucleotide polymorphism refers to differences between individuals of nucleotide sequences present in the genome, and the largest number of nucleotide polymorphisms is Single Nucleotide Polymorphism (SNP), and A, T, C, There is a difference between individuals in one base of the base sequence consisting of G.
  • Sequence polymorphism is a form of polyalleic variation including single nucleotide variation (SNV), short tandem repeat polymorphism (STRP), or variable number of tandem repeat (VNTR) and copy number variation (CNV), including SNPs. May appear.
  • sequence variation or polymorphism information found in an individual's genome is collected in association with proteins associated with pharmacodynamics or pharmacokinetics of uterine contraction inhibitors. That is, the nucleotide sequence information used in the method of the present invention is one or more genes involved in the pharmacokinetics or pharmacokinetics of the uterine contraction inhibitors, such as a target protein associated with the drug, Mutation information found in the exon region, in particular but not limited to, genes encoding enzyme proteins, transporter proteins or carrier proteins involved in drug metabolism.
  • the genome sequence information of an individual used in the present invention may be determined using a known sequence decoding method, and services such as Complete Genomics, BGI (Beijing Genome Institute), Knome, Macrogen, DNALink, etc., which provide commercially available services. May be used, but is not limited thereto.
  • Gene sequence variation information present in the genome sequence of an individual in the present invention can be extracted using a variety of methods, a sequence comparison program with a genomic sequence of a reference group, for example HG19, for example, ANNOVAR ( Wang et al., Nucleic Acids Research, 2010; 38 (16): e164), Sequence Variant Analyzer (SVA) (Ge et al., Bioinformatics. 2011; 27 (14): 19982000), Break Dancer (Chen et al., Nat Methods.2009 Sep; 6 (9): 677-81) and the like.
  • the gene sequence variation information may be received / obtained through a computer system, and in this aspect, the method of the present invention may further include receiving the genetic variation information into a computer system.
  • the computer system used in the present invention is a gene involved in the pharmacokinetics or pharmacokinetics of the uterine contraction inhibitors, for example, a gene encoding a target protein associated with a drug, an enzyme protein involved in drug metabolism, a transporter protein or a carrier protein. Include or have access to one or more databases containing information about them.
  • Such databases include, for example, DrugBank (http://www.drugbank.ca/), KEGG Drug (http://www.genome.jp/kegg/drug/), PharmGKB (http://www.pharmgkb.org /) May include, but is not limited to, public or private databases or knowledge bases that provide information about genes / proteins / drug-protein interactions, and the like.
  • the uterine contraction inhibitor may be information input by a user, information input from a prescription (pre), or information input from a database including information on the uterine contraction inhibitor.
  • the prescription includes, but is not limited to, electronic prescription.
  • pk pharmaco-kinetics
  • pk pharmacokinetic parameters
  • Distribution volume (Vd), clearance (CL), bioavailability (F), absorption rate coefficient (ka), maximum plasma concentration (Cmax), and time point of maximum plasma concentration, Tmax) area under the curve (AUC) measurements of changes in blood drug concentration over time.
  • pharmacodynamics or pharmacodynamic parameters refers to the characteristics related to the physiological and biochemical action of the drug on the living body and its mechanism of action, ie the reaction or effect of the living body of the drug.
  • the term “gene sequence variation score” refers to an amino acid sequence variation (substitution or addition) of a protein encoded by the gene when the genome sequence variation is found in the exon region of the gene encoding the protein. Or deletion) or a score that quantifies the extent to which transcriptional control mutations result, thereby causing significant changes or damage to the structure and / or function of the protein, wherein the gene sequence variation score is the evolution of amino acids on the genome sequence It can be calculated in consideration of the degree of preservation and the degree of change in the structure or function of the protein according to the physical properties of the modified amino acid.
  • the method of calculating the gene sequence variation score may be performed using a method known in the art. See, eg, SIFT (Sorting Intolerant From Tolerant, Pauline C et al., Genome Res. 2001 May; 11 (5): 863874; Pauline C et al., Genome Res. 2002 March; 12 (3): 436446; Jing Hul et al., Genome Biol. 2012; 13 (2): R9), PolyPhen, PolyPhen-2 (Polymorphism Phenotyping, Ramensky V et al., Nucleic Acids Res.
  • fathmm (Shihab et al., Functional Analysis through Hidden Markov Models, Hum Mutat 2013; 34 : 57-65, http://fathmm.biocompute.org.uk/) may be used to calculate the gene sequence variation score from the gene sequence variation information, but is not limited thereto.
  • the purpose of the algorithms described above is to determine how each gene sequence mutation affects protein function, how this damage damages the protein, or whether there is little effect. They have a common point in that they determine the impact of individual gene sequence variations on the structure and / or function of the protein in consideration of the changes that will result in the amino acid sequence of the protein encoded by the gene.
  • a Sorting Intolerant From Tolerant (SIFT) algorithm was used to calculate an individual gene sequence variation score.
  • SIFT Sorting Intolerant From Tolerant
  • gene sequence variation information is input to a VCF (Variant Call Format) format file, and each gene sequence variation is scored for damaging the gene.
  • VCF Variant Call Format
  • the method of the present invention calculates individual protein damage scores based on the gene sequence variation scores described above in the next step.
  • protein damage score means that two or more significant sequence mutations are found in a gene region encoding one protein, so that one protein has two or more gene sequence mutation scores. Refers to a score calculated by combining the gene sequence variation score. If there is a significant sequence variation in a gene region encoding a protein, the gene sequence variation score and the protein damage score are the same. In this case, when there are two or more gene sequence mutations encoding a protein, the protein damage score is calculated as an average value of the gene sequence variation scores calculated for each variation, and the average value is, for example, a geometric mean, an arithmetic mean, or a harmonic mean.
  • Arithmetic geometric mean, arithmetic harmonic mean, geometric harmonic mean, Pythagorean mean, quadrant mean, quadratic mean, cutting mean, windsorized mean, weighted mean, weighted geometric mean, weighted arithmetic mean, weighted harmonic mean, function mean, ⁇ average Can be computed as a generalized f-means, percentiles, maximums, minimums, modes, medians, median ranges, measures of central tendency, simple products or weighted products, or as a function of these calculations. This is not restrictive.
  • the protein damage score was calculated by Equation 1 below, and Equation 1 may be variously modified and is not limited thereto.
  • Equation 1 Sg is the protein damage score of the protein encoded by the gene g, n is the number of the nucleotide sequence analysis of the nucleotide variation of the gene g, vi is the gene sequence variation score of the i-th gene sequence variation And p is a nonzero real number.
  • p when the value of p is 1, it is an arithmetic mean, and when the value of p is -1, it is a harmonic mean, and in the extreme case where the value of p is close to 0, it is a geometric mean.
  • the protein damage score was calculated by Equation 2 below, and Equation 2 may be variously modified and is not limited thereto.
  • Equation 2 Sg is the protein damage score of the protein encoded by the gene g, n is the number of the nucleotide sequence analysis of the nucleotide sequence variation of the gene g, vi is the gene sequence variation score of the i-th gene sequence variation , wi is a weight given to vi. When all weights wi have the same value, the protein damage score Sg becomes the geometric mean value of the gene sequence variation score vi.
  • the weight may be given in consideration of the type of the protein, the pharmacokinetic or pharmacodynamic classification of the protein, the pharmacokinetic parameters of the drug enzyme protein, and the population or race distribution.
  • Vmax is the maximum enzyme reaction rate when the substrate concentration is very high
  • Km is the concentration of the substrate that causes the reaction to reach 1/2 Vmax.
  • Km can be seen as an affinity between the enzyme and the substrate. The smaller the Km, the stronger the bond between the enzyme and the substrate.
  • Kcat also called the enzyme's metabolic rate, refers to the number of substrate molecules that are metabolized at one second per enzyme active site when the enzyme is active at its maximum rate, and how fast the enzyme reaction actually occurs.
  • the method of the present invention correlates the protein damage score described above in the next step with the correlation between the drug and the protein to yield an individual drug score.
  • drug score refers to a given protein, eg, a target protein involved in the pharmacodynamics or pharmacokinetics of a given drug, an enzyme protein involved in drug metabolism, a transporter protein or Carrier proteins are found, the protein damage scores of the proteins are calculated, and then summed again to refer to the values calculated for one drug.
  • the drug score is calculated as an average value of the protein damage scores when the damage of the protein involved in the pharmacokinetics or pharmacokinetics of the uterine contraction inhibitors, for example, geometric mean, arithmetic mean, harmonic mean, Arithmetic geometric mean, Arithmetic harmonic mean, Geometric harmonic mean, Pythagorean mean, Quarter mean, Secondary mean, Cutting mean, Windsorized mean, Weighted mean, Weighted geometric mean, Weighted arithmetic mean, Weighted harmonic mean, Function mean, ⁇ mean, Generalized f-means, percentiles, maximums, minimums, modes, medians, median ranges, measures of central tendency, or simple products or weighted products, or arithmetic operations of these calculations This is not restrictive.
  • the drug score may be calculated by adjusting the weights of the drug, that is, the target protein involved in the pharmacodynamics or pharmacokinetics of the uterine contraction inhibitor, the enzyme protein involved in the drug metabolism, the transporter protein, and the carrier protein in consideration of pharmacological properties.
  • the weight may be given in consideration of the pharmacokinetic parameters of the corresponding drug metabolizing enzyme, the population group or the race distribution.
  • drug scores are also taken into account when considering protein damage scores of proteins that do not interact directly with the drug but interact with precursors or metabolites of the drug, such as proteins that make up the pharmacological pathway. Can be calculated.
  • the drug score may be calculated by considering the protein damage scores of the proteins that significantly interact with the proteins involved in the pharmacodynamics or pharmacokinetics of the drug.
  • PharmGKB Wang-Carrillo et al., Clinical Pharmacology & Therapeutics 2012; 92 (4): 414-4171
  • the MIPS Mammalian Protein-Protein Interaction Database Panetl al., Bioinformatics 2005; 21 (6): 832-834
  • BIND Boder et al., Biomolecular Interaction Network Database, Nucleic Acids Res. 2003 Jan 1; 31 (1): 248-50
  • Reactome Joshi-Tope et al., Nucleic Acids Res. 2005 Jan 1; 33 (Database issue): D428-32
  • the drug score was calculated by the following Equation 3, and the following Equation 3 may be variously modified, but is not limited thereto.
  • Equation 3 Sd is a drug score of drug d, n is a protein directly involved in the pharmacodynamics or pharmacokinetics of drug d or interacts with a precursor of the drug or metabolites of the drug, for example, a pharmacological pass.
  • the number of proteins encoded by one or more genes selected from the group of genes participating in the way, gi is a protein that directly participates in the pharmacodynamics or pharmacokinetics of drug d or interacts with precursors or metabolites of the drug, eg
  • p when the value of p is 1, it is an arithmetic mean, and when the value of p is -1, it is a harmonic mean, and in the extreme case where the value of p is close to 0, it is a geometric mean.
  • the drug score was calculated by Equation 4 below, and Equation 4 may be variously modified, and is not limited thereto.
  • Sd is a drug score of drug d
  • n is a protein directly involved in the pharmacodynamics or pharmacokinetics of drug d or interacts with a precursor of the drug or metabolites of the drug, eg, a pharmacological pass.
  • the number of proteins encoded by one or more genes selected from the group of genes constituting the way, gi are proteins that directly participate in the pharmacodynamics or pharmacokinetics of drug d or interact with precursors or metabolites of the drug, eg
  • the protein damage score of the protein encoded by one or more genes selected from the gene group constituting the pharmacological pathway, wi is the weight given to the gi.
  • the drug score Sd becomes the geometric mean value of the protein damage score gi when all weights wi have the same value.
  • the weight may be given in consideration of the type of the protein, the pharmacokinetic or pharmacodynamic classification of the protein, the pharmacokinetic parameters of the drug enzyme protein, and the population or race distribution.
  • the weights were equally given regardless of the drug-protein association characteristics, but the weight was given by considering the respective characteristics of drug-protein association. It is possible to calculate the drug score. For example, different scores may be assigned to the drug's target protein and the drug's transporter protein.
  • the drug metabolizing enzyme may be weighted by the pharmacokinetic parameters Km, Vmax, and Kcat / Km to calculate the drug score.
  • the target protein may be given a higher weight by judging that the target protein is more important in pharmacological action than the transporter protein, and the transporter protein or the carrier protein may be given a high weight for the concentration-sensitive drug. This is not restrictive.
  • Weights can be closely adjusted according to the correlation between drug and drug-related proteins, and the nature of drug-protein interactions. For example, a sophisticated algorithm can be used that assigns a weight to the nature of the drug-protein interaction, such as giving the target protein two points and the transporter protein one point.
  • the drug that is, the protein that directly interacts with the uterine contraction inhibitor
  • the protein interacts with the precursor of the drug or its metabolites, and the proteins involved in the pharmacodynamics or pharmacokinetics of the drug. It is possible to improve the predictive power of the formula by utilizing protein information that interacts easily, and related protein information that participates in the signaling pathway. In other words, the protein-protein interaction network or pharmacological pathway information can be utilized to use the information of various proteins involved in it.
  • the mean value (eg, geometric mean) of the protein damage scores of related proteins participating in the same signaling pathway may be used as a drug score calculation instead of the protein damage score of the protein.
  • the individual drug scores may be calculated for all drugs for which information on one or more related proteins can be obtained or for some selected drugs.
  • individual drug scores can be converted into rank (rank).
  • the method of the present invention may further include determining whether to use a drug applied to the individual, ie, a uterine contraction inhibitor, by using the aforementioned individual drug score.
  • the individual drug scores of the present invention can be applied individually to all drugs, but are more useful if they are classified by disease, clinical characteristics, or mode of action, or applied to drugs for medical comparison.
  • Drug classification systems that can be used in the present invention are, for example, the ATC (Anatomical Therapeutic Chemical Classification System) code, the top 15 frequently prescribed drug classes during 2005-2008 in the United States (Health, United States, 2011, Centers for Disease Control and Prevention), a list of drugs that have been released from the market due to known pharmacogenomic markers that may affect drug action information on the drug label, or side effects. It may include.
  • the method of the invention may further comprise calculating a prescription score.
  • the term “prescription score” refers to the sum of the drug scores determined for each drug when two or more drugs are administered at the same time or at intervals short enough to significantly affect the pharmacological action of each other. Say your score is calculated.
  • the prescription score may be calculated by combining the drug scores determined for each drug when two or more drugs determined by the priority between the drugs and simultaneous administration are required. The calculation of the prescription score can be calculated by simply averaging, summing or multiplying the drug scores of the plurality of drugs, for example, when no protein interacts in common with the plurality of drugs. If there are proteins that interact in common with the plurality of drugs, the drug damage scores of the common interacting protein are weighted twice, for example, to calculate each drug score and then the corresponding drug scores are calculated. By summing up, the prescription score can be calculated.
  • Prescription scores are intended to determine the adequacy or risk of a multi-drug prescription that is included in the prescription applied to an individual, beyond the effects of individual drugs.
  • the method of the present invention may further comprise determining the appropriateness or risk of the prescription (pre) applied to the individual.
  • the method of the present invention includes, but is not limited to, being performed for the purpose of preventing adverse effects of uterine contraction inhibitors.
  • FIG. 1 is a flow chart showing each step of the method for providing information for the selection of uterine contraction inhibitors using individual genome sequence variation according to an embodiment of the present invention.
  • S150 Individual drug score calculation for uterine contraction inhibitors
  • S150 Individual drug score calculation for uterine contraction inhibitors
  • Drug score notation by drug score ranking
  • the step of providing a pharmacogenomic calculation process and the basis for calculating the drug scores by providing information such as pictures, charts and explanations to help the prescriber in making decisions It may further include. That is, the method according to the present invention may further include providing one or more information of gene sequence variation information, gene sequence variation score, protein damage score, drug score, and information used to calculate the same.
  • the present invention provides a uterine contraction inhibitor that can be applied to an individual, the database for retrieving or extracting information related to the gene or protein associated with the uterine contraction inhibitor; A communication unit accessible to the database; A first calculation module configured to calculate one or more gene sequence variation information related to pharmacodynamics or pharmacokinetics of the uterine contraction inhibitor based on the information; A second calculation module for calculating an individual protein damage score using the gene sequence variation information; A third calculating module that calculates an individual drug score by associating the individual protein damage score with a correlation between a drug and a protein; And it relates to a uterine contraction inhibitor selection system using a personal genome sequence variation comprising a display unit for displaying the calculated value calculated by the calculation module.
  • the module may mean a functional and structural combination of hardware for performing the technical idea according to the present invention and software for driving the hardware.
  • the module may mean a logical unit of a predetermined code and a hardware resource for performing the predetermined code, and does not necessarily mean a physically connected code or a kind of hardware. Will be apparent to those skilled in the art.
  • output module refers to the gene sequence variation score, protein damage score, drug score, and information on which the calculation is made for the uterine contraction inhibitor and gene to be analyzed according to the method of the present invention.
  • a predetermined code for calculating each score based on the information and a logical unit of a hardware resource for performing the predetermined code and means a physically connected code or a kind of code. It doesn't mean hardware.
  • the system according to the present invention may further include a fourth calculation module for determining whether to use the uterine contraction inhibitor applied to the individual by using the individual drug score calculated in the third calculation module.
  • the system according to the present invention further includes a fifth calculation module for calculating the prescription score by combining the drug scores determined for each drug when two or more drugs determined by the priority between drugs are required. It may include.
  • the system according to the present invention inputs a list of uterine contraction inhibitors or accesses a database including information on uterine contraction inhibitors, extracts relevant information, and calculates and provides a drug score of the drug accordingly. It may further include a user interface.
  • the system according to the present invention may further include a display unit for further displaying a calculation process in which a value calculated in each calculation module or a priority between drugs is determined, and information on which the calculation or calculation is based.
  • the server including the database or its access information, the calculated information and the user interface device connected thereto may be used in conjunction with each other.
  • the system according to the invention can be updated immediately when new pharmacological / biochemical information on the drug-protein correlation is produced and can be used for further improved uterine contraction inhibitor selection.
  • the gene sequence variation information, gene sequence variation score, protein damage score, drug score and information on which the basis of the calculation stored in each calculation module Is updated.
  • System 10 of the present invention is a database (DB) 100, communication unit 200, user interface or terminal 300, the calculation unit 400 capable of searching or extracting information related to genes or proteins related to the uterine contraction inhibitors And a display unit 500.
  • DB database
  • the calculation unit 400 capable of searching or extracting information related to genes or proteins related to the uterine contraction inhibitors
  • a display unit 500 a display unit 500.
  • the user interface or the terminal 300 may request, receive and / or store uterine contraction inhibitor selection process using a personal genome sequence variation from a server, and may be a smartphone, a personal computer (PC), or a tablet. It may be configured as a terminal having a mobile communication function having a computing capability by mounting a microprocessor such as a PC, a personal digital assistant (PDA), a web pad, or the like.
  • a server may be a smartphone, a personal computer (PC), or a tablet. It may be configured as a terminal having a mobile communication function having a computing capability by mounting a microprocessor such as a PC, a personal digital assistant (PDA), a web pad, or the like.
  • a microprocessor such as a PC, a personal digital assistant (PDA), a web pad, or the like.
  • the server is a means for providing access to the database 100 for uterine contraction inhibitors, genetic variation or drug-protein correlations, and is connected to the user interface or the terminal 300 through the communication unit 200. It is configured to exchange various information.
  • the communication unit 200 may communicate in the same hardware, as well as a local area network (LAN), a metropolitan area network (MAN), a wide area network (WAN), the Internet, 2G, 3G, 4G mobile communication network, Wi-Fi (Wi-Fi), Wibro (Wibro) and the like can be included, and the communication method is wired, wireless, any communication method.
  • the database 100 may also be connected to various life science databases accessible through the Internet as well as being installed directly on the server.
  • the calculation unit 400 may include the first calculation module 410 for calculating one or more gene mutation information related to pharmacodynamics or pharmacokinetics of the uterine contraction inhibitor using the collected / input information as described above, A second calculation module 420 for calculating an individual protein damage score and a third calculation module 430 for calculating an individual drug score may be included.
  • a storage medium includes any medium for storage or delivery in a form readable by a device such as a computer.
  • a computer readable medium may include read only memory (ROM); Random access memory (RAM); Magnetic disk storage media; Optical storage media; Flash memory devices and other electrical, optical or acoustic signaling media, and the like.
  • the present invention comprises the steps of obtaining genetic sequence variation information involved in the pharmacokinetics or pharmacokinetics of the uterine contraction inhibitor from the individual genome sequence information; Calculating an individual protein damage score using the gene sequence variation information; And an execution module for associating the individual protein damage score with the correlation between the drug and the protein to execute a processor to perform an operation comprising calculating the individual drug score.
  • the processor may further include determining whether to use a uterine contraction inhibitor applied to the individual by using the individual drug score.
  • the present invention provides a biomarker composition for predicting adverse effects of uterine contraction inhibitors.
  • Genes that may be included in the biomarker composition according to the present invention include BLK, SPTA1, IFT74, RSPH3, CYP8B1, ICE1, NKAIN3, AASDH, FUT6, SLC12A7, CD1A, CYP1A1, CARS2, ZDHHC12, CSPG5, PXT1, HHATL, SERPINA7 TNKS, PSMD9, ZNF273, FAT4, GALNT10, OR6B1, RBBP8NL, KNDC1, UGT1A10, ARL13B, SLC15A2, SPINK6, C10orf113, TP53, TRIML2, MAD1L1, ASZ1, MAN2B2, CAPN14, BAAT3 LRRC3C, EFCAB4A, CPOX, VARS2, and the like, but are not limited to these.
  • By analyzing the mutation of the gene or its protein it is possible to predict the occurrence of adverse effects of the uterine contraction inhibitor, it can be used as a marker using the agent that
  • Preterm labor refers to regular uterine contraction prior to 37 weeks of gestation and thus to gradual cervical dilatation and maturation, which is one of the leading causes of premature birth.
  • the birth rate is decreasing and the premature birth rate is gradually increasing due to the increase of elderly mothers (4.3% in 1995, 7% in 1998, 8.3% in 2000, 10% in 2003), which is becoming a big social problem.
  • An increase in the rate of premature births is a problem that cannot be overlooked in terms of maternal and child health. This is why the development of treatment technology for early labor, which is the main cause of premature birth, is essential.
  • uterine contraction inhibitors that have been widely used in Korea include ritodrine, magnesium (MgSO 4 ), nifedipine (Nifedipine), and atoshiban (Atosiban).
  • ritodrine, magnesium and nifedipine which are used most frequently, are adversely affected by the side effects of these drugs.
  • complications such as tachycardia, hypotension, anxiety, chest pain, abnormal ECG, pulmonary edema, etc. of pregnant women is a problem
  • the frequency and severity of side effects are very different for each pregnant woman.
  • the responsiveness to a particular drug is different for each patient, so appropriate drug administration cannot be made to each patient and treatment failure or delay is indicated.
  • sequence fragments analyzed were sequence alignment map (SAM) and binary alignment map (BAM) files aligned with human reference sequence (eg, HG19) through data cleaning and quality check.
  • SAM sequence alignment map
  • BAM binary alignment map
  • the output was in format.
  • the clean alignment result is detected using a software tool such as SAMTools: pileup, SAMTools: mpileup, GATK: recalibration, GATK: realignment, and the like to detect mutations such as single nucleotide variations (SNVs, Single Nucleotide Variants) and InDels. It was output to a file in VCF (Variant Calling Format) format.
  • VCF Variariant Calling Format
  • the above-described gene sequence variation score vi value was calculated for each variation by using the SIFT algorithm, and the individual protein damage score Sg was calculated using Equation 2. Subsequently, the individual protein damage scores were compared for each gene in 13 cases and 30 health control controls. 47 genes showing statistically significant differences in the adverse event group and the control group were selected as follows, and 28 genes with higher statistical significance were selected as the first group based on the p-value. The following genes are genes of high relevance to the pharmacokinetics or pharmacokinetics of ritodrine and its metabolites.
  • BLK BLK, SPTA1, IFT74, RSPH3, CYP8B1, ICE1, NKAIN3, AASDH, FUT6, SLC12A7, CD1A, CYP1A1, CARS2, ZDHHC12, CSPG5, PXT1, HHATL, SERPINA7, TNKS, PSMD9, ZBF6AL1NT, ZBF673N10 KNDC1, UGT1A10, ARL13B
  • the drug score for each individual gene group was calculated using the method of the present invention. More specifically, after calculating the gene sequence variation score using the SIFT algorithm from each individual gene sequence variation information, the individual protein damage score for the 47 genes was calculated using Equation 2, Equation 4 Using to calculate the individual drug score for ritordlin, statistical analysis for each group. The results are shown in Table 3.
  • the protein damage score and the individual drug score were calculated from the gene sequence variation information using the 28 selected group 1 genes, and statistically significant between the normal control group and the ritodrine side effects group. It was confirmed that a difference appeared.
  • the method of the present invention can be used to predict a group of patients with high risk of side effects in the future patients with early analgesia, and induce high-risk patients to adjust the concentration of the drug or to use other alternative or interventional therapy.
  • the method of the present invention can be used to predict a group of patients with high risk of side effects in the future patients with early analgesia, and induce high-risk patients to adjust the concentration of the drug or to use other alternative or interventional therapy.
  • the personalized drug selection method according to the present invention not only targets all gene sequence mutations, but also does not require expensive case-control design observation studies, and damages individual proteins by pure calculation of genome sequence mutations. Since we propose a method of calculating the score and the individual drug score and applying it, it has the great advantage that it is possible to infer a personalized drug selection for the combination of all genome sequence variations and all drugs.
  • Validity criteria data were extracted from the established knowledge of 987 gene sequence mutation-drug interaction pairs provided by PharmGKB with 650 (65.9%) having at least one link with the 497 drugs.
  • the present invention targets the nucleotide sequence variation of the exon region, overlapping portions between the verification target data and the evaluation reference data are removed for fair evaluation. More specifically, all 36 nucleotide sequence mutations located in the exon region were removed from the 650 pairs, and only a nucleotide sequence variation of the non-coding region was selected to perform a more fair evaluation. In conclusion, we selected 614 pairs as the final gold standard for evaluation.
  • the sensitivity, specificity and area under the receiver operating curve were used. After ranking 497 drugs based on individual drug scores and setting thresholds by rank at 496 splits between each rank, (1) the drug score rank of the drug is above the threshold and the PharmGKB mutation is in the personal genome.
  • D is a set of 497 total drugs
  • GS is a set of personalized PharmGKB drugs that are used as individual gold standards by matching individual genetic sequence mutations with the risk allele of PharmGKB
  • D L is a set of top-ranking drugs The vertical bar brackets indicate the number of elements in the set.
  • ROC curve was calculated by calculating the specificity and and the AUC was calculated. More specifically, first, gene sequence variation scores were calculated using a SIFT algorithm for a total population of 1092 people, and then protein damage scores and drug scores were calculated by applying Equations 2 and 4, respectively.
  • Protein group distribution and average protein damage score calculation Protein family Protein count Related drug count Number of protein-drug pairs Average protein damage score Target protein 440 486 2357 0.798 Carrier Protein 10 50 65 0.728 Metabolic protein 74 330 1347 0.733 Transporter protein 54 176 457 0.733 system 545 497 4201 0.783
  • Table 4 shows the distribution of the protein groups for the 497 drugs used in this example, and the number of protein-drug pairs and the average protein damage score were displayed together in each group.
  • each group of proteins such as target protein, carrier protein, metabolic protein, and transporter protein
  • a result of performing an AUC analysis of individual drug scores by applying weights according to the number of individual races is considered, considering race specificity (bold line).
  • the total AUC of the population was 0.666 (African 0.744, American 0.650, Asian 0.631, European 0.653), without considering race specificity (dotted line).
  • the overall population AUC was 0.633 (African 0.623, American 0.629, Asian 0.64, European 0.636), indicating that the validity of drug score calculation considering race specificity was improved compared to that of the other population.
  • the individual drug score calculation validity AUC of the individual of the present invention is 0.634, and also applied to the weight of each protein group with race specificity ( Thick line), the individual drug score calculation validity AUC of the present invention is 0.667, indicating that the different weights are useful.

Abstract

La présente invention concerne un procédé et un système destinés à sélectionner un agent inhibiteur de contractions utérines d'après des informations d'endommagement de protéines sur chaque individu, en utilisant une analyse de séquence de base d'un génome individuel. Le procédé et le système selon la présente invention, en tant que technologie capable de prédire les effets secondaires ou le danger de certains médicaments (c.à.d. des agents inhibiteurs de contractions utérines) pour chaque individu par des analyses de séquences de régions d'exons de gènes qui codent diverses protéines participant à la pharmacodynamique ou à la pharmacocinétique d'agents inhibiteurs de contractions utérines, constituent une technologie à usage général qui non seulement est hautement fiable mais possède également une gamme étendue d'applications.
PCT/KR2016/001631 2015-02-17 2016-02-17 Procédé de sélection d'un agent inhibiteur de contractions utérines d'après des informations d'endommagement de protéines sur chaque individu pour prévenir des effets secondaires de l'agent inhibiteur de contractions utérines WO2016133374A1 (fr)

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CN108566387A (zh) * 2018-03-27 2018-09-21 中国工商银行股份有限公司 基于udp协议进行数据分发的方法、设备以及系统

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KR102403778B1 (ko) * 2020-02-05 2022-05-30 서울대학교산학협력단 폐부종 진단용 바이오마커 및 그의 용도

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