WO2006126618A1 - Procédé de détermination de polymorphisme de gène pour évaluer le niveau de risque de maladie, procédé d’évaluation du niveau de risque de maladie et matrice d'évaluation correspondante - Google Patents

Procédé de détermination de polymorphisme de gène pour évaluer le niveau de risque de maladie, procédé d’évaluation du niveau de risque de maladie et matrice d'évaluation correspondante Download PDF

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WO2006126618A1
WO2006126618A1 PCT/JP2006/310405 JP2006310405W WO2006126618A1 WO 2006126618 A1 WO2006126618 A1 WO 2006126618A1 JP 2006310405 W JP2006310405 W JP 2006310405W WO 2006126618 A1 WO2006126618 A1 WO 2006126618A1
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disease
gene polymorphism
gene
risk
polymorphism
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PCT/JP2006/310405
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English (en)
Japanese (ja)
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Yoshimitsu Yamasaki
Atsuhiko Kurokawa
Muneo Takiguchi
Yuuri Arakawa
Li Yang
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Signpost Corporation
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Priority to JP2007517881A priority Critical patent/JP5121449B2/ja
Publication of WO2006126618A1 publication Critical patent/WO2006126618A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • 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
    • G16B40/00—ICT specially adapted for biostatistics; ICT specially adapted for bioinformatics-related machine learning or data mining, e.g. knowledge discovery or pattern finding
    • G16B40/10—Signal processing, e.g. from mass spectrometry [MS] or from PCR
    • 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
    • G16B20/00—ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
    • 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
    • G16B20/00—ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
    • G16B20/20—Allele or variant detection, e.g. single nucleotide polymorphism [SNP] detection
    • 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
    • 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
    • G16B40/00—ICT specially adapted for biostatistics; ICT specially adapted for bioinformatics-related machine learning or data mining, e.g. knowledge discovery or pattern finding

Definitions

  • the present invention relates to a method for determining a genetic polymorphism for disease risk determination.
  • the present invention also relates to a method for determining a disease risk level for an individual subject using a genetic polymorphism determined by a method that can be used, and a method for presenting a predicted onset value obtained using the method. More specifically, the present invention relates to a disease risk determination method that can be used for prevention, treatment, and diagnosis of various diseases, a disease risk determination device that can be used to execute the disease, a disease risk determination program, and an onset prediction presentation method.
  • the present invention provides an array for determining a disease risk, which can be used for determination of a disease risk related to arteriosclerotic disease, myocardial infarction, nephropathy, or retinopathy caused by diabetes as the above-mentioned disease, disease
  • the present invention relates to a risk determination method, a genetic marker, and an analysis kit.
  • the disease of the subject can be determined. If the so-called “disease risk” such as the ease of progression and the ease of progression can be determined, pre-measures can be taken to prevent the onset of the disease or to suppress the progression. In other words, subjects who are determined to have a high risk of the disease can try to prevent illness at an early stage. In addition, the possibility of the onset of the disease and the degree of progression after the onset can be predicted, enabling more detailed diagnosis and treatment depending on the subject. In addition, if the predicted values of the current disease risk level and future disease level can be presented in an easy-to-understand manner, It is possible to promote awareness and make diagnosis and treatment by doctors and nurses efficient and effective.
  • Patent Document 1 discloses a method for determining arteriosclerotic diseases by combining a plurality of gene polymorphisms having a significant positive relationship with the carotid intima-media thickness.
  • All of the documents (Non-Patent Documents 2 to 6) listed in the international survey of Patent Document 1 are gene polymorphisms that have a significant positive relationship with the carotid intima-media thickness. It is only mentioned, and if a genetic polymorphism having a “negative association” opposite to the “positive association” is used for the determination of disease risk, the idea is completely described.
  • Patent Document 2 discloses a method for determining a genetic polymorphism for determining a disease risk level specific to various diseases using a genetic polymorphism having “negative association”. ing. Patent Document 2 listed below describes a disease risk determination method, a disease risk determination device, a disease risk level that can be used for prevention and treatment of a disease because it is possible to determine the ease of onset and progression of various diseases. Judgment programs, and, in particular, arteriosclerotic diseases that develop due to diabetes, among other diseases, disease risk assessment arrays, disease risk assessment methods, genetic markers, and disease-specific gene polymorphisms and gene polymorphisms An analytical kit for detecting a mold set is disclosed.
  • Patent document 1 International publication WO2003Z087360
  • Patent Document 2 International Publication WO2005Z036443
  • Non-Patent Document 1 Yamada Y, Izawa H, Ichihara S, Takatsu F, Ishihara H, Hirayama H, S one T, Tanaka M, Yokota M. Prediction of the risk of myocardial infarction from pol ymorphisms in candidate genes.N.Engl .J.Med. 2002; 347 (24): 1916-23
  • Non-Patent Document 2 Rauramaa R, et al., Arterioscler Thromb Vase Biol. 2000 Dec, vol. 20, no. 12, p.2657-2662
  • Non-Patent Document 3 Chapman CM, et al "Arteriosclerosis. 2001 Nov, vol.159, no.l, p.209 -217
  • Non-Patent Document 4 McQuillan BM, et al "Circulation. 1999 May 11, vol.99, no.18, p.238 3-2388
  • Non-Patent Document 5 Terry JG, et al., Stroke. 1996 Oct. vol.27, no.10, p.1755-1759
  • Non-Patent Document 6 Castellano M, et al, Circulation. 1995 Jun 1, vol.91 , no. ll, p.2721-27
  • the genetic polymorphism is processed by distinguishing between positive association and negative association. This is necessary and the processing becomes complicated. Therefore, it is desirable that the genetic polymorphism for disease risk determination can be determined by the same processing without distinguishing the positive / negative relationship of the genetic polymorphism.
  • An object of the present invention is to solve the conventional problems related to the determination of disease risk such as the likelihood of disease progression and the ease of progression, and to achieve the following object.
  • the present invention provides a method for accurately determining a genetic polymorphism for determining a disease risk level unique to various diseases without distinguishing the positive / negative relevance of the genetic polymorphism.
  • the present invention reflects the influence of environmental factors, A highly accurate disease risk assessment method, disease risk assessment device and disease risk that can be used for the prevention and treatment of diseases by determining the ease of onset and progression of various diseases. The purpose is to provide a degree determination program.
  • the present invention relates to a disease risk determination array, disease risk determination method, arteriosclerotic disease, myocardial infarction, nephropathy, or retinopathy that develops due to diabetes, among other diseases. It is an object of the present invention to provide an analysis kit for detecting genetic markers and disease-specific gene polymorphisms and gene polymorphism sets.
  • the current disease risk level and the predicted value of the future disease level can be presented in an easy-to-understand manner, which encourages the subject's awareness and makes effective diagnosis and treatment by doctors and nurses. And it aims to provide a method that helps to make it effective.
  • a fifth object is to provide a method for determining the necessity of coping with a disease according to an individual.
  • a first step of designating a gene polymorphism by designating a gene polymorphism by designating a genotype from a plurality of gene polymorphisms designated in advance,
  • One or more gene polymorphisms related to a disease and having a genotype Reference table power consisting of a first gene polymorphism set comprising a gene polymorphism having a genotype of a test sample
  • a first step of collating the power / disability including a second set of genetic polymorphisms configured by reading out a predetermined number of genetic polymorphisms from the types;
  • the disease risk is an expression obtained by multiple regression analysis of a set of patient data using the disease degree as an objective variable and at least the first gene polymorphism set included in the reference table as an explanatory variable. Degree determination method.
  • a recording unit that records a reference table composed of a first gene polymorphism set comprising at least one gene polymorphism having a genotype and having an association with a disease;
  • the processing unit calculates a risk level for the test sample using a regression equation determined in advance by multiple regression analysis;
  • the disease risk is an expression obtained by multiple regression analysis of a set of patient data using the disease degree as an objective variable and at least the first gene polymorphism set included in the reference table as an explanatory variable. Degree determination device.
  • a function of accepting an input of a genetic polymorphism having a genotype of a test sample
  • the regression equation uses the disease degree as an objective variable and is included in at least the reference table.
  • a disease risk assessment program which is an expression obtained by multiple regression analysis of a set of patient data using the gene polymorphism set of 1 as an explanatory variable.
  • a function of accepting an input of a genetic polymorphism having a genotype of a test sample
  • the regression equation is an equation obtained by performing multiple regression analysis on a set of patient data with the disease degree as an objective variable and at least the first gene polymorphism set included in the reference table as an explanatory variable.
  • Degree judgment program
  • a computer-readable recording medium on which is recorded.
  • Probes for detection of gene polymorphisms constituting at least one gene polymorphism set selected from the group consisting of the gene polymorphism sets shown in FIGS. 2-A and 2-B and FIG. An array for determining the risk of myocardial infarction caused by diabetes.
  • a gene constituting at least one gene polymorphism set selected from the group consisting of the gene polymorphism sets described in FIGS. 1-A and 1-B and FIG. 17 can be specifically amplified.
  • a kit for analysis of a gene polymorphism associated with arteriosclerotic disease caused by diabetes comprising a primer pair or a nucleic acid probe capable of specifically hybridizing to the gene or its amplification product.
  • a gene constituting at least one gene polymorphism set selected from the group consisting of the gene polymorphism sets described in FIGS. 2-A and 2-B and FIG. 18 can be specifically amplified.
  • a gene constituting at least one gene polymorphism set selected from the group consisting of the gene polymorphism sets described in FIGS. 3A and 3B and FIG. 19 can be specifically amplified.
  • a gene polymorphism analysis kit related to nephropathy caused by diabetes comprising a primer pair or a nucleic acid probe capable of specifically hybridizing to the gene or its amplification product.
  • An axis corresponding to each disease risk of a plurality of diseases is drawn radially, a line segment connecting points on the axis corresponding to the average value of the disease risk for each disease is drawn, and A second step of creating a first radar chart by drawing a line segment connecting the points on the axis corresponding to the first disease risk for each disease;
  • An onset prediction presentation method including:
  • a value obtained by adding a predetermined time to an environmental factor related to time among the environmental factors of the second patient, the environmental factor of the second patient not related to time, and the second patient A first step of determining a second disease risk as a predicted value in the future from the risk judgment formula using the genetic polymorphism information of
  • An axis corresponding to each of the disease risks of a plurality of diseases is drawn radially, a line segment connecting the points on the axis corresponding to the first disease risk for each disease is drawn, and And a second step of drawing a line segment connecting the points on the axis corresponding to the second disease risk level for each patient to create a radar chart.
  • the risk determination formula includes an interaction term between a gene polymorphism set and an environmental factor, and a predetermined number of patient detection values related to the environmental factor included in the first interaction term among the interaction terms.
  • the value of the first interaction term is calculated using the value obtained by changing as the value of the environmental factor, and the calculated value of the first interaction term exceeds a predetermined value by V
  • a presentation method for predicting onset including a first step of presenting the necessity of coping with a case.
  • Information regarding the presence or absence of a gene polymorphism set having at least one gene polymorphism that has a genotype and is related to a disease, and environmental factors that can change in an individual are variables.
  • a determination formula for a disease risk, an ID for identifying a subject, information on the genetic polymorphism set of the subject corresponding to the ID, and a reference value for determining the necessity of treatment for the disease In a computer having a recording unit for recording, A first step of accepting designation of the subject's ID;
  • a disease risk determination method disease risk that can be used for the prevention and treatment of disease onset, which can accurately determine the likelihood of disease onset and the ease of progression as the disease risk.
  • a degree determination device and a disease risk determination program can be provided. This method can accurately determine the ease of onset or progression of arteriosclerotic disease, myocardial infarction, nephropathy or retinopathy, etc. in patients with diabetes or those who tend to have such disease. It can be used effectively for prevention and treatment.
  • the conventional method for determining the risk of a disease is to determine the risk of the disease using only the susceptibility (positive association) and resistance (negative association) to the genetic polymorphism as an index.
  • a judgment formula is used in consideration of environmental factors and further considering the interaction between genetic polymorphisms related to diseases and environmental factors. As a result, in the present invention, it is possible to make a comprehensive judgment without classifying the disease risk into sensitivity and resistance, and obtain a more accurate and accurate result regarding the disease risk. It becomes possible.
  • the present invention is also useful for determining the risk of arteriosclerotic disease, particularly arteriosclerotic disease caused by diabetes, and determining the risk of myocardial infarction, particularly myocardial infarction caused by diabetes.
  • Related polymorphisms useful factors for assessing the risk of nephropathy, particularly nephropathy caused by diabetes; and related factors useful for assessing the risk of retinopathy, particularly retinopathy caused by diabetes Clarified, arteriosclerotic disease-related gene polymorphism set, myocardial infarction-related gene polymorphism set, nephropathy-related gene polymorphism set, and retina This is provided as a disease-related gene polymorphism set.
  • the disease risk determination method, disease risk determination array, disease-related gene marker, or disease-related gene polymorphism analysis kit provided by the present invention is an arteriosclerotic disease, myocardial infarction, nephropathy, or retina. This is useful for the assessment of the risk of illness.
  • the predicted value of the future disease level is calculated using a radar chart, a disease prediction graph, and a bubble chart. It can be presented visually and easily. Therefore, the subject's own awareness can be promoted, motivation can be improved, and diagnosis and treatment by doctors and nurses can be made efficient and effective.
  • the environmental factor test results have been selected.
  • the value of the term related to the environmental factor in the disease risk judgment formula taking into account the genetic factor can be used to present the necessity of coping. Therefore, according to the present invention, it is possible to present the necessity of treatment even when the environmental factor test results are within the range where treatment is not required and treatment is not performed conventionally. Therefore, it is possible to provide a tailor-made environment where patients can receive appropriate treatment.
  • the powerful technique of the present invention can be similarly applied to arteriosclerotic diseases, myocardial infarction, nephropathy, and other diseases other than retinopathy as exemplified in the present specification.
  • the present invention can be similarly applied to cerebral infarction, diabetic neuropathy, etc. caused by diabetes.
  • FIG. 1-A A table showing gene polymorphism sets having a positive association with arteriosclerotic diseases caused by diabetes.
  • FIG. 1-B is a table showing a set of gene polymorphisms that have a negative association with arteriosclerosis caused by diabetes.
  • FIG. 2-A is a table showing a set of gene polymorphisms that have a positive association with myocardial infarction caused by diabetes.
  • FIG. 2-B is a table showing a set of gene polymorphisms that have a negative association with myocardial infarction caused by diabetes.
  • FIG. 3-A A table showing a set of gene polymorphisms that have a positive association with nephropathy caused by diabetes.
  • FIG. 3-B is a table showing a set of gene polymorphisms that have a negative association with diabetes caused by diabetes.
  • FIG. 4-A A table showing a set of gene polymorphisms positively associated with retinopathy caused by diabetes.
  • FIG. 4-B A table showing a set of gene polymorphisms that have a positive association with retinopathy caused by diabetes.
  • FIG. 4-C A table showing a set of gene polymorphisms negatively associated with retinopathy caused by diabetes.
  • FIG. 5-A A table summarizing genetic polymorphisms related to arteriosclerotic diseases, myocardial infarction, nephropathy or retinopathy caused by diabetes, and the polymorphic sites.
  • FIG. 5-B A table summarizing genetic polymorphisms related to arteriosclerotic diseases, myocardial infarction, nephropathy or retinopathy caused by diabetes, and the polymorphic sites.
  • FIG. 5-C A table summarizing gene polymorphisms associated with arteriosclerotic diseases, myocardial infarction, nephropathy or retinopathy caused by diabetes, and the polymorphic sites.
  • SNP-No. a common gene polymorphism number (SNP-No.) Is used throughout FIGS. In other words, in FIGS. 1 to 5, if the SNP-No. Is the same, it means that the polymorphism is the same.
  • FIG. 6 shows a method for determining a genetic polymorphism for disease risk determination according to an embodiment of the present invention. It is a flowchart.
  • FIG. 7 is a block diagram showing the entire system including the disease risk determination apparatus according to the embodiment of the present invention.
  • FIG. 8 is a flowchart showing risk determination processing performed by the disease risk determination apparatus according to the embodiment of the present invention.
  • FIG. 9 is a table showing an example of the degree of disease related to nephropathy.
  • FIG. 10 is a table showing an example of the degree of disease related to retinopathy.
  • FIG. 15 is a diagram showing a bubble chart created by the onset prediction presenting function according to the embodiment of the present invention.
  • FIG. 16 A table showing an example of criteria used to determine the size of a circle in a bubble chart.
  • FIG. 18 is a table showing an example of a set of gene polymorphisms that can be used to determine the risk of myocardial infarction caused by diabetes.
  • FIG. 19 is a table showing an example of a gene polymorphism set that can be used to determine the risk of nephropathy caused by diabetes.
  • FIG. 20 is a table showing an example of a set of genetic polymorphisms that can be used to determine the risk of retinopathy caused by diabetes.
  • FIG. 21 is a graph showing differences in disease risk judgment formulas depending on subjects.
  • FIG. 22 is a flowchart showing a method for determining the necessity of coping with a disease according to an embodiment of the present invention.
  • FIG. 1 is composed of two diagrams indicated by branch numbers “FIG. 1-A” and subsequent “FIG. 1-B”.
  • branch numbers FIG. 1
  • FIG. 1 B the simple reference to “FIG. 1” refers to both “FIG. 1 A” and “FIG. 1 B”.
  • FIG. 1 the same applies to items including a plurality of diagrams indicated by branch numbers other than those in FIG.
  • Gene polymorphism refers to the diversity of genes in which two or more allelic genes (alleles) exist at one locus in the same population. Specifically, it indicates a mutation in a gene that exists at a certain frequency in a certain population.
  • the gene mutations mentioned here are not limited to the region transcribed as RNA, but the promoter, It includes mutations in all DNAs that can be identified on the human genome, including the regulatory regions. 99.9% of human genomic DNA is common among individuals, and the remaining 0.1% is responsible for this diversity and is involved in individual differences in susceptibility to specific diseases, responsiveness to drugs and environmental factors. obtain. Even if there is a genetic polymorphism, the phenotype does not necessarily differ.
  • SNP base polymorphism
  • SNP base polymorphism
  • “1” is a polymorphic homology having a base that precedes the bases in alphabetical order (A, C, G, T) among the substituted bases.
  • “2” represents heterogeneity
  • “3” represents a polymorphism homozygote having a base that follows in alphabetical order of the substitution bases.
  • the genetic polymorphism is shown as ABCAKG1051A) (SNP-No “SNP- ⁇ .1” in Fig. 5)
  • GZG homozygous is genotype 1
  • heterozygous (GZA) is genotype 2
  • homozygous of ⁇ Is called gene type 3.
  • “12” represents the genotypes of both the genotypes 1 and 2
  • “23” represents the genotypes of both the 2 and 3 genotypes.
  • the "gene polymorphism set” refers to a combination of a plurality of gene polymorphisms.
  • a plurality of gene polymorphisms means two or more gene polymorphisms having different loci.
  • gene polymorphism here refers to and includes genotypes. That is, in the present invention, “gene polymorphism” means a gene polymorphism having a specific genotype.
  • the "gene polymorphism set” is particularly a "gene polymorphism combination” that is related to the target disease as an entire combination! Uh.
  • An example of such a gene polymorphism set (combination) Figure 1 and Figure 17 [Group of gene polymorphism sets that are related to arteriosclerotic disease caused by diabetes], Figure 2 and Figure 18 (Groups of gene polymorphism sets showing relevance for heart muscle infarction caused by diabetes), Fig. 3 and Fig. 19 (Groups of gene polymorphism sets showing relevance for nephropathy caused by diabetes) FIG. 4 and FIG. 20 [Group of gene polymorphism sets showing relevance for retinopathy caused by diabetes].
  • gene polymorphism set groups show a positive (susceptibility) association between gene polymorphism sets (positive t value) and a negative (resistance) association with the target disease. Both gene polymorphism sets (t value negative) are included. That is, in each of these figures, each row (one horizontal column) As a result, a combination of genetic polymorphisms (SNPs) showing a positive or negative association with the disease is shown. In Figs. 1 to 4 and Figs. 18 to 20, two or three gene polymorphisms are shown in one line! There is a case.
  • the gene polymorphism alone is an arteriosclerotic disease caused by diabetes ( Figures 1 and 17), myocardial infarction ( Figures 2 and 18), nephropathy ( Figures 3 and 19), or retinopathy. It can be said that it is a gene polymorphism showing a positive or negative association with ( Figures 4 and 20).
  • the single gene polymorphism is also described as a “gene polymorphism set” in order to avoid complicated explanation.
  • each row of the figure describes a set of gene polymorphisms that are positively or negatively related to an index of arteriosclerotic disease.
  • alycoprotein la (C807T) j Glycoprotein la gene: SNP-No.51 (Genotype: 23) and“ VEGF (C— 634G) "(VEGF gene: SNP-No. 73) (Genotype: 3) is described.
  • Glycoprotein la (C807T) j (SNP-No. 51) contains an allele that is at position 807 or T (see Fig. 5-A).
  • VEGF (C- 63 4G) J SNP-No.73 has an allele whose position -634 is C or G (see Fig. 5-A).
  • genotype 3 GZG of the gene polymorphism of “VEGF (C-634G” is described.Therefore, considering the combination of genotypes of these two gene polymorphisms, C Two types of gene polymorphisms are described, the combination (set) of / T (glycoprotein la) and GZG (VEGF), and the combination (set) of T / T (glycoprotein la) and GZG (VEGF). Clearly, C Two types of gene polymorphisms are described, the combination (set) of / T (glycoprotein la) and GZG (VEGF), and the combination (set) of T / T (glycoprotein la) and GZG (VEGF). Become.
  • Atherosclerotic disease broadly includes ischemic disease, such as angina pectoris, myocardial infarction, brain Infarctions and peripheral arterial occlusion are included.
  • the arteriosclerotic disease targeted by the present invention is an arteriosclerotic disease that develops in particular due to glucoseuria.
  • Atherosclerotic disease risk is an index representing the ease of onset and progression of the arteriosclerotic disease.
  • Myocardial infarction is a type of the above-mentioned arteriosclerotic diseases.
  • Myocardial infarction risk refers to myocardial infarction among arteriosclerotic diseases, and its ease of onset and progression. It is an index that represents.
  • Nephropathy and retinopathy targeted by the present invention are nephropathy and retinopathy that develops due to diabetes.
  • “Nephropathy risk” is an index indicating the likelihood of developing nephropathy due to diabetes and the progression of retinopathy.
  • “Retinopathy risk” is the likelihood of developing retinopathy due to diabetes. It is an index representing the ease of progress.
  • the method for determining a genetic polymorphism for determining a disease risk is used to determine how easily a subject suffers from a disease !, or how easily a disease progresses, and determines a disease (risk risk).
  • a method for determining a genetic polymorphism for determining a disease risk to be used.
  • an arteriosclerotic disease will be described as an example, but the present invention is not limited to this, and can be applied to a disease having an association with a gene.
  • the determination index according to the disease for example, carotid intima-media complex thickness for arteriosclerotic disease, urinary albumin excretion rate for nephropathy, ECG for myocardial infarction
  • the relevance described below may be evaluated (for example, edited by Japan Diabetes Society) Diabetes Treatment Guide 20 04—2005, Bunkodo).
  • the method for determining a genetic polymorphism for determining the risk of arteriosclerotic disease according to the present invention will be described with reference to the flowchart shown in FIG.
  • the processing here is described as being performed using a computer equipped with a CPU, memory, recording device (eg, hard disk), operation device (eg, keyboard, mouse), display device (eg, CRT display), and the like.
  • the processing target data is input from the operation device or the like and recorded in the recording device.
  • the CPU executes each process using the memory as a work area, and the intermediate result of the process is the maximum.
  • the final result is recorded in a predetermined area of the recording unit as necessary.
  • FIG. 5 lists 133 gene polymorphisms selected from experience among about 200 gene polymorphisms obtained from various documents (detailed explanation of FIG. 5 will be described later). .
  • the flowchart shown in FIG. 6 is performed using a predetermined number of gene polymorphisms selected by the above-described preliminary selection.
  • the degree of carotid arterial sclerosis is used as an index for determining arteriosclerotic diseases, and the relationship between this and genetic polymorphism is statistically analyzed.
  • the method for measuring the strength of carotid artery thickening is not particularly limited, but measurement of carotid intima-media complex thickness (IMT) using an ultrasonic tomograph is common. This method is a non-invasive and quantitative measurement method for measuring the thickness of the carotid artery that can be reached ultrasonically. It is desirable to use an ultrasonic tomography apparatus having a linear pulse echo probe with a center frequency of 7.5 MHz or higher. Since the extracranial carotid artery is located in the subcutaneous layer, a frequency of 7.5 MHz or higher can be used, and high resolution (distance resolution 0.1 mm) can be obtained. However, this is an example.
  • the blood vessel wall is analyzed on an echo image as a two-layer structure of a low echo luminance portion of one layer on the side of the blood vessel lumen and a high echo luminance layer on the other side.
  • the present inventor confirmed from the observation of 104 healthy cases that the IMT of the common carotid artery increased almost linearly with age from the 10s to the 70s, and the thickness did not exceed 1. Omm. is doing.
  • the common carotid artery IMT in healthy individuals is determined by age as follows:
  • IMT 0.008 X Age + 0.3 (3 ⁇ Age ⁇ 80)
  • Age is the age (in years).
  • I is a disease determination index of each person who is a constituent element of the population. It is assumed that the MT value and the genetic polymorphism (having the genotype, the same applies hereinafter) possessed by each person are associated and recorded as data to be analyzed.
  • the data to be analyzed is recorded in the form of ⁇ personal ID, IMT value, multiple gene polymorphisms ⁇ using, for example, the personal ID assigned to each person.
  • step S1 an upper limit value kmax of the counter of the iterative process used in the processes after step S2 is set, and 1 is set as an initial value in counter k.
  • k is the number of gene polymorphisms combined, and kmax is the upper limit.
  • kmax 3 is set.
  • step S2 k gene polymorphisms having a genotype are selected from the preselected gene polymorphisms and set as one set.
  • a disease determination index for the set of analyzed data including the set selected in step S2 and its complement A t-test on the value determined according to the above (hereinafter referred to as “disease degree”) is performed to determine the significance of the set.
  • the disease determination index value itself may be used as the disease degree.
  • the IMT value as the determination index is used as the disease degree. That is, using the IMT measurement value (disease degree), calculate the t value (t) and the significance level (risk rate) P corresponding to t, where P is the predetermined significance level cal cal cal cal cal cal cal cal
  • step S5 it is determined whether or not the processing of steps S2 to S4 has been completed for all sets having k gene polymorphisms, and the processing of steps S2 to S4 is repeated until the processing is completed.
  • the gene polymorphism set for determining the risk of arteriosclerosis shown in FIG. 1 was obtained.
  • the t value shown in the rightmost column of the table is the t value of each set (the same applies to Figs. 2 to 4).
  • a t test may be performed only when a predetermined condition is satisfied. For example, Odds (odds ratio) and Kai (chi-square value) are calculated for the set specified in step S2, and Odds and Kai are determined according to predetermined conditions (for example, Odds ⁇ 2 and Kai ⁇ 3.8, Alternatively, it may be determined whether or not Odds ⁇ 0.5 and Kai ⁇ 3.8), and only when this condition is satisfied, the process proceeds to step S4 and a t-test may be performed.
  • the number of & 36 cases is calculated as 7 times 0 1 "01.
  • the average value of IMT of healthy subjects is different from IMT.
  • ⁇ ⁇ ⁇ — ⁇ force ⁇ ⁇ 0.2 If it is, then Case, and if ⁇ ⁇ ⁇ 0.2, it will be Control.
  • the calculation method of Odds is described in the literature (Yamada Y, Izawa H, Ichihara S, Takatsu F, Ishihara H, Hirayama H, Sone T, Tana ka M, Yokota M.
  • step S3 A significant set may be determined by performing a t-test on all sets.
  • the carotid intima-media thickness is used as an index indicating the degree of carotid sclerosis.
  • the index indicating the degree of sclerosis of the carotid artery includes the maximum IMT (Max—IMT) that represents the maximum value of IMT, and the average IMT that represents the average value of IMT. (AvglMT), plaque score (PS), carotid stiffness, etc.
  • Max—IMT the maximum IMT
  • AvglMT plaque score
  • PS plaque score
  • carotid stiffness etc.
  • Max-IMT The maximum intima-media thickness in the longitudinal, lateral, and posterior longitudinal images is Max-IMT, and the central 1cm and the distal 1cm are centered on the site showing the Max-IMT.
  • AvglMT is the average of the three points; left and right common carotid (CC) force carotid bifurcation, internal carotid (internal carotid: IC) 3 longitudinal cross-section proximal wall to the skin (near wall ) And the distal wall (far wall) in total 12 thicknesses, the maximum value is AvglMT; and the left and right average thickness is AvglMT.
  • CC common carotid
  • IC internal carotid
  • the maximum value is AvglMT
  • the left and right average thickness is AvglMT.
  • the average thickness of a certain section of the far wall is defined as mean IMT.
  • the thickness of the far wall 10 mm from the central side of the bifurcation of the carotid artery on the one side is used as the target.
  • the plaque score is the sum of both the left and right carotid arteries with a plaque thickness of 1.1 mm or more at each site, with the carotid artery divided into four sections each 15 mm from the bifurcation. Also, The total number of plaques (IMT of 1.1 cm or more) in each of the above 3 to 4 sections can be called a plaque number (PN) and used as an index.
  • the carotid artery stiffness is a numerical value measured from the diameter of the carotid artery during systole and diastole.
  • the method using the thickening of the far wall 10mm central from the bifurcation of one carotid artery as an index is easy to measure, and it is said that the measurement error is small because there are few lesions in the common carotid artery.
  • IMT is an index indicating the largest lesion of the carotid artery.
  • PS can show the whole image of the carotid artery where arteriosclerosis has progressed, but in non-progressive cases (thickness is less than 1.1 mm), it is disadvantageous in that it becomes 0, etc. Different indicators are different. In cases with diabetes or hyperlipidemia, the carotid wall is often thickened relatively uniformly. AvglMT and mean IMT are important indicators. PS, PN and Max—IMT can be useful indicators.
  • ⁇ IMT average IMT increment
  • ⁇ PIMT maximum IMT increment
  • ⁇ is a particularly preferable index as a comprehensive expression of the risk of arteriosclerotic disease.
  • ⁇ is positioned as a clinical finding that is closely related to arteriosclerotic disease, and the method using it can determine the risk of arteriosclerotic disease very effectively.
  • the increased amount of carotid intima-media complex thickness can be used as it is to evaluate the risk of arteriosclerotic disease, but the increased amount of carotid intima-media complex thickness Therefore, it may be used for the evaluation using a function as appropriate.
  • the amount of increase in carotid intima-media thickness was calculated by the multiple regression analysis method based on the threshold value or threshold value measured from the population. It can be expressed by a coefficient.
  • the urinary albumin excretion rate g / mg'Cr is used as a disease determination index, the case or control determination based on the criteria shown in FIG. 9, and the disease degree used in the t-test To decide.
  • retinopathy the criteria shown in Fig. 10 are used to determine the degree of disease to be used in Case or Control judgment and t-test.
  • the gene polymorphism sets for disease risk determination for each disease are shown in Figs.
  • the table shown in Fig. 4 was obtained.
  • another disease risk determination gene polymorphism set can be determined using a positive t value.
  • a gene polymorphism set for determining the disease risk of arteriosclerotic disease, myocardial infarction, nephropathy, and retinopathy Fig. 17 to Fig. 20 respectively.
  • the gene polymorphism set shown in was obtained.
  • the present invention provides an array for determining a disease risk, which is used to determine the ease of disease progression and the ease of progression (disease risk) for a subject based on a genetic polymorphism possessed by the subject.
  • probes for detecting a gene polymorphism to be formed are aligned at high density and fixed on a support such as a silicon wafer or a glass slide.
  • the probe may be any probe that specifically recognizes and captures a gene polymorphism associated with a specific disease.
  • a probe having a base sequence corresponding to a gene polymorphism or a base sequence that is a part or all of a complementary sequence thereof can be mentioned.
  • the present invention particularly relates to an array for determining the risk of arteriosclerosis caused by diabetes, an array for determining the risk of myocardial infarction resulting from diabetes, and an array for determining the risk of nephropathy resulting from diabetes. And an array for determining the risk of retinopathy due to diabetes.
  • the arteriosclerotic disease risk determination array of the present invention can be used to determine the ease of developing an arteriosclerotic disease (ease of onset) and the ease of progression. Preferably, it can be used to determine the risk of arteriosclerotic disease in a subject with diabetes or its tendency.
  • the arteriosclerotic disease risk determination array of the present invention has a significant positive (susceptibility) relationship with the carotid intima-media thickness (IMT), which is a determination index for arteriosclerotic diseases.
  • IMT carotid intima-media thickness
  • Detection probes for gene polymorphisms that make up a positive (susceptible) gene polymorphism set and a negative (resistance) gene polymorphism set that has a significant negative (resistance) association
  • a probe for detecting a polymorphism of the gene is determined by the method for determining a genetic polymorphism for disease risk determination described in (1) above.
  • the t-value force shown in the explanation in can also be judged. In other words, it can be determined that there is a “negative relevance” when the t value is negative, and conversely when the t value is positive, there is a “positive relevance”.
  • the gene polymorphism set shown in FIG. 1 and FIG. 17 As a “gene polymorphism set” having a significant association with strenuous arteriosclerotic disease, Examples of the gene polymorphism set shown in FIG. 1 and FIG. More specifically, in FIG. 1 and FIG. 17, the combined force of gene polymorphisms (SNPs) listed in each row (one horizontal column) means one “gene polymorphism set significantly related to arteriosclerotic disease”.
  • the gene polymorphism set having a positive t value shown in FIGS. 1A and 17 is a “positive (susceptibility) gene polymorphism set for arteriosclerotic disease”, and the t value shown in FIG. 1B is A gene polymorphism set that is negative means “a negative (resistance) gene polymorphism set for arteriosclerotic disease”.
  • gene polymorphism means a gene polymorphism including a genotype, that is, a gene polymorphism having a specific genotype, as described above.
  • the gene polymorphism is shown as “GENE (abbreviation)” and the genotype is shown as “Genotype”. Detailed information on each gene polymorphism is shown in Figure 5.
  • the arteriosclerotic disease risk determination array of the present invention is a gene comprising at least one gene polymorphism set selected from the group power consisting of the gene polymorphism sets described in FIG. 1 and FIG. It has a probe for detecting polymorphism.
  • the selection of a gene polymorphism set is not particularly limited and can be arbitrarily performed. At that time, the t value described for each gene polymorphism set in each figure is used as an index.
  • the arteriosclerotic disease risk determination array of the present invention is a gene polymorphism that constitutes a gene polymorphism set highly related to IMT (that is, arteriosclerotic disease), as evaluated from such t values. It is preferable to provide a detection probe for IMT (that is, arteriosclerotic disease), as evaluated from such t values. It is preferable to provide a detection probe for IMT (that is, arteriosclerotic disease), as evaluated from such t values. It is preferable to provide a detection probe for
  • the forward force with a large I) is selected with priority.
  • the arteriosclerotic disease risk determination array of the present invention comprises a detection probe for a gene polymorphism constituting a positive (susceptibility) gene polymorphism set and a negative (resistance) gene polymorphism set. It is preferable to have both detection probes for the gene polymorphisms that constitute.
  • the arteriosclerotic disease risk determination array of the present invention may have detection probes for 133 gene polymorphisms shown in FIG. 5 as detection probes.
  • the arteriosclerotic disease risk determination array of the present invention can be used to evaluate the sensitivity and resistance to arteriosclerotic disease for a subject. Specifically, for example, the detection probe on the array and the probe prepared from the test sample are hybridized, and the gene polymorphism detected for the subject is corrected with the IMT, which is an index for determining arteriosclerotic disease. It can be carried out by collating with a gene polymorphism set having a negative association with IMT and a gene polymorphism set having a negative association with IMT.
  • Information obtained at this time can be used to assess a subject's susceptibility and resistance to arteriosclerotic disease.
  • the arteriosclerotic disease risk determination array of the present invention is used to evaluate the presence or absence of a risk for an arteriosclerotic disease and the level (existence and degree of progression). Can be used for This is because, for example, a detection probe on the array is hybridized with a probe whose test sample force is also prepared, the detected gene polymorphism is collated with a set of gene polymorphisms related to IMT, and the collation result has a predetermined result. It can be implemented by applying the judgment formula. Details on how to determine the risk of a disease are given below.
  • the myocardial infarction risk determination array according to the present invention can be used to determine the ease with which a myocardial infarction is applied (the likelihood of onset) and the ease with which it progresses. Preferably, it is used to determine the risk of myocardial infarction for diabetics or borderline diabetics. You can.
  • the myocardial infarction risk determination array of the present invention is a gene polymorphism that constitutes a “positive (susceptibility) gene polymorphism set” having a significant positive (susceptibility) relationship with a myocardial infarction determination index.
  • a detection probe for a gene polymorphism constituting a “negative (resistance) gene polymorphism set” having a negative (resistance) relationship is not particularly limited as long as it is conventionally used in the industry, but preferably, there is an old myocardial infarction wavelength (abnorma 1 Q) observed on an electrocardiogram. Alternatively, a history of myocardial infarction for the subject can be used.
  • t Value power can be judged. That is, it can be determined that there is a “positive relevance” when the t value is positive, and conversely when the t value is negative, there is a “negative relevance”.
  • the "gene polymorphism set” having a significant association with a strong myocardial infarction can include the gene polymorphism sets listed in Figs. More specifically, in FIG. 2 and FIG. 18, the combined power of gene polymorphisms (SNPs) listed in each row (one horizontal column) means one “gene polymorphism set significantly associated with myocardial infarction”.
  • the gene polymorphism set with positive t values shown in Fig. 2-A and Fig. 18 is the "positive (susceptibility) gene polymorphism set for myocardial infarction", and the t value shown in Fig. 2-B is negative. This means that the gene polymorphism set is “negative (resistance) gene polymorphism set for myocardial infarction”.
  • the myocardial infarction risk determination array of the present invention is a gene that constitutes at least one gene polymorphism set selected from the group power consisting of the gene polymorphism sets described in FIG. 2 and FIG. It has a probe for detecting polymorphism.
  • the selection of a gene polymorphism set is not particularly limited and can be arbitrarily performed. In this case, the t value described for each gene polymorphism set in FIGS. 2 and 18 can be used as an index.
  • the myocardial infarction risk determination array includes a detection probe for a gene polymorphism that constitutes a gene polymorphism set that is highly relevant to a myocardial infarction determination index by evaluating a powerful t-value force. I prefer that.
  • the myocardial infarction risk determination array of the present invention comprises a detection probe for a gene polymorphism constituting a positive (susceptibility) gene polymorphism set and a gene constituting a negative (resistance) gene polymorphism set. It is preferable to have both detection probes for polymorphism.
  • the present inventor is also useful for determining the risk of myocardial infarction, in particular, myocardial infarction caused by diabetes, and the gene polymorphism shown in Fig. 5 is useful. From the above, it was confirmed that the risk of myocardial infarction can be determined with high accuracy. Therefore, the myocardial infarction risk determination array of the present invention can also have detection probes for 133 gene polymorphisms shown in FIG. 5 as detection probes.
  • the myocardial infarction risk determination array of the present invention can be used for evaluating the resistance (hardness) to myocardial infarction for a subject, and for the subject to resistance to myocardial infarction and Can be used to assess susceptibility (susceptibility). Furthermore, the myocardial infarction risk determination array of the present invention can be used to evaluate the presence or absence of the risk of myocardial infarction and its level (presence or absence and degree of progression).
  • the risk of myocardial infarction can be determined by the same method as the above-described method for determining the risk of myocardial infarction.
  • the array for determining the risk of nephropathy of the present invention can be used to determine how easily diabetic nephropathy is likely to be exerted (easy to develop) or easily progress. Preferably, it can be used to determine the risk of nephropathy for diabetics or borderline diabetics.
  • the array for determining the risk of nephropathy of the present invention relates to gene polymorphisms constituting a “positive (susceptibility) gene polymorphism set” having a significant positive (sensitivity) relationship with a nephropathy determination index. It has a detection probe and a detection probe for a gene polymorphism constituting a “negative (resistance) gene polymorphism set” having a negative (resistance) relationship.
  • the index for determining nephropathy is not particularly limited as long as it is commonly used in the art, and preferably the urinary albumin excretion rate g / mg′Cr) can be used.
  • Whether the genetic polymorphism set has a “positive association” or “negative association” for nephropathy is shown in the explanation in the determination method in (1) above.
  • the t-value force can also be judged. That is, it can be determined that there is a “positive relevance” when the t value is positive, and conversely when the t value is negative, there is a “negative relevance”.
  • the “gene polymorphism set” having a significant association with striking nephropathy include the gene polymorphism sets shown in FIG. 3 and FIG. More specifically, in FIG. 3 and FIG. 19, it means “a set of gene polymorphisms significantly associated with nephropathy”, which is a combination of gene polymorphisms (SNPs) listed in each row (one horizontal column).
  • the gene polymorphism set with positive t values shown in Fig. 3-A and Fig. 19 is the "positive (susceptibility) gene polymorphism set for nephropathy", and the t value shown in Fig. 3-B is negative.
  • a gene polymorphism set means “a negative (resistance) gene polymorphism set for nephropathy”.
  • the array for determining the risk of nephropathy of the present invention comprises gene polymorphisms constituting at least one gene polymorphism set selected from the group consisting of gene polymorphism sets described in FIG. 3 and FIG. Has a probe for detection.
  • the ability to select a gene polymorphism set is not particularly limited and can be arbitrarily performed.
  • the t value described for each gene polymorphism set in FIGS. 3 and 19 can be used as an index.
  • the array for determining the risk of nephropathy of the present invention includes a detection probe for a gene polymorphism that constitutes a gene polymorphism set that is highly relevant to nephropathy by evaluating a powerful t-value force. Is preferred.
  • the nephropathy risk determination array of the present invention comprises a detection probe for a gene polymorphism set that constitutes a positive (susceptibility) gene polymorphism set and a negative (resistance) gene polymorphism set. It is preferable to have both detection probes for gene polymorphism.
  • the present inventor uses the gene polymorphism shown in Fig. 5 for the determination of the risk of nephropathy, particularly nephropathy due to diabetes, and uses the gene polymorphism to be effective alone or in combination. This confirmed that the risk of nephropathy can be determined with high accuracy. Therefore, the nephropathy risk determination array of the present invention may have detection probes for 133 gene polymorphisms shown in FIG. 5 as detection probes.
  • the nephropathy risk determination array of the present invention can be used for evaluating resistance to nephropathy for a subject, and also for nephropathy for a subject. Can be used to assess resistance and sensitivity (easy to apply). Furthermore, the nephropathy risk determination array of the present invention can be used to evaluate the risk of nephropathy in a subject and its level (presence / absence and degree of progression).
  • Determination of nephropathy can be performed by the same method as the above-described risk determination method for nephropathy.
  • the array for determining the risk of retinopathy of the present invention can be used to determine the likelihood of developing retinopathy (ease of onset) and the ease of progression. Preferably, it can be used to determine the risk of retinopathy for diabetics or borderline diabetics.
  • the array for determining the risk of retinopathy of the present invention comprises a gene constituting a “positive (susceptibility) gene polymorphism set” having a significant positive (susceptibility) relationship with a retinopathy determination index.
  • a detection probe for a polymorphism and a detection probe for a gene polymorphism constituting a “negative (resistance) gene polymorphism set” having a negative (resistance) relationship are included.
  • the determination index of retinopathy is not particularly limited as long as it is commonly used in the industry, but preferably clinical findings (normal, simple retinopathy, preproliferative retinopathy, proliferative retinopathy) ) Can be used as a determination index.
  • t Value power can be judged. In other words, it can be determined that there is a “positive relevance” when the t value is positive, and conversely when there is a negative t value, there is a “negative relevance”.
  • Specific examples of the "gene polymorphism set" that has a significant relationship with active retinopathy include the gene polymorphism sets listed in Figs. More specifically, in FIG. 4 and FIG.
  • the gene polymorphism sets with positive t values shown in FIG. 4A, FIG. 4B and FIG. 20 are “positive (susceptibility) gene polymorphism sets for retinopathy”, and the t values shown in FIG.
  • a negative polymorphism set means a negative (resistance) polymorphism set for retinopathy.
  • the array for determining the risk of retinopathy of the present invention is a gene polymorphism constituting at least one gene polymorphism set selected from the group consisting of gene polymorphism sets described in FIG. 4 and FIG. It has a detection probe for the mold.
  • the selection of gene polymorphism sets is not particularly limited and can be performed arbitrarily.
  • the t value described for each gene polymorphism set in FIGS. 4 and 20 can be used as an index.
  • the array for determining the risk of retinopathy of the present invention includes a probe for detecting a gene polymorphism that constitutes a gene polymorphism set that is highly relevant to retinopathy by evaluating a powerful t-value force. Is preferred.
  • the retinopathy risk determination array of the present invention comprises a detection probe for a gene polymorphism constituting a positive (susceptibility) gene polymorphism set and a gene constituting a negative (resistance) gene polymorphism set. It is preferable to have both detection probes for polymorphism.
  • the present inventor is also useful for determining the risk of retinopathy, in particular, retinopathy caused by diabetes, and the gene polymorphism shown in Fig. 5 is useful. It was confirmed that the risk of retinopathy can be determined with high accuracy. Therefore, the retinopathy risk determination array according to the present invention may have detection probes for 133 gene polymorphisms shown in FIG. 5 as detection probes.
  • the retinopathy risk degree determination array of the present invention is used for evaluating the resistance (reluctance) to retinopathy for a subject, similarly to the above-described atherosclerotic disease risk determination array. It can also be used to assess resistance and susceptibility (susceptibility) to retinopathy for a subject. Furthermore, the retinopathy risk determination array of the present invention should be used to evaluate the presence or absence of retinopathy and the level (existence and degree of ease of force and progression) of the subject. Is possible.
  • the determination of the risk of retinopathy can be performed by the same method as the method of determining the risk of retinopathy described above.
  • the disease risk determination array of the present invention described above has a probe other than the above within the scope of achieving the object of the present invention as long as it has a gene polymorphism detection probe corresponding to each disease. Or you may have a well-known probe suitably. In addition, the gene polymorphism detection probe may be appropriately labeled and used.
  • the disease determination array of the present invention can be prepared by a method of Affimetrix, which is synthesized on a base material in addition to a method of fixing a probe prepared on the base material.
  • a method of Affimetrix which is synthesized on a base material in addition to a method of fixing a probe prepared on the base material.
  • the substrate on which the probe is fixed there are no particular restrictions on the substrate on which the probe is fixed, and known materials such as a glass plate and a filter can be used.
  • the length of the probe to be immobilized and the type of nucleic acid to be used are not particularly limited as long as the gene polymorphism can be detected. It is desirable to amplify the region containing the gene polymorphism by PCR in advance.
  • the method of amplifying a region containing a gene polymorphism using a labeled primer can also preferably use points such as sensitivity and simplicity.
  • a region containing a gene polymorphism is amplified using a primer labeled with piotin, this is added to an array and hybridized, and then nucleic acid that has not been hybridized is washed. Excluded. Subsequently, the hybridized probe is detected with an avidin-labeled fluorescent dye.
  • gene polymorphism can be detected with high sensitivity.
  • the array for disease determination of the present invention includes the following embodiments:
  • the group power consisting of the gene polymorphism set described in Fig. 1 and Fig. 17 is also selected at least.
  • (B) Genes constituting a gene polymorphism set of more than half of the group consisting of the gene polymorphism set described in Fig. 1-A and Fig. 17 or the group consisting of the gene polymorphism set described in Fig. 1-B
  • (C) Myocardial infarction risk determination having a detection probe for a gene polymorphism constituting at least one gene polymorphism set in which the group power consisting of the gene polymorphism set described in FIG. 2 and FIG. 18 is also selected Array.
  • (D) Genes constituting the gene polymorphism set of more than half of the group consisting of the gene polymorphism set described in Fig. 2-A and Fig. 18 or the group consisting of the gene polymorphism set described in Fig. 2-B
  • Test specimen strength is also hybridized with the prepared probe and detected for the subject.
  • the detected polymorphisms are compared with the gene polymorphism sets that are significantly related to arteriosclerotic diseases, and the detected gene polymorphism sets!
  • the test sample force is also hybridized with the prepared probe, the gene polymorphism detected for the subject is compared with the gene polymorphism set significantly related to myocardial infarction, and the detected gene polymorphism set against myocardial infarction
  • test polymorphism is also hybridized with the prepared probe, and the gene polymorphism detected for the subject is compared with the gene polymorphism set significantly related to diabetic nephropathy, and the detected gene polymorphism
  • the test sample force is also hybridized with the prepared probe, and the gene polymorphism detected for the subject is matched with a gene polymorphism set significantly related to diabetic retinopathy to detect the detected gene polymorphism.
  • the determination apparatus, determination program, and determination method of the disease risk according to the present invention determine the degree of the subject's strength S, how easily the disease is affected, or how easily the disease progresses, and the determination of the disease (disease risk). Is to do.
  • an arteriosclerotic disease will be described as an example, but the present invention is not limited to this, and can be applied to a disease associated with a gene.
  • FIG. 7 shows an atherosclerotic disease risk determination device (hereinafter referred to as a determination device) according to the present invention. It is a block diagram which shows the whole system including. The configuration shown in FIG.
  • FIG. 7 is the same as the configuration disclosed in Patent Document 2. As shown in Fig. 7, blood collection means 11 and computer 12 installed in hospital 1, gene polymorphism analysis array 21 and computer 22 installed in analysis facility 2, and judgment installed in service provider 3 Device 31. Here, the computers 11 and 21 and the determination device 31 are connected to a communication line 4 such as the Internet.
  • the determination device 31 includes a CPU 32, a memory 33, a recording unit 34 such as a hard disk, a communication interface (hereinafter referred to as IZF) unit 35 for communication with the outside, an operation unit 36 such as a keyboard, A display unit 37 such as a CRT display, an input / output IZF unit 38, and an internal bus 39 for exchanging data between each unit are provided.
  • IZF communication interface
  • a display unit 37 such as a CRT display
  • an input / output IZF unit 38 an internal bus 39 for exchanging data between each unit are provided.
  • information on the genetic polymorphism set for determining disease risk is recorded as a reference table.
  • the reference table for each of arteriosclerotic disease, myocardial infarction, nephropathy, and retinopathy uses 133 gene polymorphisms, and the above-mentioned gene polymorphism for disease risk determination is used. This corresponds to the gene polymorphism set for disease risk determination shown in Figs.
  • the present invention uses a judgment formula determined by performing multiple regression analysis using environmental factors in addition to a gene polymorphism set for disease risk judgment. Thereby, the evaluation accuracy of the disease risk can be improved.
  • the details of the risk determination processing by the determination device 31 will be described later.
  • the overall operation of the system is the same as that disclosed in Patent Document 2, and the outline of the system is as follows.
  • the blood of the subject hereinafter referred to as a test sample
  • clinical data (subject ID, test value, medical history information, blood collection information, etc.) is recorded in the recording unit of the computer 12.
  • the test sample is provided to the analysis facility 2 and analyzed using the gene polymorphism analysis array 21 to detect a gene polymorphism having a genotype.
  • the array 21 for gene polymorphism analysis for example, the above-described array for determining the degree of risk of arteriosclerosis can be used.
  • the detected genetic polymorphism information is once recorded in the recording means of the computer 22, and then the service provider 3 via the communication line 4. It is transmitted to the judgment device 31.
  • the determination device 31 receives the genetic polymorphism information via the communication IZF unit 35 and records it in the recording unit 34. Further, the determination device 31 receives clinical data from the computer 12 and records it in the recording unit 34. Thereafter, the determination device 31 searches whether or not the received gene polymorphism is included in the reference table recorded in the recording unit 34 in advance, and the risk of arteriosclerotic disease is determined according to the result. Determine. Further, the determination device 31 transmits the determination result to the computer 12 of the hospital 1 via the communication line 4.
  • the determination result received by the computer 12 is recorded in the recording unit of the computer 12 in association with the clinical data (at least the subject ID), and is appropriately called and used (for example, presented to the subject).
  • Information specifying the computer 12 of the hospital 1 that transmits the determination result may be included in the clinical data from the computer 12 of the hospital 1 and transmitted.
  • any method can be used as long as it is a method for detecting the genotype of the subject.
  • a test sample containing DNA such as blood, sputum, skin, bronchoalveolar lavage fluid, other body fluids or tissues of the subject is used.
  • Many analysis methods are known, for example, sequencing method, PCR method, ASP-PCR method, TaqMan method, Invader Atsey method, MALDI-TOF ZMS method, molecular beacon method, ligation method, etc. (Clin. Chem. 43: 1114—1120, 1997).
  • the sequencing method is a method for directly sequencing a DNA region containing a gene polymorphism.
  • a specific gene polymorphism is specifically amplified using primers specific to the gene polymorphism.
  • Allele Specific Primer (ASP) The second gene from the 3' end as in the PCR method.
  • Primer design such as how to place a polymorphism in a primer, and what kind of nucleic acid sequence to put in addition to the gene to be detected There is no particular limitation as long as the gene polymorphism can be identified.
  • an allele-specific probe labeled at both ends with a fluorescent dye and a quenching substance is hybridized to the target site, and a PCR reaction is performed with primers designed to amplify the region containing this site.
  • Taq polymerase's 5 prime nuclease activity The fluorescent dye present at the 5 'end of the hybridized probe is cleaved and separated from the quencher to generate fluorescence. This technique shows how much the allele-specific probe was hybridized.
  • an allele probe that has a specific sequence 5 'from the ⁇ type gene polymorphic site and a flap sequence on the 3' side, and 3 'of the ⁇ ⁇ ⁇ type gene polymorphic site force.
  • an invader probe with a specific sequence on the other side and three oligonucleotides with a FRET probe containing a sequence complementary to the flap sequence, allele probes are hybridized on the same principle as the TaqMan method. Can be identified.
  • the MALDI-TOF / MS method a primer adjacent to the gene polymorphic site is prepared and amplified, and then only one base of the gene polymorphic site is amplified using ddNTP.
  • the polymorphism is identified by identifying the type of ddNTP attached.
  • DNA chip methods such as the Hybrigene method, an oligonucleotide probe containing a gene polymorphism is placed on the array, and hybridization with sample DNA amplified by PCR is detected. .
  • FIG. 8 is a flowchart showing the determination process performed by the determination device 31.
  • the risk determination processing by the determination device 31 will be specifically described with reference to the flowchart of FIG. In the following, it is described as processing performed by the CPU 32 unless otherwise specified.
  • the CPU 32 uses the memory 33 as a work area or an area for temporarily storing data in the middle of processing, and records data in the middle of processing and processing results in the recording unit 34 as necessary.
  • step S21 genetic polymorphism information is acquired from the analysis organization 2 via the communication line 4, and recorded in the recording unit 34.
  • a set of genetic polymorphism codes (each set represented by G) is recorded as a reference table corresponding to Fig. 1.
  • step S23 it is determined whether or not the plurality of flags in which the processing results in step S22 are recorded for each set are all 0, and the flags are all 0, that is, the gene polymorphism code set is referenced. If it is not in the table, the process proceeds to step S25. If any flag is set to a value other than 0, the process proceeds to step S24.
  • step S24 the degree of risk is determined using a predetermined determination formula according to the value of each flag in which the processing result in step S22 is recorded.
  • the determined risk is recorded in the recording unit 34 in association with ⁇ Hospital Code, Subject ID ⁇ .
  • the degree of disease value determined according to the disease judgment index
  • the regression equation determined by conducting multiple regression analysis is used as a variable. That is, for the calculation of the value of the judgment formula, the value of the environmental factor included in the clinical data recorded in the recording unit 34 and the value of the flag that is information on the gene polymorphism set are used.
  • ⁇ is i i j j mn m n for each i, j, m, n
  • A, b, d and c are partial regression coefficients determined by multiple regression analysis.
  • Sex sex, age, disease duration, systolic blood pressure, blood total cholesterol level, blood neutrality, respectively. They are fat level, blood HbAlc level, blood HDL level, BMI (Body-mass-index), and smoking calendar.
  • CSNP is a gene
  • the IMT value is used as the objective variable, and the set shown in Fig. 1 is used as the gene polymorphism set.
  • Environmental factors include, for example, sex, age, BMKBody-mass-index), disease duration, systolic blood pressure (SBP), blood HDL level, blood HbAlc level, blood total cholesterol level, blood neutrality. Use fat level (TG), smoking calendar, etc.
  • SBP systolic blood pressure
  • TG blood total cholesterol level
  • smoking calendar etc.
  • the value y obtained by this judgment formula can be used as the risk level as it is, but it can be classified into multiple ranks according to y.
  • Steps S22 to S24 are repeated until it is determined in step S25 that all ⁇ hospital code, subject ID ⁇ have been completed.
  • step S26 When processing is completed for all ⁇ hospital code, subject ID ⁇ , in step S26, a risk code corresponding to the risk determined in step S24 (for example, a high risk level or a low risk level). (Corresponding code) and the subject ID are transmitted to the computer 12 corresponding to the hospital code via the communication line 4.
  • any other index may be used as long as it indicates the degree of sclerosis of the carotid artery.
  • Max-IMT maximum IMT
  • AvglMT average IMT
  • PS plaque score
  • cervical heart rate etc.
  • the apparatus of the present invention can be an apparatus to which other means are appropriately added as necessary as long as the above-described determination function can be realized.
  • the value y determined by the above judgment formula is an analog value, it can be used for future prediction. For example, for a specific individual, the explanatory variable age can be changed, and the change in risk due to the age of calories can be predicted. Therefore, it is possible to predict the future risk level for younger subjects who have not yet thickened at the time of measurement. As a result, when the degree of risk is high, prevention of lifestyle habits can be performed, and the onset of arteriosclerotic diseases can be prevented.
  • the average value used at this time for example, the average value of the corresponding explanatory variable can be used for each patient data that is an element of the set used to determine the determination formula.
  • the average value of the entire set of test values can be obtained, and for sex, for example, 1 and 2 can be assigned to men and women, respectively, and the average can be obtained.
  • sex for example, 1 and 2 can be assigned to men and women, respectively, and the average can be obtained.
  • gene polymorphism sets for example, assign a value of 1 or 0 according to the presence or absence, and calculate the average value of the entire set.
  • the determination apparatus of the service providing organization uses the genetic polymorphism information of the subject acquired from the analysis organization as a determination target.
  • the individual's genetic polymorphism information analyzed in the past is recorded in some recording means (for example, portable recording means such as an IC card or a memory card provided for each individual). It may be read out and the disease risk determination process may be performed. Since the genetic information of living organisms does not change, if genetic polymorphism information that has been analyzed once is recorded, even if the reference table or risk criteria is changed and the accuracy of judgment is improved, genetic information is again obtained. The burden on subjects who do not need to collect blood for child analysis is reduced.
  • the individual's genetic polymorphism information obtained from the analysis institution is recorded in the database of the service provider in correspondence with the individual ID, and the individual ID is notified to each individual. It is possible to determine the risk level again using the corresponding gene polymorphism recorded in the database.
  • the application target of the disease risk determination method according to the present invention is not limited to arteriosclerotic diseases, and can also be applied to myocardial infarction, nephropathy, and retinopathy as described below.
  • the myocardial infarction risk determination method of the present invention can be used to determine the likelihood of myocardial infarction and the ease of progression. Preferably, it can be used to determine the risk of myocardial infarction (e.g., predisposition to progression, etc.) for diabetic patients or prone patients (boundary diabetes).
  • myocardial infarction e.g., predisposition to progression, etc.
  • a table corresponding to Fig. 2 may be used as a reference table used to determine the risk level related to myocardial infarction.
  • the disease index is binary data (0 or 1)
  • multiple logistic regression analysis is used instead of normal multiple regression analysis. Since multiple logistic regression analysis is well-known, description is abbreviate
  • the nephropathy risk determination method of the present invention can be used to determine the likelihood of nephropathy and the ease of progression. Suitably, it can be used to determine the risk of nephropathy (ease of susceptibility, ease of progression, etc.) for diabetics or prone patients (boundary diabetes).
  • the reference table used to determine the risk level for nephropathy is a table corresponding to FIG. Use a single bull.
  • the retinopathy risk determination method of the present invention can be used to determine the likelihood of retinopathy and the likelihood of progression. Preferably, it can be used to determine the risk of retinopathy (susceptibility, ease of progression, etc.) for diabetics or prone patients (boundary diabetes).
  • tables corresponding to Figs. 1 to 4 are used as reference tables for determining the risk of arteriosclerotic disease, myocardial infarction, nephropathy and retinopathy, respectively.
  • tables corresponding to FIGS. 17 to 20 may be used as reference tables for determining the risk of arteriosclerotic disease, myocardial infarction, nephropathy and retinopathy, respectively.
  • the present invention provides genetic markers that are significantly related to arteriosclerotic diseases caused by diabetes.
  • the gene marker can be suitably used for detection and selection of a genetic polymorphism associated with arteriosclerotic disease for a test sample.
  • Such genetic markers include genetic markers that are resistant to and sensitive to arteriosclerotic diseases. Specifically, it includes gene polymorphisms constituting at least one gene polymorphism set selected from the group power consisting of the gene polymorphism sets described in FIG. 1 and FIG.
  • the gene polymorphisms constituting the gene polymorphism set shown in FIGS. 1A and 17 are used as gene markers that are resistant to arteriosclerotic diseases.
  • Can include gene polymorphisms constituting the gene polymorphism set shown in FIG. 1B.
  • the present invention also provides a genetic marker that is significantly related to myocardial infarction due to diabetes.
  • the gene marker can be suitably used for the detection or selection of a genetic polymorphism associated with myocardial infarction for a test sample.
  • the powerful genetic markers include a genetic marker that exhibits resistance to myocardial infarction and a genetic marker that exhibits sensitivity.
  • the gene polymorphism sets included in FIG. 2 and FIG. 18 include gene polymorphisms constituting at least one gene polymorphism set to be selected.
  • the gene polymorphisms constituting the gene polymorphism set shown in Fig. 2-A and Fig. 18 are used.
  • As gene markers that show resistance to myocardial infarction Fig. 2 is used.
  • the gene polymorphisms that make up the gene polymorphism set shown in B can be listed.
  • the present invention further provides genetic markers that are significantly related to nephropathy caused by diabetes.
  • the gene marker can be suitably used for detecting or selecting a gene polymorphism associated with nephropathy in a test sample.
  • Energetic genetic markers include genetic markers that are resistant to and sensitive to nephropathy. Specifically, it includes gene polymorphisms constituting at least one gene polymorphism set from which the group power consisting of the gene polymorphism sets described in FIG. 3 and FIG. 19 is also selected.
  • the gene polymorphisms that make up the gene polymorphism set shown in Fig. 3-A and Fig. 19 are used as gene markers that are resistant to nephropathy.
  • genetic markers that are significantly related to nephropathy are used for detection and selection of genetic polymorphisms associated with nephropathy, as well as genetic markers for the determination and measurement of nephropathy. It can also be used as such.
  • the present invention further provides a genetic marker that is significantly related to retinopathy caused by diabetes.
  • the gene marker can be suitably used for detection or selection of a gene polymorphism associated with retinopathy in a test sample.
  • Such genetic markers include genetic markers that are resistant to retinopathy and genetic markers that are sensitive. Specifically, it includes gene polymorphisms constituting at least one gene polymorphism set selected from the group power consisting of the gene polymorphism sets described in FIG. 4 and FIG.
  • the gene polymorphisms that make up the gene polymorphism set shown in Figure 4-A, Figure 4-B, and Figure 20 are resistant to retinopathy. Examples of gene markers include gene polymorphisms constituting the gene polymorphism set shown in FIG. 4C.
  • the gene polymorphism analysis kit of the present invention is a primer pair capable of specifically amplifying a gene constituting at least one gene polymorphism set selected from a gene polymorphism set group significantly related to a disease. Or a nucleic acid probe capable of specifically hybridizing to the gene or its amplification product.
  • the analysis kit can be suitably used as an analysis kit for detecting a disease-related gene polymorphism.
  • the gene polymorphism set there can be mentioned at least one gene polymorphism set in which the group power consisting of the gene polymorphism sets described in Fig. 1 and Fig. 17 is also selected.
  • An analysis kit comprising a primer pair that can specifically amplify a gene constituting such a gene polymorphism set, or a nucleic acid probe that can specifically hybridize to the gene or its amplification product, is an arterial disease caused by diabetes. It can be suitably used as an analytical kit for detecting genetic polymorphisms significantly related to sclerotic diseases.
  • the gene polymorphism set there can be mentioned at least one gene polymorphism set in which the group power composed of the gene polymorphism sets shown in Fig. 2 and Fig. 18 is also selected.
  • an analysis kit containing a nucleic acid probe capable of specifically hybridizing to the gene or its amplification product is preferably used as an analysis kit for detecting a gene polymorphism significantly associated with myocardial infarction caused by diabetes. it can.
  • At least one gene polymorphism set in which the group power of the gene polymorphism set described in Fig. 3 and Fig. 19 is also selected can be mentioned.
  • An analytical kit containing a primer pair that can specifically amplify a gene that constitutes a gene polymorphism set, or a nucleic acid probe that can specifically hybridize to the gene or its amplification product is caused by diabetes It can be suitably used as an analytical kit for detecting genetic polymorphisms significantly related to nephropathy.
  • At least one gene polymorphism set selected from the group power of the gene polymorphism set described in FIG. 4 and FIG. 20 can be mentioned.
  • An analysis kit comprising a primer pair that can specifically amplify a gene constituting such a gene polymorphism set, or a nucleic acid probe that can specifically hybridize to the gene or its amplification product, is a retina caused by diabetes. It can be suitably used as an analysis kit for detecting a genetic polymorphism significantly associated with the disease.
  • the gene polymorphism analysis kit of the present invention comprises a primer pair or a nucleic acid probe as described above, other nucleic acids or reagents, etc. within the range not impairing the object of the present invention. May be included as appropriate.
  • primers or probes for detecting the gene polymorphisms constituting these sets it is necessary to have primers or probes for detecting the gene polymorphisms constituting these sets. Even if one gene polymorphism includes a gene polymorphism detection primer and the other gene polymorphism includes a gene polymorphism detection probe, as long as the gene polymorphism can be analyzed, Included in genetic polymorphism analysis kit
  • the detection of a gene polymorphism can be performed using the method described in the above gene polymorphism detection step, but the hybrigene method using PCR, TaqMan method, invader method, and gene polymorphism.
  • An ASP-PCR method using a nucleic acid probe that specifically hybridizes to a gene having an amino acid can be suitably used.
  • the gene polymorphism analysis kit includes a process for detecting these gene polymorphisms. At least one of the primers and probes to be used must be included. In PCR methods for detecting genetic polymorphism, it is common to place the polymorphic nucleic acid at the 3 'end. Allele Specific Primer (ASP) — Like the PCR method, the 3' end As in the method of placing a primer with gene polymorphism in the second side, the primer where the gene polymorphism is placed in the primer, and what nucleic acid sequence other than the gene to be detected is inserted There is no particular limitation on the design of the gene as long as it can identify the gene polymorphism. Similarly, in the design of a probe, as long as a gene polymorphism can be identified, the sequence can be used without restriction.
  • the disease risk determination formula y is an analog value, and the time-related factors are It can be used to predict the future of the disease. Therefore, if the disease risk obtained by changing environmental factors related to time can be presented so that it can be easily understood by the patient, it is effective in clinical practice.
  • the method will be described below.
  • similar to the risk determination process for four diseases myocardial infarction, nephropathy, retinopathy, and arteriosclerotic disease caused by diabetes explained using the flowchart shown in FIG.
  • the processing performed by the determination device 31 will be described. Further, unless otherwise specified, it is described as a process performed by the CPU 32 of the determination device 31.
  • FIG. 11 is a flowchart showing the onset prediction presentation function of the determination apparatus 31.
  • step S31 in order to designate a subject (also referred to as a patient) who is a subject of the onset prediction, the subject ID entered by operating the operation unit 36 is temporarily stored in the memory 33.
  • step S32 information corresponding to the subject ID temporarily stored in the memory 33 in step S31 is read from the recording unit 34 to the memory 33.
  • the information read out at this time includes the subject's genetic information (presence of genetic polymorphism), environmental factors (sex, age, BMI, disease duration, systolic blood pressure (SBP), blood HDL level, blood HbAlc value, This is a test value of blood total cholesterol level, blood neutral fat level (TG), smoking calendar, etc.).
  • step S33 the risk determination equation (regression equation) y corresponding to the disease is read from the recording unit 34 to the memory 33.
  • step S24 ⁇ a G + ⁇ b E + ⁇ d EG + c, where each coefficient a, b, d, c is a given population
  • step S34 the subject information (presence / absence of gene polymorphism set, environmental factor value) read in step S32 is applied to the judgment formula y read in step S33, and the same as in step S24.
  • Calculate the risk At this time, for the environmental factors (age, disease duration, etc.) related to time that is not just calculated by using the current environmental factor value of the subject, the value obtained by adding the predetermined time to the current value is used. To calculate the risk. For example, the risk is calculated using the value obtained by adding 5 to each of the current age and disease duration.
  • the calculated risk can be considered as a predictive value of the subject's disease severity 5 years from now.
  • the current inspection data is used for environmental factors not related to time.
  • step S35 it is determined whether or not the current risk level and the predicted value of the future disease level have been calculated for all the four diseases described above. Return to step S33. As a result, the processes in steps S33 to S34 are repeated, and the current state and future degree of disease related to myocardial infarction, nephropathy, retinopathy, and arteriosclerotic disease are obtained.
  • step S36 the calculation results are recorded in the recording unit 34, the calculation result presentation method menu is displayed on the display unit 37, and the selection from the operation unit 36 is accepted. .
  • step 37 it is determined whether or not "radar chart display" is selected. If it is determined that the radar chart display is selected, the process proceeds to step S38 , and step S33.
  • FIG. 12 is a diagram showing an example of a radar chart displayed on the display unit 37.
  • Fig. 12 on each of the left and right radar charts, an axis representing the disease degree of each disease is drawn radially from the central origin, and the grade of each disease (degree of disease) is shown near each axis. Is displayed.
  • the radar chart on the left displays the current risk level (solid line) for each subject along with the mean (dashed line) of the same generation of diabetics!
  • the risk of each disease after 5 years (dotted line) is displayed along with the current risk of each disease (solid line).
  • the average value of each disease is an average value obtained in advance from the disease level of a diabetic patient of the same age as the subject with respect to the data set of the diabetic patient used to determine the risk assessment formula y. Recorded in Part 34.
  • the grade display differs depending on the disease, and also depends on the objective variable used to derive the risk judgment formula y for each disease.
  • Fig. 12 shows the case where Max-IMT is used as the objective variable for arteriosclerotic diseases, and the Max-IMT value is at the position on the axis corresponding to 0.8, 1.4, and 2.8. Each value (0.8, 1.4, 2.8) is displayed.
  • the urinary albumin excretion rate (g / mg'Cr) is used as the objective variable, and the criteria shown in Fig. 9 indicate ⁇ None '' at the positions on the axes corresponding to the disease degrees 1, 2, and 3, respectively. ”,“ Early ”, and“ obvious ”.
  • “None”, “early”, and “apparent” mean “no nephropathy (normal)”, “early nephropathy”, and “apparent nephropathy”, respectively, and are used in actual practice Is an expression.
  • the expression used in actual practice is “none” at the position on the axis corresponding to the degree of disease 1, 2, 3, 4 , “Simpleness”, “Preproliferative”, and “Proliferative” are displayed.
  • myocardial infarction myocardial infarction incidence is used as the objective variable, and myocardial infarction incidence (disease degree) by age shown in Fig.
  • the myocardial infarction incidence corresponding to the age of the subject is 1Z8 times , 1x, 3x, and 5x on the axis corresponding to the values, ⁇ Same as healthy people '', ⁇ Same as diabetics of the same generation '', ⁇ History of myocardial infarction '', ⁇ First time recurrence “Risk”.
  • the myocardial infarction incidence value corresponding to the age of the subject and the above magnification are displayed side by side. In FIG.
  • step 39 it is determined whether or not “onset prediction graph display” is selected, and if it is determined that onset prediction graph display is selected, the process proceeds to step S40, and the recording unit 34 as in step S38. The risk level of each disease related to the subject is read out from this, and an onset prediction graph is created and displayed on the display unit 37.
  • FIG. 14 is a diagram illustrating an example of the onset prediction graph displayed on the display unit 37.
  • Fig. 14 four graphs present information for each disease, the horizontal axis represents the disease degree of each disease, and the vertical axis represents the onset frequency (number of corresponding data) corresponding to the disease degree. is there.
  • the curve is a graph showing the incidence of patients of the same age as the subject in the diabetic patient data set used to determine the risk criterion y, and this is superimposed on the subject's current risk and 5 years later. The predicted value of the disease degree and the average value of each disease of the same age are drawn.
  • the horizontal axis for each disease is accompanied by a letter indicating the Great.
  • step 41 it is determined whether or not “presentation of therapy” is selected, and if it is determined that presentation of therapy is selected, the process proceeds to step S42.
  • step S42 the risk level of each disease related to the subject is read from the recording unit 34 in the same manner as in step S38, and a bubble chart is created.
  • step S43 a treatment method corresponding to each examination data is read from the recording unit 34 and displayed on the display unit 37 together with the bubble chart created in step S42.
  • FIG. 15 is a diagram showing an example of a bubble chart displayed on the display unit 37.
  • Fig. 15 four partial forces (a) to (d) arranged in the horizontal direction are also configured.
  • the names of environmental factors that can be changed by treatment among the environmental factors included in the risk assessment formula y for the four diseases are displayed.
  • the test values of each environmental factor obtained by the test are classified using known guidelines for each disease, and a circle with a size corresponding to the classification is drawn (No. 1). 1 bubble chart).
  • four diseases are arranged in the horizontal direction, and a circle with a size corresponding to the contribution of environmental factors in each disease is drawn in the vertical direction (second bubble chart).
  • part (d) a list of countermeasures (including treatment methods) for bringing the test values of each environmental factor closer to those of healthy individuals is displayed.
  • the indication “HbAlc (disease duration)” The HbAlc test value is used to determine the size of the circle drawn in the first bubble chart on the right, and the disease duration is used to determine the size of the circle drawn in the second bubble chart on the left. Indicates that it is used.
  • the size (for example, diameter) of the circle drawn in the first bubble chart shown in (c) is disclosed in, for example, “Diabetic Treatment Guidelines” (edited by the Japan Diabetes Society). It can be determined according to the classification. In other words, if the range of each test value and the parameter for designating a circle having a size indicating the degree of disease corresponding to the range are recorded in the recording unit 34 in advance as a table corresponding to each other. When the test value of each environmental factor of the subject is determined to which test value range in the table of the recording unit 34, the corresponding parameter is determined and the size of the circle to be drawn is determined. .
  • the treatment ranking shown in (d) will be described.
  • the degree of disease is classified according to each test value, and there are usually several known countermeasures to improve each test value. Accordingly, the range of each inspection value and the text data indicating the countermeasure corresponding to the range are associated with each other, and the rank information is attached to the countermeasure, and the table is previously stored in the recording unit 34 as a table. If it is recorded, the test value of each environmental factor of the patient. If the test value range in the table of the recording unit 34 is determined, the corresponding countermeasure (including rank information) is determined and the response Text data to be presented.
  • CSNP3 SNP-No.l-3 and SNP-No.89-3 (ie ABCA1-3 and IL-10 (C-819T) -3)
  • CSNP6 SNP-No.l-3 and SNP-No.121 — 23 (ie ABCA1—3 and GLUT (Xbal) —23)
  • CSNP10 SNP-No.3-1— and SNP-No.69—1 (ie ACE-1 and CD18 (C1323T) _ 1)
  • CSNP14 SNP -No.4—23 and SNP-No.86—12 (ie a-estrogen—23 and IL-18 (C-607A) —12)
  • CSNP16 SNP-No.5-3 and SNP-No.32-3 (ie Enos786-3 and MTHFR (C677T) _3)
  • CSNP26 SNP-No.17-12 and SNP-No.28-1 (ie , Fractalkine—receptor-12 and angio tensinogen_l)
  • CSNP90 SNP-No.86—12 and SNP-No.125—1 (ie IL-18 (C-607A) —12 and RANTES (-28CG) —1)
  • the size of the circle to be drawn is determined according to the size of the product of each environmental factor and the coefficient including the gene polymorphism set. That is, the size of the circle is determined by whether the value of this product is less than the first quartile, greater than the first quartile, less than the third quartile, or greater than the third quartile. .
  • the first quartile and the third quartile are the distribution products of the product of each environmental factor and the coefficient including the gene polymorphism set in the diabetic patient data set used to determine the criterion y. Calculated from the above.
  • the first and third quartiles used to determine the size of the circle drawn for total cholesterol are the product of the coefficients that include the total cholesterol and gene polymorphism sets for the entire data set. Is done.
  • the total cholesterol with interaction term is as follows. Calculate the product of the coefficients including total cholesterol and gene polymorphism set in the judgment formula y, and if the product value is 0 and the first quartile holds, If the quantile product value ⁇ the third quartile holds, the second circle is drawn. If the third quartile product value holds, the third circle is drawn. Where the three circles are number 1, The second and third circles increase in order. For each environmental factor that has an interaction term, the same calculation is performed to determine the size of the circle to be drawn.
  • Fig. 16 shows an example of the criteria for determining the size of the circle for each disease.
  • the numbers 1 to 3 at the beginning of each criterion correspond to the size of the circle to be drawn.
  • the circles drawn in the order of 1, 2, and 3 become larger.
  • step S44 it is determined whether or not an end instruction is given, and steps S37 to S43 are repeated until an end instruction is given.
  • the predicted value of the future disease level can be presented as a radar chart and an onset prediction graph to the patient in an easy manner.
  • the countermeasures corresponding to the test results can be ranked and presented, and the effect of each change in the test results on the risk level of each disease can be presented in a bubble chart.
  • the process performed by the determination device 31 has been described, and the case where the process result is displayed on the display unit 37 has been described.
  • the present invention is not limited to this. Instead of displaying the results processed by the judgment device 31 on the display unit 37, the radar chart, the symptom prediction graph, and the bubble chart as shown in FIGS. 12, 14, and 15 are printed on paper or electronic data. May be recorded on a recording medium and sent to Hospital 1.
  • the processing result may be transmitted from the determination device 31 to the computer 12 of the hospital 1 via the communication line 4 (see FIG. 7).
  • the doctor operates the computer 12 to access the determination device 31 and designates the patient's ID, and the corresponding processing result, i.e., a radar created in advance. Request charts, onset prediction graphs, and bubble charts.
  • the computer 12 can present the received processing result to the patient by displaying it on a graphical display device.
  • hospital 1 computer In response to the access from 12, the determination device 31 performs processing in real time, generates a radar chart, an onset prediction graph, and a bubble chart, and transmits the result to the computer 12 via the communication line 4. ,.
  • the risk judgment formula is a regression formula determined by multiple regression analysis using a patient data set.
  • the judgment formula is not limited to this.
  • the judgment formula is a formula including genetic factors (gene polymorphism set) and environmental factors, and at least some of the environmental factors may be environmental factors (age, disease duration, etc.) related to time.
  • obtaining the predicted value of the future disease degree in step S34 is not limited to five years later. Also, calculate the predicted values after multiple years, and generate a radar chart and an onset prediction graph.
  • onset prediction graphs are presented side by side as shown in FIG. 14 .
  • the present invention is not limited to this, and one onset prediction graph may be presented.
  • the predicted value of the disease level after 5 years, and the average value of each disease of the same age instead of drawing all of the current risk level of the subject, the predicted value of the disease level after 5 years, and the average value of each disease of the same age, only a part may be presented. For example, you may draw only the subject's current risk and the average value of each disease of the same age, or the subject's current risk and only the predicted value of the disease after 5 years. .
  • the environmental factors shown in Fig. 15 are examples, and bubble charts may be generated including other environmental factors.
  • a bubble chart with a different circle size has been described.
  • the present invention is not limited to this, and the influence on the risk determination formula y when each inspection value changes is large.
  • Any bubble chart may be used to visually represent this.
  • a different color circle may be drawn according to the classified values of 0 to 3 in FIG. 16, or a circle of a different color may be drawn depending on 0 to 3. .
  • polygons such as triangles and squares and other shapes may be drawn.
  • the above describes a bubble chart in which a plurality of diseases are arranged in a horizontal direction. It is not limited to this, and it may be a bubble chart related to one disease.
  • test result of the environmental factor is within a range that does not require treatment, and the necessity of treatment can be presented according to the present invention even when treatment is not performed conventionally. Therefore, it is possible to provide a tailor-made environment where patients can receive appropriate treatment.
  • Predictive presentation method there is a term related to environmental factors and gene polymorphism sets, especially an interaction term between environmental factors that can change over time and variables indicating the presence or absence of gene polymorphism sets. He explained that by focusing his attention, he can predict the onset of disease at an early stage and present the need for treatment. In the following, we will explain a method for determining the necessity of coping with the disease, further expanding this idea.
  • the determination formula of the disease risk can be obtained by a method other than the multiple regression analysis. Therefore, it is assumed here that the judgment formula is expressed by a more general function. However, the judgment formula shall include at least the product of the environmental factor function and the gene polymorphism set.
  • the disease risk criterion R is an arbitrary function f (x) whose environmental factor E is a variable X, and a variable G that represents the presence or absence of a gene polymorphism set (hereinafter, simply Gene polymorphism set G)).
  • R ⁇ ⁇ f (E) XG ⁇ + ⁇ ⁇ ⁇ ⁇ (Equation 1)
  • ⁇ represents the addition for each i and j, that is, the addition for each environmental factor and gene polymorphism set.
  • ⁇ does not include the genetic polymorphism set G at all, and is a function consisting of only environmental factors ⁇ and constants.
  • the gene polymorphism set is, for example, a gene polymorphism set determined according to the disease by, for example, “(1) Method for determining gene polymorphism for disease risk determination” (for example, FIG. 1 to FIG. Fig. 4 and Figs. 17-20).
  • Each function f (x) may be various functions such as a higher-order polynomial, a trigonometric function, and an exponential function in addition to the linear expression described above.
  • FIG. 21 are graphs showing the judgment formula R of two different subjects (referred to as A and B) related to a certain disease.
  • the vertical axis represents the disease risk level R
  • the horizontal axis X represents the environmental factors that can change among the environmental factors E.
  • the judgment formula R contains a plurality of variable environmental factors, so the judgment formula R is a multidimensional curved surface.
  • a is the current value of the environmental factor X
  • X b is the value of the environmental factor x changed by the ⁇ force predetermined value ⁇
  • R The value of R is represented by R and R. Therefore, ⁇ is not a single value (scalar) Change value ⁇ relates; environmental factors E represents a set of a vector quantity.
  • r is a reference value for determining the necessity of coping according to the degree of disease. Here, it is assumed that some treatment is necessary when R> r.
  • the degree R is sufficiently smaller than the reference value r (R ⁇ r) force If the value of the environmental factor x changes to x,
  • Risk R is expected to exceed the reference value r (R> r) and be considered as needing treatment d
  • FIG. 22 is a flowchart relating to a method for determining the necessity of coping with a disease using the determination formula of Formula 1.
  • a specific description will be given with reference to FIG.
  • each process is executed using the CPU power memory 33 of the determination device 31 as a work area, and the intermediate result and final result of the process are recorded in a predetermined area of the recording unit 34 as necessary.
  • the judgment formula and reference value r expressed by Equation 1 are recorded in the recording unit 34 for each disease, and subject information (test values of environmental factors, presence / absence of genetic polymorphism set) corresponds to the subject ID. And recorded in the recording unit 34.
  • step S51 the subject ID inputted by operating the operation unit 36 to designate the subject is temporarily stored in the memory 33.
  • step S52 information corresponding to the subject ID temporarily stored in the memory 33 in step S51 is read from the recording unit 34 to the memory 33.
  • Information read at this time includes the subject's genetic information (presence or absence of gene polymorphism set), environmental factors (sex, age, BMI, disease duration, systolic blood pressure (SBP), blood HDL value, blood HbAlc value , Blood total cholesterol level, blood triglyceride level (TG), smoking calendar, etc.).
  • step S53 designation of the disease is accepted, and in step S54, the disease risk judgment formula R and the reference value!: Corresponding to the disease designated in step S53 are stored in the memory 33 from the recording unit 34. read out.
  • step S55 the determination formula R for the subject specified in step S51 is applied to the determination formula scale read in step S54 by applying the presence or absence of the gene polymorphism set in the subject information read in step S52. From the relationship between the degree of change in this criterion R and the reference value r, the necessity of countermeasures is determined.
  • Subject has a specific gene polymorphism set G
  • the current risk factor R (R, R in Fig. 21) is first calculated by substituting the current environmental factor value into the judgment formula R.
  • Necessity of handling can be determined.
  • the current environmental factor value (X in Fig. 21) and the environmental factor value (X in Fig. 21) when the risk R is equal to the reference value r are obtained, and a c
  • step S56 it is determined whether or not there is an end instruction. If not, the process returns to step S53 in order to make a determination on another subject, and steps S53 to S55 are repeated.

Abstract

L’invention concerne un procédé d’évaluation du niveau de risque de maladie permettant d’apprécier la tendance au développement d’une maladie donnée, la tendance de progression de la maladie, etc., comme niveau de risque de maladie avec grande précision pour ainsi rendre le procédé utile dans la prévention et la thérapie de la maladie. Elle porte également sur un procédé approprié de détermination d’un polymorphisme de gène pour apprécier le niveau de risque de maladie, une matrice d'évaluation, un kit d’analyse de polymorphisme de gène et un appareil d’évaluation de niveau de risque de maladie. Selon le procédé de détermination de polymorphisme de gène pour évaluer le niveau de risque de maladie, on détermine un ensemble de polymorphisme de gène associé à la maladie, selon un test t en utilisant un niveau de maladie de valeur analogue, et selon un procédé d’évaluation d’un niveau de risque de maladie, on détermine le niveau de risque de maladie sur la base, comme formule d'évaluation, d’une formule de régression déterminée par une analyse à régression multiple employant, comme variables d’explication, un ensemble de polymorphisme de gène, un facteur environnemental et une interaction entre l’ensemble de polymorphisme de gène et le facteur environnemental.
PCT/JP2006/310405 2005-05-26 2006-05-24 Procédé de détermination de polymorphisme de gène pour évaluer le niveau de risque de maladie, procédé d’évaluation du niveau de risque de maladie et matrice d'évaluation correspondante WO2006126618A1 (fr)

Priority Applications (1)

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JP2007517881A JP5121449B2 (ja) 2005-05-26 2006-05-24 疾患の発症予測提示方法

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WO2009125851A1 (fr) * 2008-04-11 2009-10-15 株式会社サインポスト Procédé pour la détection de l’efficacité d’un composé de type dérivé de phénylalanine chez un patient diabétique
JP2010142187A (ja) * 2008-12-22 2010-07-01 Mie Univ 慢性腎臓病の遺伝的リスク検出法
JP2015043770A (ja) * 2014-08-29 2015-03-12 株式会社ＤｅＮＡライフサイエンス 表示画面生成装置、表示画面生成方法、プログラム、および、記録媒体
JP2016067323A (ja) * 2014-10-01 2016-05-09 株式会社サインポスト 糖尿病治療薬の有効性を判定する方法、判定装置、プログラムおよび記録媒体
JP2020178560A (ja) * 2019-04-23 2020-11-05 ジェネシスヘルスケア株式会社 動脈硬化のリスクを判定する方法

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JP2008191716A (ja) * 2007-01-31 2008-08-21 Signpost Corp 疾患リスクの提示方法およびそのプログラム
WO2009125851A1 (fr) * 2008-04-11 2009-10-15 株式会社サインポスト Procédé pour la détection de l’efficacité d’un composé de type dérivé de phénylalanine chez un patient diabétique
JP2010142187A (ja) * 2008-12-22 2010-07-01 Mie Univ 慢性腎臓病の遺伝的リスク検出法
JP2015043770A (ja) * 2014-08-29 2015-03-12 株式会社ＤｅＮＡライフサイエンス 表示画面生成装置、表示画面生成方法、プログラム、および、記録媒体
JP2016067323A (ja) * 2014-10-01 2016-05-09 株式会社サインポスト 糖尿病治療薬の有効性を判定する方法、判定装置、プログラムおよび記録媒体
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JP7165098B2 (ja) 2019-04-23 2022-11-02 ジェネシスヘルスケア株式会社 動脈硬化のリスクを判定する方法

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