WO2006126618A1

WO2006126618A1 - Method of determining gene polymorphism for judgment of disease risk level, method of judging disease risk level and array for relevant judgment

Info

Publication number: WO2006126618A1
Application number: PCT/JP2006/310405
Authority: WO
Inventors: Yoshimitsu Yamasaki; Atsuhiko Kurokawa; Muneo Takiguchi; Yuuri Arakawa; Li Yang
Original assignee: Signpost Corporation
Priority date: 2005-05-26
Filing date: 2006-05-24
Publication date: 2006-11-30
Also published as: JP5121449B2; JPWO2006126618A1

Abstract

A method of judging a disease risk level in which the disease development tendency, progression tendency, etc. can be judged as a disease risk level with high precision to thereby render the method useful in the prevention and therapy of disease. It is also intended to provide a relevant method of determining a gene polymorphism for judgment of disease risk level, array for judgment, kit for gene polymorphism analysis and disease risk level judging apparatus. In the method of determining a gene polymorphism for judgment of disease risk level, a gene polymorphism set associated with the disease is determined by a t-test using a disease level of analog value, and according to a method of judging a disease risk level, the disease risk level is judged with the use of, as a judgment formula, a regression formula determined by multiple regression analysis employing, as explanatory variables, gene polymorphism set, environmental factor and gene polymorphism set/environmental factor interaction.

Description

Specification

Method for determining genetic polymorphism for disease risk determination, disease risk determination method, and determination array

Technical field

[0001] 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.

[0002] Further, 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. Background art

[0003] It is known that environmental requirements such as hypertension, diabetes, hyperlipidemia, obesity, and smoking are related as risk factors in the development of arteriosclerotic disease (ischemic heart disease). History is also a risk factor. Recent developments in molecular biology techniques have revealed various genetic polymorphisms on genes related to arteriosclerosis, and their involvement in diseases has been studied.

[0004] Based on information such as the genotypes of genetic polymorphisms related to each disease possessed by various subjects, such as arteriosclerotic diseases, 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.

[0005] However, in the clinically related studies of gene polymorphisms including SNPs that have been reported so far with respect to various diseases including arteriosclerosis, single gene polymorphisms are investigated and the gene polymorphisms are examined. The odds ratio of the likelihood of developing a disease is calculated by examining the ratio of patients to healthy individuals in a population of one genotype and a population of other genotypes (Non-patent Document 1). ). In such a survey method, it was impossible to predict the risk of disease such as the likelihood of disease progression and the probability of progression of most genetic polymorphisms with no significant difference.

[0006] In addition, there has been no method that can predict the risk of disease (the likelihood of developing a disease or the likelihood of progression) with a high probability for many subjects if they are tested.

[0007] Patent Document 1 below 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. Has been. In addition, 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.

[0008] On the other hand, Patent Document 2 below 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

twenty four)

Disclosure of the invention

Problems to be solved by the invention

[0009] According to the method for determining a genetic polymorphism for determining a disease risk specific to the disease disclosed in Patent Document 2, 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.

[0010] In addition, since the disease risk determination method disclosed in Patent Document 2 is determined based on how many gene polymorphism sets are included, the method is simple but sufficient in accuracy. Furthermore, the disease risk level was determined using only the gene polymorphism, and the influence of environmental factors could not be reflected.

[0011] 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.

[0012] That is, firstly, 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. For the purpose. Second, 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. Thirdly, 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.

[0013] Fourthly, 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.

[0014] A fifth object is to provide a method for determining the necessity of coping with a disease according to an individual.

Means for solving the problem

[0015] Means for solving the above-described problems are as follows.

(1) 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,

A second step of dividing a set of elements corresponding to a disease polymorphism and a genetic polymorphism having a genotype into two subsets according to the presence or absence of the genetic polymorphism set;

The third step of performing a t-test using the disease degree for the two subsets and the t-test result, and if the two polymorphisms are determined to have a significant difference, the gene polymorphism A method for determining a genetic polymorphism for disease risk determination, comprising a fourth step of adopting the set as a genetic polymorphism for disease risk determination.

[0017] (2) 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;

As a result of the matching, if there is a matching set of the first and second gene polymorphisms, a prediction is made. A second step of calculating a risk for the test sample using a regression equation determined 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 method.

[0018] (3) 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;

An interface unit for obtaining a genetic polymorphism having a genotype of a test sample; a second genetic polymorphism set comprising a predetermined number of genetic polymorphisms in the obtained genetic polymorphism of the test sample; and A processing unit that matches the first gene polymorphism set in the reference table,

When there is the first genetic polymorphism set that matches as a result of the collation, 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.

[0019] (4)

A function of accepting an input of a genetic polymorphism having a genotype of a test sample,

A function of recording a reference table consisting of a first gene polymorphism set composed of one or more gene polymorphism models having a genotype in a recording unit;

A function of collating a second gene polymorphism set composed of a predetermined number of gene polymorphisms in the gene polymorphism of the test sample with the first gene polymorphism set in the reference table; and

A program for realizing a function of calculating a risk level for the test sample using a regression equation determined in advance by multiple regression analysis when there is the first genetic polymorphism set that matches as a result of the matching And

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.

[0020] (5)

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.

(6) Probes for detecting a gene polymorphism constituting at least one gene polymorphism set selected from the group consisting of the gene polymorphism sets shown in FIGS. 1-A and 1-B and FIG. An array for determining the risk of atherosclerotic disease caused by diabetes.

[0022] (7) 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. The array for determining atherosclerotic disease risk according to (6), comprising a probe for detection of a gene polymorphism that constitutes the gene polymorphism.

[0023] (8) 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.

[0024] (9) More than half of the gene polymorphism set in 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 Configure The array for determining the risk of myocardial infarction according to (8), comprising a probe for detection of a gene polymorphism.

[10] (10) Probes for detection of gene polymorphisms 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. An array for determining the risk of nephropathy caused by diabetes.

[0026] (11) More than half of the gene polymorphism set in the group consisting of the gene polymorphism set described in FIG. 3-A and FIG. 19 or the group consisting of the gene polymorphism set described in FIG. 3-B The array for determining a risk of nephropathy disease according to (10), which has a probe for detection of a polymorphism constituting the gene.

[0027] (12) Gene polymorphisms constituting at least one gene polymorphism set selected from the group consisting of the gene polymorphism sets described in FIGS. 4A, 4B and 4C, and FIG. An array for determining the risk of retinopathy caused by diabetes, comprising a probe for detection of diabetes.

[0028] (13) Half of the group consisting of the gene polymorphism group set shown in Fig. 4-A, 4-B and Fig. 20 or the group consisting of the gene polymorphism set shown in Fig. 4-C The array for determining the risk of retinopathy according to (12), comprising a probe for detecting a gene polymorphism constituting the gene polymorphism set.

[0029] (14) Due to diabetes including genetic polymorphisms constituting at least one genetic polymorphism set selected from the group consisting of genetic polymorphism sets described in FIGS. 1-A and 1-B and FIG. Markers associated with arteriosclerotic disease.

[15] (15) Due to diabetes including genetic polymorphisms constituting at least one genetic polymorphism set selected from the group consisting of the genetic polymorphism sets shown in FIGS. 2-A and 2-B and FIG. Genetic marker associated with myocardial infarction.

[0031] (16) Caused by diabetes including a gene polymorphism constituting at least one gene polymorphism set selected from the group consisting of the gene polymorphism set described in FIGS. 3A and 3B and FIG. Genetic markers associated with nephropathy.

[0032] (17) Gene polymorphisms constituting at least one gene polymorphism set selected from the group consisting of the gene polymorphism sets shown in FIGS. 4-A, 4-B and 4-C, and FIG. A genetic marker related to retinopathy caused by uricuria. [18] (18) 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.

[19] (19) 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 kit for analyzing a gene polymorphism associated with myocardial infarction caused by diabetes, comprising a primer pair or a nucleic acid probe capable of specifically hybridizing to the gene or its amplification product.

[0035] (20) 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.

[21] (21) Specific genes constituting at least one gene polymorphism set selected from the group consisting of the gene polymorphism sets described in FIGS. 4-A, 4-B and 4-C, and FIG. A kit for analyzing a polymorphism associated with retinopathy caused by diabetes, comprising a primer pair that can be amplified, or a nucleic acid probe that can specifically hybridize to the gene or its amplification product.

[0037] (22) a disease risk assessment formula using a genetic polymorphism set and environmental factors as variables, the genetic polymorphism set having one or more genetic polymorphisms that are related to the disease and having a genotype; In a computer with a record that records the mean value of disease severity by age of the first patient in the patient data set,

Using the information of the genetic polymorphism of the second patient that does not constitute the set and environmental factors, a first step of determining a first disease risk from the risk determination formula;

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:

[23] (23) a disease risk judgment formula having a genetic polymorphism set and environmental factors as variables, the genetic polymorphism set having one or more genetic polymorphisms that are related to the disease and having a genotype; In a computer equipped with a recording unit that records the average value of disease levels by age for a set of patient data,

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.

[0039] (24) A record that records a risk assessment formula for a disease having a genetic polymorphism set and environmental factors as variables, and a genetic polymorphism set that is related to the disease and has a genotype. On a computer equipped with

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.

[0040] (25) 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 second step of reading out information on the genetic polymorphism set corresponding to the specified ID and the determination formula from the recording unit;

A third step of determining a determination formula for the subject from the read determination formula according to the read information of the genetic polymorphism set;

And a fourth step of determining whether or not the subject needs to cope with the disease using the degree of change of the judgment formula for the subject due to the change of the environmental factor that is a variable and the reference value. A method for determining the necessity of dealing with a disease.

The invention's effect

[0041] According to the present invention, 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.

[0042] 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. On the other hand, in the present invention, 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.

[0043] 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. As a result, the risk assessment, prevention and treatment of arteriosclerotic diseases, myocardial infarction, nephropathy, and retinopathy, etc. for subjects, especially diabetic patients or prone patients, can be more It can be performed in an appropriate manner. 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.

[0044] Further, according to the disease prediction presentation method according to the present invention, in addition to the current disease risk level of the patient, 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.

[0045] Further, on the basis of the conventional environmental factor test results only! / And countermeasures such as treatment of diseases have been selected, according to the present invention, the environmental factor test results have been selected. In addition, 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.

[0046] Further, according to the present invention, it is possible to more appropriately determine the necessity of dealing with a disease of the patient based on the patient's genetic information (presence / absence of gene polymorphism set). Accordingly, appropriate observation, guidance, treatment, etc. for the disease can be performed on the patient, and a customized environment can be provided in the same manner as described above.

[0047] It should be noted that 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. In particular, the present invention can be similarly applied to cerebral infarction, diabetic neuropathy, etc. caused by diabetes.

Brief Description of Drawings [0048] [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.

[0049] As described above, 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.

[11] It is a flowchart showing the onset prediction presenting function according to the embodiment of the present invention.圆 12] A diagram showing a radar chart created by the onset prediction presenting function according to the embodiment of the present invention.

[13] Table showing the incidence of myocardial infarction in a group of diabetic patients by age. 14] A diagram showing an onset prediction graph created by the onset prediction presenting function according to the embodiment of the present invention.

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.

[17] Table showing an example of a set of genetic polymorphisms that can be used to determine the risk of arteriosclerotic disease caused by diabetes.

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. In the drawings, FIG. 1 is composed of two diagrams indicated by branch numbers “FIG. 1-A” and subsequent “FIG. 1-B”. In this specification, the simple reference to “FIG. 1” refers to both “FIG. 1 A” and “FIG. 1 B”. The same applies to items including a plurality of diagrams indicated by branch numbers other than those in FIG.

Explanation of symbols

1 Hospital

2 Analytical organization

3 Service provider

4 Communication line

11 Blood collection method

12, 22 computer

21 Array for gene polymorphism analysis

31 Judgment device

32 CPU

33 memory

34 Recording section

35 Communication interface

36 Operation unit

37 Display

38-person output interface

39 Internal bus

BEST MODE FOR CARRYING OUT THE INVENTION

[0052] Hereinafter, the present invention will be described in more detail.

(the term)

“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) is also a kind of gene polymorphism The gene polymorphism targeted by the present invention is not limited to this.

[0053] In the genotype shown in this specification, “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, and “3” represents a polymorphism homozygote having a base that follows in alphabetical order of the substitution bases. For example, if the genetic polymorphism is shown as ABCAKG1051A) (SNP-No “SNP-Νο.1” in Fig. 5), GZG homozygous is genotype 1, heterozygous (GZA) is genotype 2, and homozygous of ΑΖΑ. Is called gene type 3. “12” represents the genotypes of both the genotypes 1 and 2, and “23” represents the genotypes of both the 2 and 3 genotypes.

[0054] The "gene polymorphism set" refers to a combination of a plurality of gene polymorphisms. Here, a plurality of gene polymorphisms means two or more gene polymorphisms having different loci. In addition, “gene polymorphism” here refers to and includes genotypes. That is, in the present invention, “gene polymorphism” means a gene polymorphism having a specific genotype.

[0055] In the present invention, 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]. These 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. In this 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). In this specification, the single gene polymorphism is also described as a “gene polymorphism set” in order to avoid complicated explanation.

[0056] Taking FIG. 1 as an example, each row of the figure describes a set of gene polymorphisms that are positively or negatively related to an index of arteriosclerotic disease. Specifically, in the eighth column of Fig. 1-A, “glycoprotein 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). According to the definition above, "la (C807T)" gene polymorphism genotype 2: CZT and gene polymorphism 3: ΤΖΤ will be described. “VEGF (C- 63 4G) J (SNP-No.73) has an allele whose position -634 is C or G (see Fig. 5-A). In the middle column, 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). Become.

[0057] It should be noted that these two types of gene polymorphism sets can be used individually as gene polymorphism sets, but what are C / T (glycoprotein la) and T / T (glycoprotein la)? / T (glyco protein la) [? Are possible candidates, here we mean C and T)? It can also be used as a set of gene polymorphisms for / T (glycoprotein la) and GZG (VEGF).

[0058] "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.

[0059] "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.

[0060] (1) Determination method of genetic polymorphism for disease risk determination

The method for determining a genetic polymorphism for determining a disease risk according to the present invention is used to determine how easily a subject suffers from a disease !, or how easily a disease progresses, and determines a disease (risk risk). Provided is a method for determining a genetic polymorphism for determining a disease risk to be used. In the following, 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. In that case, 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 Using the presence or absence of myocardial infarction waveform or history of myocardial infarction, or clinical findings for retinopathy, the relevance described below may be evaluated (for example, edited by Japan Diabetes Society) Diabetes Treatment Guide 20 04—2005, Bunkodo).

[0061] (1-1) In the case of gene polymorphism for risk determination of arteriosclerotic disease

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. To do. That is, 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.

[0062] First, information on genes related to the arteriosclerotic disease, which is the target disease, is collected in advance such as literatures and patient charts, and gene polymorphisms used in this determination method are selected. This preliminary selection can be made based on the experience of a person skilled in the art, but by searching the database constructed by various specialized institutions using a computer with a disease name or related words as a keyword, the number of hits You may select according to. An example of a preselected genetic polymorphism is shown in FIG.

[0063] 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). .

[0064] The flowchart shown in FIG. 6 is performed using a predetermined number of gene polymorphisms selected by the above-described preliminary selection.

[0065] Further, the degree of carotid arterial sclerosis, particularly the carotid arterial hyperplasia, 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.

[0066] 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)

Where Age is the age (in years).

[0067] In addition, in the recording unit in advance, 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.

[0068] In 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. Here, kmax = 3 is set. Although the analysis becomes complicated, the processing described below may be performed on a gene polymorphism set composed of four or more gene polymorphisms, ie, an upper limit value of kmax force or more.

[0069] In step S2, k gene polymorphisms having a genotype are selected from the preselected gene polymorphisms and set as one set. The set is a combination that includes genetic polymorphisms without duplication. Initially k = l, so only one gene polymorphism is selected. Therefore, the term “set” in the present specification is not limited to a case of being composed of a plurality of gene polymorphisms, but includes a case of only one gene polymorphism.

[0070] In step S3, the set selected in step S2 includes the gene polymorphism set determined to be significant in the processing in step S4 described later in the previous iteration. If it is determined that it is included, the process proceeds to step S5. If it is determined that it is not included, the process proceeds to step S4. If k = l, the process moves to step S4. Also, for example, in the case of k = 2, if a specific set has already been determined to be significant in the treatment with k = l, the step including the gene polymorphism (having the genotype) is performed. The process proceeds to step S5 without performing the process of S4.

[0071] In step S4, out of all the analyzed data, 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. Note that the disease determination index value itself may be used as the disease degree. Here, 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

If P is less than or equal to ≤P), there is a significant difference between the two sets, and the set is determined to be significant. In order to leave the determination result, for example, set “1” to a predetermined flag for each set (assuming that it is set to “0” by default). Here, since the t value calculation method and t test are well known, the description thereof is omitted.

[0072] In 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.

[0073] In step S6, it is determined whether or not k is not less than the upper limit value kmax (= 3). If it is determined that k is not kmax, the process proceeds to step S7 and the counter k is incremented by one and Return. As a result, the processes in steps S2 to S5 are repeated until k = l to kmax (= 3).

[0074] A set of gene polymorphisms (gene polymorphism set for determining the risk of arteriosclerotic disease) that is effective in determining the risk of arteriosclerotic disease is determined by the processing of steps S2 to S7 described above. . For example, if the gene polymorphism shown in Fig. 5 is used and kmax = 3 and P = 0.05, the above process is performed.

As a result, the gene polymorphism set for determining the risk of arteriosclerosis shown in FIG. 1 was obtained. In Fig. 1, 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).

[0075] It should be noted that various modifications can be made to the flowchart shown in FIG. 6 as described below, or additional processing can be performed.

[0076] For example, determining whether the genetic polymorphism set selected in step S2 immediately after step S3 does not perform a t-test, and the statistical significance of the association with the disease determination index, 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. Each set of Odds determines the onset (Case) or non-occurrence (control) of the disease using the IMT corresponding to the individual ID including all of the polymorphisms constituting the set, and 0 (1 (13 = same 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. Δ ΙΜΤ = ΙΜΤ—ΙΜΤ force Δ ΙΜΤ≥0.2 If it is, then Case, and if Δ ΙΜΤ <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. Prediction of the risk of myocardial infarction from polymorphisms in candidate genes.N . Engl. J. Med. 2002; 347 (24): 1916-23). Also, the calculation method of Kai (chi-square value) is well known in statistics, so the details of the calculation method are omitted.

[0077] Further, in the above, the significance level P corresponding to the calculated t value (t), the predetermined significance level P, and

cal cal 0 was compared to determine the significance of the set, but the absolute value of the calculated t value (t) and the given significance

cal

T value (t> 0) corresponding to level P

If 0 0 cal I ≥t, the set is significant

0

It may be determined that there is sex.

[0078] Regarding the set including the genetic polymorphism set that has already been determined to be significant, the case where the t-test is not performed has been described. However, the present invention is not limited to this, and the determination in step S3 is not performed. A significant set may be determined by performing a t-test on all sets.

[0079] In the above, the carotid intima-media thickness is used as an index indicating the degree of carotid sclerosis.

(IMT) has been explained, but the present invention is not limited to this. 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. Various measurement methods have been established for each of these indicators. 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. In addition, there is a method in which the average thickness of a certain section of the far wall is defined as mean IMT. In addition, 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.

[0080] The plaque score (PS) 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.

[0081] 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.

[0082] Further, as clinical findings closely related to arteriosclerotic diseases, an increased amount of carotid intima-media thickening can also be mentioned. As the amount of increase in carotid intima-media thickness, the above-mentioned average IMT increment (ΔIMT), maximum IMT increment (ΔPIMT), and the like can be used as indices. Among them, ΔΙΜΤ is a particularly preferable index as a comprehensive expression of the risk of arteriosclerotic disease. There have been many reports on the relationship between the increase in carotid intima-media thickness and arteriosclerotic disease, especially for ΔΙΜΤ, ΔΙΜΤ increases by 0.339 mm. It is known that the odds of myocardial infarction increase 4.9 times each time (Yamasaki. Diabetes Care 2000 (9)). Therefore, ΔΙΜΤ 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 (Δ ΙΜΤ and Δ ΡΙΜΤ, etc.) 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.

[0083] Further, when clinical data increases, it is more effective by applying the above-described method for determining a genetic polymorphism for disease risk determination to a set of new analyzed data including them. An effective gene polymorphism set can be determined, and the accuracy of determination of disease risk can be improved.

[0084] (1-2) In the case of genetic polymorphism for risk assessment of myocardial infarction

With regard to myocardial infarction, by using the presence or absence of an abdominal myocardial infarction waveform on the electrocardiogram or the history of myocardial infarction as a disease determination index, It is possible to determine a genetic polymorphism and a set of genetic polymorphisms that are effective for risk assessment. For example, if the myocardial infarction has not yet occurred, the disease degree = 1, and if it has the disease, the disease degree = 2. Using the value of 1 or 2 as a real value, the t-test is performed in the same manner as above (kmax = 3, P = 0.05), so that the gene polymorphism set for risk assessment of myocardial infarction shown in Fig. 2 is set. was gotten.

[0085] (1-3) In the case of genetic polymorphism for nephropathy risk assessment

In the case of nephropathy, for example, 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.

[0086] Using the values of disease degree determined by Fig. 9 = 1 to 3 as real values, the t-test is performed in the same manner as above (km ax = 3, P = 0.05) to obtain Fig. 3. The gene polymorphism set for determining the risk of nephropathy shown could be obtained.

[0087] (1 4) In the case of genetic polymorphism for retinopathy risk assessment

In the case of 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.

[0088] By using t-test as described above (k max = 3, P = 0.05) using the values of disease degree = 1 to 4 determined by Fig. 10 as real values, Fig. 4 The gene polymorphism set for judging the risk of retinopathy shown can be obtained.

[0089] In the above, by using the 133 gene polymorphisms shown in Fig. 5 and considering the positive and negative t values, the gene polymorphism sets for disease risk determination for each disease are shown in Figs. We explained that the table shown in Fig. 4 was obtained. Similarly, another disease risk determination gene polymorphism set can be determined using a positive t value. For example, as 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.

[0090] (2) Disease risk assessment array

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. provide. In the array according to the present invention, 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. Here, the probe may be any probe that specifically recognizes and captures a gene polymorphism associated with a specific disease. Specifically, 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.

[2-1] (2-1) Arteriosclerotic disease risk assessment array

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. 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 And a probe for detecting a polymorphism of the gene. Whether or not a gene polymorphism set has a “positive association” or “negative association” with respect to IMT 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”.

[0093] 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”. Here, 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”.

[0094] Here, "gene polymorphism" means a gene polymorphism including a genotype, that is, a gene polymorphism having a specific genotype, as described above. In each of the above figures, 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.

[0095] 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.

It can be. 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

[0096] From the group consisting of the gene polymorphism set shown in Fig. 1-A and Fig. 17 or from the group consisting of the gene polymorphism set shown in Fig. 1-B, more than half, 60% or more, respectively. When selecting a genetic polymorphism set of 70% or more, 80% or more, or 90% or more, there is no limitation, but “positive (susceptibility) gene polymorphism set for arteriosclerotic disease” and “arteriosclerosis” The absolute value of the t value (I t value)

It is preferable that the forward force with a large I) is selected with priority.

[0097] 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.

As a result of examining the above various requirements, the present inventor has found that the genetic polymorphism shown in FIG. 5 is useful for determining the risk of arteriosclerotic diseases, particularly arteriosclerotic diseases caused by diabetes. It was confirmed that the risk of arteriosclerotic disease can be determined with high accuracy by using powerful polymorphisms alone or in combination. Therefore, 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.

[0099] 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 (whether or not the subject has a gene polymorphism set that has a positive association with IMT and whether or not the subject has a gene polymorphism set that has a negative association with IMT. Such information) can be used to assess a subject's susceptibility and resistance to arteriosclerotic disease.

[0100] 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.

[0101] (2-2) Myocardial infarction risk assessment array

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. And a detection probe for a gene polymorphism constituting a “negative (resistance) gene polymorphism set” having a negative (resistance) relationship. Note that the myocardial infarction determination index 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.

[0102] Whether the genetic polymorphism set has “positive relevance” or “negative relevance” for myocardial infarction is shown in the explanation in the determination method in (1) above. 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”.

[0103] Specific examples of 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”. Here, 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”.

[0104] 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 according to the present invention 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.

[0105] From the group consisting of the gene polymorphism set shown in Fig. 2-A and Fig. 18, or from the group consisting of the gene polymorphism set shown in Fig. 2-B, more than half, 60% or more, respectively. 70% As mentioned above, when selecting a gene polymorphism set of 80% or more, or 90% or more, there is no limitation, but “positive (susceptibility) gene polymorphism set for myocardial infarction” and “negative for myocardial infarction ( In any of the (resistance) gene polymorphism sets, it is preferable that an order having a large absolute value of t value (I t value I) is also selected with priority.

[0106] 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.

[0107] 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.

[0108] 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).

[0109] The risk of myocardial infarction can be determined by the same method as the above-described method for determining the risk of myocardial infarction.

[0110] (2-3) Array for determining the risk of nephropathy

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. Where 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.

[0111] 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”.

[0112] Specific examples of 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). Here, 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”.

[0113] 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. At that time, 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.

[0114] From the group consisting of the gene polymorphism set shown in Fig. 3-A and Fig. 19 or from the group consisting of the gene polymorphism set shown in Fig. 3-B, more than half, 60% or more, respectively. When selecting a genetic polymorphism set of 70% or more, 80% or more, or 90% or more, there is no limitation, but “positive (susceptibility) gene polymorphism set for nephropathy” and “negative nephropathy set” It is preferable that all of the (resistance) gene polymorphism sets be selected with priority given to the descending order of the absolute value of the t value (I t value I).

[0115] 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.

[0116] 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.

[0117] 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.

[0119] (2—4) Retinopathy risk array

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. Here, 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.

[0120] Whether the genetic polymorphism set has a “positive association” or “negative association” for retinopathy is shown in the explanation in the determination method in (1) above. 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”. [0121] 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. 20, it means “a set of gene polymorphisms significantly related to retinopathy” that is one of the combination powers of gene polymorphisms (SNPs) listed in each row (one horizontal column). Here, 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.

[0122] 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. At that time, 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.

[0123] More than half each from the group consisting of the gene polymorphism set shown in Fig. 4-A, 4-B and Fig. 20, or from the group consisting of the gene polymorphism set shown in Fig. 4-C When selecting a polymorphism set of 60% or more, 70% or more, 80% or more, or 90% or more, there is no restriction, but “positive (susceptibility) gene polymorphism set for retinopathy” and “retina” “Negative (resistance) polymorphism set for disease” has a large t-value (It value I), and it is preferable to select strength.

[0124] 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.

[0125] 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. [0126] 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.

[0127] 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.

[0128] 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.

[0129] 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. There are no particular restrictions on Also, 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.

[0130] In particular, the method of amplifying a region containing a gene polymorphism using a labeled primer can also preferably use points such as sensitivity and simplicity. For example, in the Hybrigene method, 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. By this method, gene polymorphism can be detected with high sensitivity.

[0131] The array for disease determination of the present invention includes the following embodiments:

(A) The group power consisting of the gene polymorphism set described in Fig. 1 and Fig. 17 is also selected at least. An array for determining the risk of atherosclerotic disease, comprising a detection probe for a gene polymorphism constituting one gene polymorphism set.

(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 The array for determining atherosclerotic disease risk according to (A), which has a probe for detection of a polymorphism.

(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 The array for determining the risk of myocardial infarction according to (C), comprising a probe for detecting a polymorphism.

(E) Nephropathy risk assessment 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. 3 and FIG. 19 is also selected Array.

(F) Genes constituting the gene polymorphism set of more than half of the group consisting of the gene polymorphism set described in Fig. 3-A and Fig. 19 or the group consisting of the gene polymorphism set described in Fig. 3-B The array for determining the risk of nephropathy according to (E), which has a probe for detecting a polymorphism.

(G) Group power consisting of the gene polymorphism set described in FIG. 4 and FIG. 20 An array for determining the degree of risk of reticulitis having a detection probe for the gene polymorphism constituting at least one selected gene polymorphism set .

(H) More than half the genes in the group consisting of the gene polymorphism set described in Fig. 4-A, Fig. 4-B, and Fig. 20 or the group consisting of the gene polymorphism set described in Fig. 4-C. The array for determining the risk of retinopathy according to (G), which has a probe for detecting a gene polymorphism constituting the polymorphism set.

(I) 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 array for determining the risk of atherosclerotic disease according to (A) or (B), which is used for evaluating the relevance to arteriosclerotic disease.

ω 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 The myocardial infarction risk determination array described in (C) or (D), which is used to evaluate relevance.

(Iii) The 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 array for determining the risk of diabetic nephropathy according to any one of (i) to (F), which is used for evaluating the relevance of the set to diabetic nephropathy.

(L) 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 array for determining the risk of diabetic retinopathy described in (G) or (Η), which is used to evaluate the relevance to diabetic retinopathy for the type set.

(3) Disease risk determination device, determination program, and determination method

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. In the following, 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. In that case, depending on the disease, the disease determination index (for example, carotid intima-media thickness in the case of atherosclerotic disease, urinary albumin excretion rate in nephropathy, cardiac infarction If there is, the relationship can be evaluated using the presence or absence of an abnormal EC waveform on the electrocardiogram and the presence or absence of a myocardial infarction, or clinical findings in the case of retinopathy. (3-1) Determination Device, Determination Program, and Determination Method for Arteriosclerotic Disease Risk 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. 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.

[0134] 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. In the recording unit 34, information on the genetic polymorphism set for determining disease risk is recorded as a reference table. Here, unlike Patent Document 2, 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. Also, unlike Patent Document 2, 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. First, in the hospital 1, the blood of the subject (hereinafter referred to as a test sample) is collected by the blood collection means 11. At this time, 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. Here, as 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.

For the analysis of the test sample, any method can be used as long as it is a method for detecting the genotype of the subject. As a general method, 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. In the PCR method, a specific gene polymorphism is specifically amplified using primers specific to the gene polymorphism. In PCR methods, it is common to place genetic polymorphic nucleic acids on the 3 'side. 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. In the TaqMan method, 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. When the PCR reaction from the primer reaches the hybridized region of this allele-specific probe, 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. In the Invader Atsey method, an allele probe that has a specific sequence 5 'from the 铸 type gene polymorphic site and a flap sequence on the 3' side, and 3 'of the 遺伝子 type gene polymorphic site force. Using 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. In 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. Then, using MALDI-TOF / MS, the polymorphism is identified by identifying the type of ddNTP attached. For methods generally called 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. Hereinafter, 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. In addition, 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.

[0138] In step S21, genetic polymorphism information is acquired from the analysis organization 2 via the communication line 4, and recorded in the recording unit 34. Here, the gene polymorphism information is transmitted as a gene polymorphism code assigned to each gene polymorphism having a genotype, and the data format is assigned to each hospital code given to each requesting hospital and each subject, for example. This is a format in which a plurality of genetic polymorphism codes g (i = l to n) are associated with each set of subject IDs.

[0139] In step S22, a plurality of gene polymorphism codes g (i = l to n) relating to one {hospital code, subject ID} are read from the recording unit 34, and the gene polymorphism code g force is recorded in the recording unit 34 in advance. It is determined whether or not the force is included in the reference table. For example, a set of genetic polymorphism codes (each set represented by G) is recorded as a reference table corresponding to Fig. 1. The gene polymorphism codes _gi (i = l to n), one, two or three gene polymorphism codes g 1

select i and set them {g

Determine whether k} is included in the reference table (including set G) corresponding to the figure, and if it is included, the flag corresponding to that set {g} (same as G) Set 1 "(The flag is set to" 0 "in advance.

Suppose).

[0140] In 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.

[0141] In 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}. Here, in the judgment formula, the degree of disease (value determined according to the disease judgment index) is used as the objective variable, and the gene polymorphism set, environmental factor, and the interaction between the gene polymorphism set and the environmental factor are explained. 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. Degree of disease, G for each gene polymorphism set, and E for each environmental factor

1 J

, The interaction between the gene polymorphism set and the environmental factor is the product of both, E G

m n

The (regression equation) is y = ∑a G + ∑b E + ∑d E G + c. Where ∑ 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.

1 j mn

The Since multiple regression analysis is well known, the description is omitted.

[0142] Specifically, the determination formula is

y = c X (l + ∑a X CSNP) X

k k

(1 + b X Sex + b XAge + b X Dur + b X SBP + b X Tch + b X TG +

1 2 3 4 5 6

(b X HbAlc + b X HDLC + b X BMI + b X SM)

7 8 9 10

It is. Where Sex, Age, Dur, SBP, Tch, TG, HbAlc, HDLC, BMI, and SM are 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. As for gender, Sex = 1 for men and Sex = 2 for women. CSNP is a gene

k

A variable that takes 1 or 0 depending on the presence or absence of a polymorphic set. Further, the left side of the above judgment formula may be replaced with log (p / (l-p) instead of y. P is the expression rate.

[0143] In the case of arteriosclerotic disease, 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. 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.

[0144] Steps S22 to S24 are repeated until it is determined in step S25 that all {hospital code, subject ID} have been completed.

[0145] 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.

[0146] With the above processing, a series of risk determination processing by the determination device 31 is completed. The above risk determination process is performed using a general-purpose computer, hard disk, CD-RO

It is also possible to read a computer program recorded on a computer-readable recording medium such as M or obtain a computer program via a communication line and execute it by the CPU.

[0147] Although the case where the IMT value is used as the objective variable has been described above, the present invention is not limited to this.

Any other index may be used as long as it indicates the degree of sclerosis of the carotid artery. For example, the above-mentioned maximum IMT (Max-IMT), average IMT (AvglMT), plaque score (PS), cervical heart rate, etc. can be used as objective variables.

[0148] Further, 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.

[0149] In addition, the case where the regression equation is obtained by performing multiple regression analysis including the interaction between the judgment formula force gene polymorphism set used in step S24 and the environmental factor has been described. You may use the regression equation obtained by performing multiple regression analysis without the interaction between the gene polymorphism set and the environmental factor, or without the environmental factor.

[0150] Further, since 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.

[0151] In addition, as a result of genetic testing of the test sample, the presence or absence of some genetic polymorphisms could not be determined, or the test values of some environmental factors were ineffective, that is, included in the judgment formula. If the genetic polymorphisms that make up the gene polymorphism set and the information on environmental factors are unknown, the risk cannot be calculated using the above judgment formula. However, even in that case, the value of unknown explanatory variables (gene polymorphism set and environmental factor) in the judgment formula can be replaced with a predetermined average value. This calculated value is less accurate than when all genetic polymorphisms and environmental factors are divided, but can be used for risk assessment. As 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. Among environmental factors, for test values, 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. For 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.

[0152] In the above description, the case has been described in which 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. However, the present invention is not limited to this. 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.

[0153] In addition, 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.

[0154] Furthermore, by using the gene polymorphism information itself as an ID, in addition to newly acquired analysis data (for example, IMT measurement values in the case of arteriosclerotic diseases), it is necessary to use a personal ID. Past analysis data can be used. Therefore, it becomes possible to track the history of risk determination accuracy and to determine the risk considering the history. Here, in addition to the value of the disease index, various clinical data may be added to the data to be analyzed.

[0155] 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.

[0156] (3-2) Myocardial infarction risk assessment method

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).

[0157] A table corresponding to Fig. 2 may be used as a reference table used to determine the risk level related to myocardial infarction. For myocardial infarction, since 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 | omitted.

[0158] (3-3) Nephropathy risk assessment method

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).

[0159] The reference table used to determine the risk level for nephropathy is a table corresponding to FIG. Use a single bull.

[0160] (3-4) Retinopathy risk assessment method

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).

[0161] Use a table corresponding to Fig. 4 as a reference table for determining the risk of retinopathy.

[0162] The above describes the case where the 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. However, it is not limited to these. For example, 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.

[0163] (4) Genetic markers

(4-1) Genetic markers that are significantly related to atherosclerotic disease

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. As gene markers that are sensitive to arteriosclerotic diseases, 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.

[0164] These genetic markers that are significantly related to arteriosclerotic diseases are used for detection and selection of genetic polymorphisms associated with arteriosclerotic diseases, as well as for determination and measurement of arteriosclerotic diseases. It can also be used as a genetic marker for the purpose. [0165] (4 2) Genetic marker showing significant association with myocardial infarction disease

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. Specifically, the gene polymorphism sets included in FIG. 2 and FIG. 18 include gene polymorphisms constituting at least one gene polymorphism set to be selected. As gene markers that are sensitive to myocardial infarction, 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.

[0166] These genetic markers that are significantly associated with myocardial infarction are used for detection and selection of genetic polymorphisms associated with myocardial infarction, as well as genetic markers for determining and measuring myocardial infarction. Can also be used.

[0167] (4- 3) Genetic marker showing significant association with nephropathy

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. As gene markers that are sensitive to nephropathy, 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. Can include the gene polymorphisms that make up the gene polymorphism set shown in Figure 3-B.

[0168] These 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.

[0169] (4 4) Genetic markers significantly related to retinopathy 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. As genetic markers that are susceptible to retinopathy, 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.

[0170] These genetic markers that are significantly associated with retinopathy are used for detection and selection of genetic polymorphisms associated with retinopathy, as well as genetic markers for the determination and measurement of retinopathy. Can also be used.

[0171] (5) Genetic polymorphism analysis kit

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.

[0172] As an example of 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.

[0173] Furthermore, as another example of 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. There is a primer pair that can specifically amplify the genes that make up a powerful polymorphism set. Alternatively, 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.

[0174] Furthermore, as another example of the gene polymorphism set, 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.

[0175] As another example of the gene polymorphism set, 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.

[0176] If 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. In order to detect gene polymorphism 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

[0177] 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.

[0178] Therefore, 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.

[0179] (6) Onset prediction presentation method

As explained in “(3) Disease risk determination device, determination program, and determination method” above, 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. In the following, 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.

[0181] In 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.

[0182] In 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.).

[0183] In step S33, the risk determination equation (regression equation) y corresponding to the disease is read from the recording unit 34 to the memory 33. As shown in the explanation of step S24 (Fig. 8), = ∑a G + ∑b E + ∑d EG + c, where each coefficient a, b, d, c is a given population

1 1 j j mn m n 1 j mn

It is a value determined for each disease by multiple regression analysis using a group.

[0184] In 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. In the risk calculation, the current inspection data is used for environmental factors not related to time.

[0185] In 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.

[0186] When the calculations for the four diseases are completed, in 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. .

In the following, a description will be given of a process for effectively presenting the calculation result recorded in the recording unit 34 on the display unit 37 in accordance with an instruction from the operation unit 36.

[0188] In 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.

The current and future risk levels of each disease relating to the subject determined in S34 are read from the recording unit 34, and a radar chart is created using these, and displayed on the display unit 37. FIG. 12 is a diagram showing an example of a radar chart displayed on the display unit 37.

[0189] In 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! In the radar chart on the right, the risk of each disease after 5 years (dotted line) is displayed along with the current risk of each disease (solid line). Here, 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. For nephropathy, 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. Similarly, with respect to retinopathy, according to the criteria shown in FIG. 10, 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. On the other hand, for myocardial infarction, myocardial infarction incidence is used as the objective variable, and myocardial infarction incidence (disease degree) by age shown in Fig. 13 is used, and 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”. In addition, at the position on the left side of the axis corresponding to these displays, the myocardial infarction incidence value corresponding to the age of the subject and the above magnification are displayed side by side. In FIG. 12, the value of the incidence of myocardial infarction corresponding to the age of the subject is 0.8, and 1 and 0.8 representing a magnification of 1 are placed at the positions corresponding to “same as diabetes of the same generation”. Are displayed side by side. In addition, 1Z8 times is displayed as 0.1. The radar chart displayed in this way is easy to understand not only for doctors and nurses but also for patients. [0191] In 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.

[0192] In 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. Like the radar chart (eg, Fig. 12), the horizontal axis for each disease is accompanied by a letter indicating the Great.

[0193] In 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. In 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. Next, in 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.

[0194] In Fig. 15, four partial forces (a) to (d) arranged in the horizontal direction are also configured. In (b), 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. In part (c), 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). In part (a), 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). In 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. Of the environmental factors shown in part (b), 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.

[0195] Here, 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. .

Next, the treatment ranking shown in (d) will be described. As described above, 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.

Next, the second bubble chart shown in (a) will be described. Draw a circle only if the risk assessment formula y for each disease uses the environmental factors displayed in part (c) as explanatory variables. For example, when Max-IMT is used as an objective variable for arteriosclerotic diseases, the judgment formula y can be expressed by the following formula.

y = Sex X (al X CSNP3 + a2 X CSNP14 + a3 X CSNP26) + Age X (bl X CSNP90 + b2) + HbAlc X c + Dur X (dl X CSNP6 + d2 X CSNP10 + d3) + Tch X (el X CSNP16 + e

2)

+ HDLC X f + g

Where Sex, Age, HbAlc, Dur, Tch and HDLC are gender, age (year), blood HbAlc value (%), disease duration (year), blood total cholesterol level (mg / dl), And blood HDL level (mg / dl). As for gender, Sex = 1 for men and Sex = 2 for women. CSNP3, CSNP6, CSNP10, CSNP14, CSNP16, CSNP26, and CSNP90 are variables that take 1 or 0 depending on the presence or absence of the gene polymorphism set, and are shown in Fig. 5-A and 5-B. It is defined as follows using the notation. For example, if the subject has ABCA1_3 and IL-10 (C-819T) _3, CSNP3 = 1, otherwise CSNP3 = 0

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. . Here, 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. For example, 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.

For example, in the case of arteriosclerotic disease, for example, 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.

[0199] Regarding nephropathy, retinopathy, and myocardial infarction, the size of the circle can be similarly determined. 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.

[0200] As described above, the size of each circle in the first bubble chart in (a) and the second bubble chart in (c) and the ranked countermeasures presented in (d) are determined. Then, according to the determined conditions, image data as shown in FIG. 15 is created and displayed on the display unit 37.

[0201] Finally, in 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. Thus, in addition to the current risk level for each disease of the subject, 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. In addition, 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. Thus, it is possible to determine a more desirable treatment method for the patient.

[0202] In the above, 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. However, 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.

[0203] 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). For example, when a patient visits Hospital 1 again, 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. Also 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. ,.

[0204] In the above description, the risk judgment formula is a regression formula determined by multiple regression analysis using a patient data set. However, the risk 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.

[0205] Further, 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.

[0206] In the above description, the case where two radar charts are presented side by side as shown in FIG. 12 has been described. However, the present invention is not limited to this, and only one of the radar charts may be presented.

[0207] In the above, the case where four onset prediction graphs are presented side by side as shown in FIG. 14 has been described. However, the present invention is not limited to this, and one onset prediction graph may be presented. Furthermore, 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. .

[0208] The environmental factors shown in Fig. 15 are examples, and bubble charts may be generated including other environmental factors.

[0209] In Fig. 15, the case where a bubble chart with a different circle size is displayed has been described. However, 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. For example, 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. . In addition to circles, polygons such as triangles and squares and other shapes may be drawn.

[0210] In addition, 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.

[0211] In the above description, a case has been described in which the size of a graphic drawn as a bubble chart represents the degree of the influence of environmental factors on the risk of a disease. However, the present invention is not limited to this. In other words, in the past, a therapeutic method was selected based on the test result of a predetermined environmental factor as the basis of the presentation by the bubble chart, whereas in the present invention, a genetic factor is added to the test result of the environmental factor. The value of the term related to the environmental factor and the genetic factor in the considered disease risk judgment formula (for example, the interaction term between the environmental factor and the gene polymorphism set) exceeded the predetermined value. In some cases, it is necessary to present treatment needs such as treatment. As a result, the 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.

[0212] (7) Judgment method of the necessity of coping with the disease

In the above “(3) Disease risk determination device, determination program, and determination method”, the case where the disease risk determination formula y is determined by multiple regression analysis has been described. In this case, the judgment formula can be expressed as y = ∑a G + ∑b E + ∑d E G + c. In addition, the above

1 1 j j mn m n

In “(6) 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.

[0213] 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.

[0214] First, as shown in Equation 1, 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)).

[0215] R = ∑ {f (E) XG} + α · · · (Equation 1) Here, ∑ represents the addition for each i and j, that is, the addition for each environmental factor and gene polymorphism set. α does not include the genetic polymorphism set G at all, and is a function consisting of only environmental factors Ε and constants.

Here, 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).

[0217] Judgment formula shown above

y = SexX (al X CSNP3 + a2 X CSNP14 + a3 X CSNP26) + Age X (bl X CSNP90 + b2

)

+ HbAlc X c + DurX (dl X CSNP6 + d2 X CSNP10 + d3) + Tch X (el X CSNP16 + e

2)

+ HDLC Xf + g

Then the function f (x) is f (x) = al X x (where x is Sex) for the genetic polymorphism set CSNP3 and f (x) = bl X for the genetic polymorphism set CSNP90 x (where X is Age), and f (x) = dl X x (where X is Dur) for the genetic polymorphism set CSNP6.

[0218] 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.

[0219] Even if there is only one judgment formula for a disease, since the genetic polymorphism set G that the subject has is generally different, the specific judgment formula for each subject is also different. Environmental factors include factors that do not change from patient to patient (for example, gender) and factors that can change (eg, measured values of blood HDL, blood HbAlc, etc.).

[0220] (a) and (b) of 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, and the horizontal axis X represents the environmental factors that can change among the environmental factors E. Actually, the judgment formula R contains a plurality of variable environmental factors, so the judgment formula R is a multidimensional curved surface. However, for convenience, in FIG. Show. X

a is the current value of the environmental factor X, X b is the value of the environmental factor x changed by the χ force predetermined value Δ, and the corresponding judgment formula a

The value of R is represented by R and R. Therefore, Δ is not a single value (scalar) Change value Δ _{_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.

[0221] Graph power of judgment formulas for two subjects, A and B. As shown in (a) and (b) of Fig. 21, the difference in gene polymorphism set G between the two is different. Comparing (a) and (b) in Fig. 21, in subject A (Fig. 21 (a)), the current risk R is sufficiently smaller than the reference value r that is judged to require treatment ( R r), even if the value of the environmental factor X changes to X, the risk R is the basis ab

It is sufficiently smaller than the quasi-value r (R r). On the other hand, for subject B (Fig. 21 (b)), the current risk b

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,

C b

Risk R is expected to exceed the reference value r (R> r) and be considered as needing treatment d

It is. In this way, even if the current environmental factor value is the same, the present and future risks vary depending on the subject. Therefore, it is possible to determine the necessity of dealing with the disease according to the individual using this determination formula.

[0222] For example, if the results are evaluated using values in a range that can be easily changed as (a) and (b) force Δ in FIG. 21, subject A is normal in the present and future, At present, it can be judged that no action is required. On the other hand, it can be judged that subject B needs to be observed more carefully because it can be easily treated as it is normally normal, and it needs to be treated early.

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. Hereinafter, a specific description will be given with reference to FIG. Here, it is described as a process performed by the determination device 31 (see FIG. 7), similarly to the above-described disease risk determination method and onset prediction presentation method. That is, 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. In addition, 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.

[0224] In step S51, the subject ID inputted by operating the operation unit 36 to designate the subject is temporarily stored in the memory 33. In 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.).

[0226] In 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.

[0227] In 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

k

If so, Equation 1 becomes R = ∑f (Ε) + α (where 表す represents the addition for k).

k k

[0228] Various methods can be used to determine the necessity of countermeasures. For example, 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.

a c

Is compared with the reference value r. Next, change the environmental factor by a predetermined value to change the risk R (R in Figure 21).

b

, R) and compare this with the reference value r. Finally, based on the results of these comparisons, d

Necessity of handling can be determined. In another method, 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

Depending on the magnitude of the difference (Δ ′ = χ −X), the necessity of handling may be determined. In particular,

c a

The value of each environmental factor when the risk R is equal to the reference value r is specified by ∑f (E) + a = r

k k

Since this represents a situation, the shortest distance from this situation is obtained. In addition, the slope of the judgment formula R at the present time (when the environmental factor is X) (calculate the total derivative), and the reference value r

You can decide whether or not you need it.

[0229] In 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.

[0230] As described above, the judgment formula R for disease risk including environmental factors and gene polymorphism sets! Of judgment formula Taking into account the degree of change and the reference value r, it is possible to decide how to deal with it. According to the method for determining the necessity of coping with a disease according to the present embodiment, the necessity of coping with individual needs, which was not possible with the conventional method of judgment, without considering the presence or absence of a gene polymorphism set, is required. Sex can be judged, and a custom-made medical environment can be provided. In particular, the necessity of coping with the disease can be determined with high accuracy by using the judgment formula R including the product of the function of the environmental factor and the variable indicating the presence or absence of the gene polymorphism set.

Claims

The scope of the claims

[1] A first step in which a predetermined number of gene polymorphisms are selected from a plurality of gene polymorphisms designated in advance and a predetermined number of gene polymorphisms are extracted to form a gene polymorphism set;

[2] Repeat the second to fourth steps each time the genetic polymorphism set is determined without duplication in the first step,

The first step includes a fifth step of determining whether or not a gene polymorphism set composed of a number of gene polymorphisms, which is smaller than the gene polymorphism set, is already adopted in the fourth step. Including

The method for determining a genetic polymorphism for disease risk determination according to claim 1, wherein if it is determined as a result of the determination, the third and fourth steps are not executed!

[3] The disease is an arteriosclerotic disease, and

The method for determining a genetic polymorphism for determining a disease risk according to claim 1 or 2, wherein the disease degree is a carotid intima-media thickness.

[4] the disease is myocardial infarction, and

The method for determining a genetic polymorphism for disease risk determination according to claim 1 or 2, wherein the disease degree is 0 when normal and 1 when onset.

[5] the disease is nephropathy, and

The disease level is 1 when the urinary albumin protein is less than 30 g / mg'Cr), and the urine albumin protein is 30 g / mg-Cr) or more and less than 300 (μg / mg-Cr). The method for determining a genetic polymorphism for disease risk determination according to claim 1 or 2, wherein Case 2 is 3, and the amount of albumin protein in urine is 300 g / mg'Cr) or more.

[6] the disease is retinopathy, and

The disease degree is 1 for normal, 2 for simple retinopathy, 3 for preproliferative retinopathy, and 4 for proliferative retinopathy. A method for determining genetic polymorphisms for disease risk assessment.

[7] A reference table consisting of a first set of genetic polymorphisms composed of one or more genetic polymorphisms associated with a disease and having a genotype is included in A first step of checking whether or not a second set of genetic polymorphisms configured by reading out a predetermined number of genetic polymorphisms is included,

As a result of the matching, when there is a matching set of the first and second gene polymorphisms, a second step of calculating a risk level for the test sample using a regression equation determined by preliminary multiple regression analysis Including

The regression equation has a disease degree as an objective variable and is included in at least the reference table.

A method for determining a disease risk, which is an expression obtained by performing multiple regression analysis on a set of patient data using the gene polymorphism set of 1 as an explanatory variable.

8. The disease risk determination method according to claim 7, wherein the explanatory variable further includes an environmental factor and an interaction between the environmental factor and the first genetic polymorphism set included in the reference table.

[9] The disease to be judged is an arteriosclerotic disease,

The first gene polymorphism set is a set described in FIG. 1-A and 1-B, or FIG.

The explanatory variable includes at least one selected as an environmental factor selected from the group consisting of age, disease duration, sex, blood HDL level, blood HbAlc value, and blood total cholesterol level. Item 9. The disease risk determination method according to Item 8.

[10] The disease to be judged is myocardial infarction,

The first gene polymorphism set is the set described in FIG. 2-A and 2-B, or FIG.

8. The disease risk determination method according to claim 7, wherein the multiple regression analysis is a multiple mouth istic regression analysis.

[11] The disease to be judged is retinopathy,

The first gene polymorphism set is a set described in FIG. 4-A, 4-B and 4-C, or FIG.

9. The disease risk determination method according to claim 8, wherein the explanatory variable includes at least one of disease duration and systolic blood pressure as an environmental factor.

[12] The target disease is nephropathy,

The first genetic polymorphism set is a set described in FIG. 3A and 3B or FIG.

The above explanatory variables are environmental factors such as age, disease duration, gender, blood HDL level, blood HbA lc value, blood total cholesterol level, blood triglyceride, and smoking calendar power. 9. The disease risk determination method according to claim 8, comprising at least one of the above.

[13] The explanatory variable further includes an environmental factor related to time,

Using the value of the environmental factor related to the time corresponding to the second time obtained by adding a predetermined time at the first time when the test sample was collected, the regression equation relates to the test sample. The disease risk determination method according to claim 7, further comprising a third step of calculating a risk level and setting it as a predicted value in the future.

[14] In the second step, σ, which calculates the risk related to the test sample from the regression equation,

When it is unknown whether the test sample has a predetermined genetic polymorphism or when the value of a predetermined environmental factor is unknown, the first gene containing the unknown genetic polymorphism in the regression equation The risk value for the test sample is calculated from the regression equation by replacing the value indicating the presence or absence of the polymorphism set or the value of the environmental factor with the average value calculated using the patient data that is an element of the set. The disease risk determination method according to claim 7.

[15] a recording unit that records a reference table composed of a first gene polymorphism set composed of one or more gene polymorphisms that are related to a disease and have a genotype;

An interface unit for obtaining a genetic polymorphism having a genotype of a test sample; a second genetic polymorphism set comprising a predetermined number of genetic polymorphisms in the obtained genetic polymorphism of the test sample; and The first genetic polymorphism set in the lookup table And a processing unit for matching

A disease risk determination apparatus, which is an expression obtained by multiple regression analysis of a set of patient data, with the gene polymorphism set of 1 as an explanatory variable.

16. The disease risk determination apparatus according to claim 15, wherein the explanatory variable further includes an environmental factor and an interaction between the environmental factor and a first genetic polymorphism set included in the reference table.

[17] On the computer,

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 judgment program.

18. The disease risk determination program according to claim 17, wherein the explanatory variable further includes an environmental factor and an interaction between the environmental factor and a first genetic polymorphism set included in the reference table.

[19] On the computer,

A function of accepting an input of a genetic polymorphism having a genotype of a test sample, A function for recording a reference table comprising a first gene polymorphism set composed of one or more gene polymorphism models having a genotype in a recording unit;

Patient 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 computer-readable recording medium on which is recorded.

[20] Probes for detection of gene polymorphisms constituting at least one gene polymorphism set in which the group power consisting of the gene polymorphism sets described in FIGS. 1-A and 1-B and FIG. 17 is also selected. An array for determining atherosclerotic disease risk.

[21] Configure more than half of the gene polymorphism set 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 21. The arteriosclerotic disease risk determination array according to claim 20, comprising a detection probe for the gene polymorphism to be detected.

[22] Fig. 2-A and 2-B, and the group power consisting of the gene polymorphism set described in Fig. 18 Detection probe for the gene polymorphism constituting at least one gene polymorphism set selected An array for determining myocardial infarction risk.

[23] Configure more than half of the gene polymorphism set in 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 23. The myocardial infarction risk determination array according to claim 22, further comprising a detection probe for the gene polymorphism to be detected.

[24] Group power consisting of the gene polymorphism set shown in Fig. 3-A and 3-B, and Fig. 19 A detection program for the gene polymorphism constituting at least one selected gene polymorphism set An array for determining the risk of nephropathy.

[25] Configure more than half of the gene polymorphism set in the group consisting of the gene polymorphism set described in Fig. 3-A and Fig. 19 or the group consisting of the gene polymorphism set described in Fig. 3-B 25. The array for determining the risk of nephropathy according to claim 24, comprising a probe for detecting a polymorphism of the gene polymorphism to be detected.

[26] For detection of gene polymorphisms constituting at least one gene polymorphism set selected from the group consisting of the gene polymorphism sets shown in Fig. 4-A, 4-B and 4-C, and Fig. 20. An array for determining the risk of retinopathy having a probe.

[27] Fig. 4-A, 4-B and the group consisting of the gene polymorphism sets described in Fig. 20, or Fig. 4-

27. The array for risk determination of retinopathy according to claim 26, comprising a detection probe for a gene polymorphism constituting a gene polymorphism set of more than half of the group consisting of the gene polymorphism set described in C. .

[28] Arteriosclerotic diseases including gene polymorphisms constituting at least one gene polymorphism set in which the group power consisting of the gene polymorphism sets described in FIG. 1-A and 1-B and FIG. 17 is also selected Related genetic markers.

[29] Group power consisting of the gene polymorphism set described in Fig. 2-A and 2-B and Fig. 18 Myocardial infarction-related including a gene polymorphism constituting at least one gene polymorphism set selected Sex genetic marker.

[30] Group power consisting of the gene polymorphism set described in Fig. 3-A and 3-B, and Fig. 19 Nephropathy-related including gene polymorphism constituting at least one gene polymorphism set selected Genetic markers.

[31] Includes gene polymorphisms constituting at least one gene polymorphism set selected from the group consisting of the gene polymorphism sets described in FIGS. 4A, 4B and 4C, and FIG. Retinopathy related genetic marker.

[32] A pair of primers capable of specifically amplifying genes constituting at least one gene polymorphism set in which the group power consisting of the gene polymorphism sets described in FIGS. 1-A and 1-B and FIG. 17 is also selected. A kit for analyzing an arteriosclerotic disease-related gene polymorphism comprising a nucleic acid probe capable of specifically hybridizing to the gene or its amplification product.

[33] A pair of primers capable of specifically amplifying a gene constituting at least one gene polymorphism set in which the group power consisting of the gene polymorphism set described in FIGS. 2-A and 2-B and FIG. 18 is also selected. A kit for analyzing a gene polymorphism associated with myocardial infarction, comprising a nucleic acid probe capable of specifically hybridizing to the gene or its amplification product.

[34] A pair of primers capable of specifically amplifying genes constituting at least one gene polymorphism set in which the group power consisting of the gene polymorphism sets described in FIGS. 3A and 3B and FIG. 19 is also selected. A kit for nephropathy-related gene polymorphism analysis comprising a nucleic acid probe capable of specifically hybridizing to the gene or its amplification product.

[35] Fig. 4-A, 4-B and 4-C, and the gene constituting at least one gene polymorphism set selected from the group consisting of the gene polymorphism set shown in Fig. 20 are specifically amplified. A retinopathy-related gene polymorphism analysis kit comprising a primer pair that can be obtained, or a nucleic acid probe that can specifically and hybridize with the gene or its amplification product.

[36] A risk polymorphism set consisting of one or more genetic polymorphisms that are related to the disease and have a genotype, and a disease risk assessment formula with environmental factors as variables, and the first patient In a set of data, a computer provided with a recording unit that records the average value of disease degrees according to age of the first patient,

An axis corresponding to each disease risk of a plurality of diseases is drawn radially, a line segment connecting the points on the axis corresponding to the average value of the disease risk for each disease is drawn, and the disease And a second step of creating a first radar chart by drawing a line segment connecting the points on the axis corresponding to each first disease risk level.

[37] The risk polymorphism set consisting of one or more genetic polymorphisms that are related to the disease and have a genotype, and a disease risk assessment formula with environmental factors as variables, In a computer equipped with a recording unit that records the average value of disease levels by age for a set of data,

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 first A first step of obtaining a second disease risk as a predicted value in the future from the risk judgment formula using information on the genetic polymorphism of the second patient;

[38] 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 first A third step of obtaining a second disease risk as a future predicted value from the risk judgment formula using information on the genetic polymorphism of the second patient;

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 40. The fourth step of creating a second radar chart by drawing a line segment connecting the points on the axis corresponding to the second disease risk level for each patient. Presentation method of onset prediction.

[39] The risk judgment formula is:

Including an interaction term between the gene polymorphism set and environmental factors,

40. Any one of claims 36 to 38, which is an expression obtained by performing multiple regression analysis on the set of data of the first patient using the disease degree as an objective variable and the genetic polymorphism set and the environmental factors as explanatory variables. The onset prediction presentation method according to any one of the items.

[40] The onset prediction presentation method according to any one of claims 36 to 39, wherein the plurality of diseases are arteriosclerotic diseases caused by diabetes, myocardial infarction, nephropathy, and retinopathy.

[41] A fifth step of drawing a character string representing the degree of disease at a predetermined position near the axis in which a myocardial infarction incidence table by age for the set is recorded in the recording unit and drawn radially. In addition,

The axis corresponding to the atherosclerotic disease represents the maximum intima-media thickness, the character string is a character string corresponding to 0.8, 1.4, and 2.8, and the predetermined position is The maximum intima-media thickness value is a position corresponding to each of 0.8, 1.4, and 2.8. The onset prediction presentation method of description.

[42] The method further includes a fifth step of drawing a character string representing the degree of disease at a predetermined position in the vicinity of the axis drawn radially.

The axis corresponding to nephropathy represents the urinary albumin excretion rate, the character string is a character string representing no nephropathy, early nephropathy, and overt nephropathy, and the predetermined position is nephropathy 41. The onset prediction presenting method according to claim 40, which is a position corresponding to the urinary albumin excretion rate representing each of no, early nephropathy, and overt nephropathy.

[43] The method further includes a fifth step of drawing a character string representing the degree of disease at a predetermined position near the axis drawn radially.

The axis corresponding to retinopathy represents a disease degree, and the character string is a character string representing no retinopathy, simple retinopathy, preproliferative retinopathy, and proliferative retinopathy, and the predetermined position is no retinopathy 41. The onset prediction presentation method according to claim 40, which is a position corresponding to the degree of disease representing each of simple retinopathy, preproliferative retinopathy, and proliferative retinopathy.

[44] A fifth step of drawing a character string representing the degree of disease at a predetermined position near the axis in which the age-specific myocardial infarction incidence table for the set is recorded in the recording unit and drawn radially. In addition,

The axis corresponding to myocardial infarction represents the incidence of myocardial infarction, and the character string is the same character as a healthy person, the same generation as a diabetic patient, a history of myocardial infarction, and a character string representing the risk of recurrence, The predetermined position determines the myocardial infarction rate corresponding to the age of the second patient from the age-specific myocardial infarction rate table, and the determined myocardial infarction rate is 1Z8 times, 1 time, 3 times, and 5 41. The onset prediction presentation method according to claim 40, which is a position corresponding to each of the double values.

[45] The first patient's age-specific disease degree and occurrence frequency obtained for each disease with respect to the set are recorded in the recording unit in association with each other,

A sixth step of reading out the degree of disease and the frequency of occurrence corresponding to the age of the second patient from the recording unit and drawing it on a graph with the disease level and the frequency of occurrence as two orthogonal axes, and the average of the disease risk And a seventh step of drawing a graphic representing each value of the first disease risk of the second patient at a position on the axis corresponding to each value. The onset prediction presentation method according to any one of claims 36 to 44, which is included in the above.

[46] The first patient's age-specific disease degree and frequency of occurrence determined in association with the set are recorded in the recording unit in association with each other,

A sixth step of reading out the degree of disease and the frequency of occurrence corresponding to the age of the second patient from the recording unit and drawing them on a graph with the disease level and the frequency of occurrence as two orthogonal axes, and drawing the graph on the second patient And a seventh step of drawing a graphic indicating each value of the first and second disease risk levels at a position on the axis corresponding to each value.

The onset prediction presentation method according to any one of 36 to 44.

[47] A genetic polymorphism set consisting of one or more genetic polymorphisms that are related to the disease and have a genotype, and a recording section that records the disease risk assessment formula with environmental factors as variables Computer

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. When the value of the first interaction term is calculated using the value obtained by changing it as the value of the environmental factor, and the calculated value of the first interaction term exceeds a predetermined value V And a method for presenting the onset prediction including a first step of presenting the necessity of coping.

[48] The predetermined number is a value estimated that the test value can be easily changed,

48. The method of claim 47, wherein the predetermined value is a value that is determined to have a high risk of onset.

[49] The risk judgment formula is an expression obtained by multiple regression analysis of the first patient data set using the disease degree as an objective variable and the genetic polymorphism set and the environmental factors as explanatory variables. 49. The onset prediction presentation method according to claim 47 or 48.

[50] In a computer comprising a recording unit that records the standard deviation of the test value of the environmental factor obtained for each disease with respect to the first patient data set,

Among the environmental factors used in the disease risk judgment formula, a first character string representing each of a plurality of environmental factors that change depending on treatment is arranged and drawn in a first direction, and is orthogonal to the first direction. A second step of arranging and drawing a second character string representing each of a plurality of diseases in a second direction; A plurality of first line segments passing through the first character string and parallel to the second direction, and a plurality of second line segments passing through the second character string and parallel to the first direction are drawn in a grid pattern. The step of determining the degree of disease corresponding to the intersection of the lattice includes an interaction term of an environmental factor corresponding to the intersection and a predetermined gene polymorphism set; and a second patient In the case of having a gene polymorphism set, a graphic having a size corresponding to the magnitude of the influence of the predetermined change of the environmental factor corresponding to the intersection on the disease degree determination formula of the disease corresponding to the intersection is set at the intersection. The onset prediction presentation method according to any one of claims 47 to 49, comprising a third step of drawing.

[51] the figure is circular;

The magnitude of the influence of the predetermined change of the environmental factor on the disease degree determination formula is a product of the sum of the coefficients of the terms including the environmental factor and the standard deviation corresponding to the environmental factor. Item 47. The method for presenting onset prediction according to Item 47.

52. The onset prediction presentation method according to claim 47 or 49, wherein the plurality of diseases are arteriosclerotic diseases caused by diabetes, myocardial infarction, nephropathy, and retinopathy.

[53] The method according to any one of claims 47 to 49, further comprising a fourth step of drawing a plurality of countermeasures for improving the inspection value of the environmental factor represented by the first character string in a predetermined order. The onset prediction presentation method of description.

[54] Diseases that are related to disease and have information about the presence or absence of a gene polymorphism set consisting of one or more gene polymorphisms having genotypes, and environmental factors that can change in individuals as variables A risk judgment formula, an ID for identifying the 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 were recorded. In a computer comprising a recording unit,

A first step of accepting designation of the subject's ID;

A degree of change in the judgment formula for the subject due to a change in the environmental factor being a variable; and A method for determining the necessity of coping with a disease, comprising: a fourth step of determining whether the subject needs to coping with the disease using the reference value.

55. The method for determining the necessity for coping with a disease according to claim 54, wherein the determination formula includes a product of a function of the environmental factor and information indicating the presence or absence of the genetic polymorphism set.

[56] In the fourth step, the first value of the environmental factor at a predetermined time of the subject is changed by a predetermined value to obtain a second value, and the environment that is a variable of the judgment formula for the subject Substituting the second value as a factor to calculate the disease risk of the subject, and comparing the calculated disease risk with the reference value determines the necessity of dealing with the disease The method for determining the necessity of coping with a disease according to claim 55, wherein

[57] When the disease is an arteriosclerotic disease, the gene polymorphism set is shown in FIGS. 1A and 1.

Corresponds to one of the sets described in B,

When the disease is myocardial infarction, the gene polymorphism set corresponds to one of the sets described in FIGS. 2-A and 2-B,

When the disease is nephropathy, the gene polymorphism set corresponds to any of the sets described in FIGS. 3A and 3B.

57. The disease according to any one of claims 54 to 56, wherein when the disease is retinopathy, the gene polymorphism set corresponds to any of the sets described in FIGS. 4A, 4B and 4C. How to determine the need to deal with

[58] When the disease is an arteriosclerotic disease, the gene polymorphism set corresponds to any of the sets shown in FIG.

When the disease is myocardial infarction, the gene polymorphism set corresponds to any of the sets described in FIG.

When the disease is nephropathy, the genetic polymorphism set corresponds to any of the sets described in FIG.

57. A method for determining the necessity of coping with a disease according to any one of claims 54 to 56, wherein when the disease is retinopathy, the gene polymorphism set corresponds to any of the sets shown in FIG. .