JP6296752B2 - Method, apparatus, program and recording medium for determining dosage of antidiabetic drug - Google Patents

Description

  The present invention relates to a method for determining a dosage of a therapeutic drug for diabetes, and more particularly, to a method for determining a dosage of a therapeutic drug based on genetic information of a diabetic patient.

  Conventionally, it has been known that, when a drug treatment is performed for a certain disease, a single drug does not act on all patients having the same disease in the same manner. In response to this, in recent years, the momentum of genomic pharmacology and custom-made medical care, which provides the most efficient drug administration according to the genetic characteristics of patients, has been increasing. According to genomic pharmacology, it is considered that whether or not the effect of a drug works effectively is determined based on the genetic background of the patient himself. In response to the growing momentum of genomic pharmacology, in the future, by identifying each patient as a responder and non-responder for the drug, the optimal drug dosing determination and dosing plan for each patient will be determined. Is expected to do.

  Patent Document 1 below discloses a method for selecting a drug. According to the selection method of Patent Document 1, an optimal drug corresponding to a patient can be selected from a plurality of sympathetic nerve blockers based on the genetic background for each patient with benign prostatic hyperplasia.

JP 2008-005785 A

  Thus, the momentum of drug selection based on the genetic background of patients is increasing, and as shown in Patent Document 1 below, drug selection methods have been proposed for some diseases. However, among the various diseases, for diabetes whose number of patients has increased due to the recent increase in lifestyle-related diseases, the relationship between the therapeutic effect of drugs and genetic factors has not been sufficiently reported yet. It is a fact.

  The present invention has been made in order to solve the above-mentioned problems, and its purpose is to make a more appropriate determination based on the genetic background of each patient regarding the necessity and dose of administration of a therapeutic drug for diabetes. is there.

  The inventor has been diligently studying to achieve the above object, and among various gene polymorphisms, oxidative stress-related gene polymorphism p22phox C242T allele, glycation-related gene polymorphism AR (Aldose reductase) -106T allele, or infection-related gene polymorphism CD14 (cluster of differentiation 14) -159T allele and a significant difference in the blood HbA1c level of diabetic patients It was found that pioglitazone, which is a therapeutic agent for diabetes, is effective in patients with type 2 diabetes having any of these three gene polymorphisms. For PPAR-r (Pro12Ala), resistin (C-420G), PGC-1 (G1564A), and IRS-1 (G3494A), sEH (G860A) gene polymorphisms related to insulin sensitivity, blood HbA1c in diabetic patients It was found that there was no significant association with the value change.

  In addition, based on this finding, the present inventor determined that the blood HbA1c level in diabetic patients, the presence or absence of the p22phox C242T allele and the presence or absence of the AR-106T allele, after a predetermined period (6 months) had elapsed. We found that it was possible to estimate the degree of decrease in blood HbA1c level, and found a regression equation for estimation. Many patients with type 2 diabetes (about 39%) have the p22phox C242T allele or AR-106T allele and found that pioglitazone is an effective case.

  That is, the present invention includes the following aspects.

The first determination method according to the present invention is:
In a device comprising a calculation unit and a recording unit, a method for determining the dosage of a therapeutic agent for diabetes,
The recording unit records the obtained genetic polymorphism information and clinical data of the subject;
The operation unit identifies whether or not a specific genetic polymorphism exists in the acquired genetic polymorphism information;
A step of determining the dosage of a therapeutic agent for diabetes based on the presence / absence of the specific gene polymorphism and the clinical data;
Including
In the determination method, the clinical data includes a blood HbA1c value of the subject, and the specific gene polymorphism includes a C242T gene polymorphism of p22phox and a 106T gene polymorphism of aldose reductase (Aldose reductase). is there.

Moreover, the 1st determination apparatus which concerns on this invention is
An apparatus that includes a calculation unit and a recording unit, and that determines a dose of a therapeutic agent for diabetes,
The recording unit records the obtained genetic polymorphism information and clinical data,
The arithmetic unit identifies whether a specific genetic polymorphism exists in the acquired genetic polymorphism information,
The arithmetic unit determines the dosage of a therapeutic drug for diabetes based on the presence or absence of the specific gene polymorphism and the clinical data,
In the determination apparatus, the clinical data includes a blood HbA1c value of the subject, and the specific gene polymorphism includes a C242T gene polymorphism of p22phox and a 106T gene polymorphism of aldose reductase. is there.

Moreover, the determination program according to the present invention includes:
A program for determining the dosage of an antidiabetic drug,
On the computer,
A function to record the acquired genetic polymorphism information and clinical data;
A function for identifying whether or not a specific genetic polymorphism exists in the obtained genetic polymorphism information;
A function of determining the dosage of a therapeutic agent for diabetes based on the presence or absence of the specific gene polymorphism and the clinical data;
Realized,
In the determination program, the clinical data includes a blood HbA1c value of the subject, and the specific gene polymorphism includes a C242T gene polymorphism of p22phox and a 106T gene polymorphism of aldose reductase. is there.

Further, a computer-readable recording medium on which the determination program according to the present invention is recorded,
A computer-readable recording medium storing a program for determining a dosage of a therapeutic drug for diabetes,
On the computer,
A function to record the acquired genetic polymorphism information and clinical data;
A function for identifying whether or not a specific genetic polymorphism exists in the obtained genetic polymorphism information;
A function of determining the dosage of a therapeutic agent for diabetes based on the presence or absence of the specific gene polymorphism and the clinical data;
Realized,
The determination program, wherein the clinical data includes a blood HbA1c value of the subject, and the specific gene polymorphism includes a C242T gene polymorphism of p22phox and a 106T gene polymorphism of aldose reductase A recorded computer-readable recording medium.

The second determination method according to the present invention is as follows.
A method for determining the dosage of a therapeutic agent for diabetes,
Obtaining genetic polymorphism information and clinical data of the subject;
Identifying whether a specific genetic polymorphism exists in the obtained genetic polymorphism information;
Determining the dosage of a therapeutic agent for diabetes based on the presence or absence of the specific gene polymorphism and the clinical data;
Including
In the determination method, the clinical data includes a blood HbA1c value of the subject, and the specific gene polymorphism includes a C242T gene polymorphism of p22phox and a 106T gene polymorphism of aldose reductase (Aldose reductase). is there.

Moreover, the second determination apparatus according to the present invention includes:
A device for determining the dosage of a therapeutic agent for diabetes,
Means for recording the obtained genetic polymorphism information and clinical data;
Means for identifying whether or not a specific genetic polymorphism exists in the obtained genetic polymorphism information;
Means for determining the dosage of a therapeutic agent for diabetes based on the presence or absence of the specific gene polymorphism and the clinical data;
With
In the determination apparatus, the clinical data includes a blood HbA1c value of the subject, and the specific gene polymorphism includes a C242T gene polymorphism of p22phox and a 106T gene polymorphism of aldose reductase. is there.

  According to the present invention, it is possible to administer an antidiabetic drug by identifying whether or not a specific genetic polymorphism found to be related to the therapeutic effect of the antidiabetic drug is included in the genetic polymorphism information of the patient. Therefore, more appropriate determination can be made based on the genetic background of each patient.

It is a block diagram which shows the whole system containing the apparatus which determines the dosage of the diabetes therapeutic agent which concerns on this invention. It is a flowchart which shows the determination process which a determination apparatus performs. It is a flowchart which shows the determination process of step S4 which a determination apparatus performs.

  Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings. In the following description and drawings, the same reference numerals indicate the same or similar components, and thus descriptions of the same or similar components are omitted.

  In the following description, “gene polymorphism” refers to the diversity of genes in which two or more alleles (alleles) exist at one locus in the same population. Specifically, it indicates a mutation of a gene that exists at a certain frequency or more in a certain population. The gene mutation referred to here is not limited to the region transcribed as RNA, but includes mutations in all DNAs that can be identified on the human genome including regulatory regions such as promoters and enhancers. 99.9% of human genomic DNA is common among individuals, and the remaining 0.1% is responsible for such diversity, and is involved in individual differences in susceptibility to specific diseases, responsiveness to drugs and environmental factors. obtain. A genetic polymorphism does not always make a difference in phenotype. SNP (single nucleotide polymorphism) is a kind of gene polymorphism, but the gene polymorphism targeted by the present invention is not limited to this.

  FIG. 1 is a block diagram showing the entire system including a device for determining the dose of a therapeutic drug for diabetes according to the present invention (hereinafter referred to as a determination device). As shown in FIG. 1, the system is installed in blood collection means 11 and computer 12 installed in hospital 1, gene polymorphism analysis array 21 and computer 22 installed in analysis institution 2, and service providing institution 3. The determination device 31 is provided. Here, the computers 12 and 22 and the determination device 31 are connected to a communication line 4 such as the Internet.

  The determination device 31 includes a CPU 32, a memory 33, a recording unit 34 such as a hard disk, a communication interface (hereinafter referred to as I / F) unit 35 that performs communication with the outside, an operation unit 36 such as a keyboard, and a liquid crystal display. A display unit 37 such as a display, an input / output I / F unit 38, and an internal bus 39 for exchanging data between the units are provided. In the recording unit 34, information on a specific gene polymorphism found to be related to the therapeutic effect of the diabetes drug is recorded in advance as a reference table.

  Details of the dose determination processing by the determination device 31 will be described later. The operation of the entire system including the determination device 31 will be described as follows.

  First, in the hospital 1, a specimen (hereinafter referred to as a test sample) from which a subject's gene (genome) can be extracted is collected by the blood collection means 11. At this time, clinical data (subject ID, gender, blood collection information (including current and past HbA1c values), past history, physical findings, past administration of antidiabetic drugs, etc.) are recorded in the recording unit of the computer 12. The The test sample is provided to the analysis organization 2 and analyzed using the gene polymorphism analysis array 21 to detect a gene polymorphism having a genotype. The gene polymorphism analysis array 21 is a probe in which probes for detecting a gene polymorphism are arranged at high density and immobilized on a support such as a silicon wafer or a glass slide. What is necessary is just to specifically recognize and capture a gene polymorphism associated with a disease (in the present invention, diabetes).

  In the present invention, the gene polymorphism to be detected using the array 21 for gene polymorphism analysis only needs to contain at least p22phox C242T and AR-106T used for determination. Other gene polymorphisms may be included in relation to performing other tests than the dose determination. An example of the gene polymorphism detected using the gene polymorphism analysis array 21 is shown in Table 1.

  The detected genetic polymorphism information is once recorded in the recording means of the computer 22 and then transmitted to the determination device 31 of the service providing organization 3 via the communication line 4. The determination device 31 receives genetic polymorphism information from the computer 22 of the analysis institution 2 via the communication I / F unit 35 and records it in the recording unit 34. The determination device 31 receives clinical data from the computer 12 of the hospital 1 and records it in the recording unit 34.

  Thereafter, the determination device 31 searches whether or not the received genetic polymorphism information is included in the reference table previously recorded in the recording unit 34, and the necessity of administration of the therapeutic drug is determined according to the result. And determine the dose. After the determination, 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 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 and transmitted from the computer 12 of the hospital 1, for example.

  Any method can be used for analyzing the test sample as long as it is a method for detecting the genotype of the subject. As a general method, a sample containing DNA, such as a subject's blood, sputum, skin, bronchoalveolar lavage fluid, other body fluid, or tissue, is used as a test sample. Many methods are known as analysis methods, for example, sequencing method, PCR method, ASP-PCR method, TaqMan method, invader assay method, MALDI-TOF / MS 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, only a certain gene polymorphism is specifically amplified using primers specific to the gene polymorphism. In the PCR method, it is common to place the polymorphic nucleic acid on the 3′-most side, but the genetic polymorphism is second from the 3′-end side as in the Allele Specific Primer (ASP) -PCR method. In the primer design, such as where to place the gene polymorphism in the primer, and what kind of nucleic acid sequence other than the gene to be detected There is no particular limitation as long as it 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 a target site, and a PCR reaction is performed with primers designed to amplify a region containing this site. When the PCR reaction from the primer reaches the region where this allele-specific probe is hybridized, the fluorescent dye present at the 5 ′ end of the hybridized probe is cleaved by the 5-prime nuclease activity of Taq polymerase, leaving the quencher. Causes fluorescence. By this method, it can be seen how much the allele-specific probe has been hybridized. In the invader assay method, an allele probe having a specific sequence 5 ′ from the gene polymorphic site of the template and a flap sequence on the 3 ′ side, and a specific sequence 3 ′ from the gene polymorphic site of the template It is possible to specify which allele probe has hybridized using the same principle as the TaqMan method, using three types of oligonucleotides: an invader probe having a FRET probe and a FRET probe containing a sequence complementary to a flap sequence. In the MALDI-TOF / MS method, a primer adjacent to a gene polymorphic site is prepared and this region is amplified, and then only one base of the gene polymorphic site is amplified using ddNTP. Subsequently, gene polymorphism is identified by identifying the kind of added ddNTP using MALDI-TOF / MS. In a method generically called a DNA chip method such as the Hybridene method, an oligonucleotide probe containing a gene polymorphism is placed on an array, and hybridization with sample DNA amplified by PCR is detected.

  FIG. 2 is a flowchart illustrating the determination process performed by the determination device 31. Hereinafter, according to the flowchart of FIG. 2, the dose determination process by the determination apparatus 31 is demonstrated concretely. In the following description, the processing performed by the CPU 32 is described unless otherwise specified. Further, the CPU 32 uses the memory 33 as a work area or an area for temporarily storing data during processing, and records data during processing and processing results in the recording unit 34 as necessary.

  In step S1, genetic polymorphism information and clinical data of a subject used for determination are acquired.

First, genetic polymorphism information is acquired from the analysis organization 2 via the communication line 4 and recorded in the recording unit 34. The gene polymorphism information is transmitted and recorded as a gene polymorphism code assigned to each gene polymorphism having a genotype, and the data format is, for example, a hospital code assigned to each requesting hospital and a subject assigned to each subject. This is a format in which a plurality of gene polymorphism codes g _i (i = 1 to n) are associated with each ID group. In addition, the clinical data of the subject is acquired from the hospital 1 via the communication line 4 and is recorded in the recording unit 34 after being given the requesting hospital code. As the data format of clinical data, for example, sex is recorded in clinical data as variable SEX = 1 for males and SEX = 2 for females. For past medical history and physical findings, for each disease name or symptom, the variable name to be used on the system is determined in advance, and the value is 1 if there is a medical history or if there is a symptom. The value is set to 0, and the variable name and value are set and recorded in clinical data. For example, the clinical history is recorded as clinical history [prostate tumor] = 0 and physical findings [lower leg edema] = 1.

  In step S2, it is identified whether or not a specific genetic polymorphism exists in the genetic polymorphism information of the subject obtained in step S1.

Specifically, for one {hospital code, subject ID}, a plurality of gene polymorphism codes g _i (i = 1 to n) are read from the recording unit 34, and the read gene polymorphism codes g _i are recorded in advance. Whether it is included in the reference table recorded in the section 34 is identified. In the reference table, information on a specific gene polymorphism found to be related to the therapeutic effect of a diabetic drug is recorded in advance. Specifically, in this embodiment, the p22phox C242T gene polymorphism is recorded. And AR-106T gene polymorphisms are recorded in the form of genetic polymorphism codes.

For example, it reads out the polymorphism encoding g ₁ from the recording unit 34, identifies whether this polymorphism code g ₁ is included in the reference table. If it is included, a value “1” (true) is set in the flag corresponding to the genetic polymorphism code g ₁ (assuming that the flag is initialized to “0” (false) in advance). This identification process is executed for all of the plurality of gene polymorphism codes g _i (i = 1 to n).

  In step S3, determination is made based on the flag value recorded in step S2, and all the flag values are “0” (false), that is, the specific gene described in the reference table in the genetic polymorphism information of the subject. If the polymorphism does not exist, it is determined that there is no need to administer the therapeutic agent at this point, and the process proceeds to step S5 without performing the process of step S4. If the value of any one of the flags is “1” (true), the process proceeds to step S4 using a predetermined determination formula.

  In step S4, the necessity of the therapeutic drug administration and the dosage are determined based on a predetermined determination formula using the flag value recorded in step S2 and the clinical data acquired in step S1.

  First, the determination formula used in step S4 will be described. In the judgment formula, the amount of change in blood HbA1c value dHbA1c is the objective variable, and the current blood HbA1c value and the presence or absence of the p22phoxC242T allele and the presence or absence of the AR-106T allele are explanatory variables. Use regression equations determined by analysis. For calculation of the value of the regression equation, the flag value, which is information indicating the presence or absence of the specific gene polymorphism, identified in step S2, and the clinical data of the subject obtained in step S1 (current blood HbA1c value) And use. The regression equation for obtaining the change amount dHbA1c of the blood HbA1c value is as follows.

dHbA1c = a * HbA1c + b * p22phox + c * AR + d (Formula 1)
Here, HbA1c is the current blood HbA1c value (unit%, NGSP international standard value), and p22phox and AR are the presence or absence of the p22phox C242T allele and the presence or absence of the AR-106T allele, respectively, “1” or “0” ”. The constants a, b, c, and d are partial regression coefficients determined by multiple regression analysis. Since multiple regression analysis is well known, description thereof is omitted.

  Table 2 shows an example of the results of the multiple regression analysis performed to determine the constants a, b, c, and d. In the example shown in Table 2, constants a = −0.4384, b = −0.6728, c = −0.3187, d = 2.9624.

  From the amount of change dHbA1c calculated by (Equation 1), the estimated value HbA1c (3m) of blood HbA1c after the first period (3 months) and blood HbA1c after the second period (6 months) have passed. The respective estimated values HbA1c (6m) are calculated as follows.

HbA1c (3m) = HbA1c + 0.5 * dHbA1c (Formula 2)
HbA1c (6m) = HbA1c + 1.0 * dHbA1c (Formula 3)
The blood HbA1c value obtained by (Expression 2) and (Expression 3) is an index for estimating how much the blood HbA1c value changes when a therapeutic drug for diabetes is administered to a subject.

  Next, an example of the specific determination procedure performed in step S4 will be described below. FIG. 3 is a flowchart showing the determination process of step S4 performed by the determination apparatus 31. In an example of the determination procedure described below, clinical data including the current blood HbA1c value, and an estimated value of the blood HbA1c value after a predetermined period (3 months and 6 months) obtained from the regression equation HbA1c (3m) and HbA1c (6m), the therapeutic drug dose is determined.

  In step S41, it is determined whether or not the subject should be excluded from the medication target. For example, if the subject's gender is male and there is a history of prostate tumor, it is determined in step S42 that there is no need to administer a therapeutic agent, and then the determination process in step S4 ends. If the condition is met, the process proceeds to step S43.

  In step S43, it is determined whether or not the current blood HbA1c value is greater than or equal to a predetermined first threshold value (eg, 8.0). If the conditions are met, HbA1c (3m) and HbA1c (6m) are calculated based on (Equation 1) to (Equation 3) and the process proceeds to step S44. If not, the process proceeds to step S48 described later. To do.

  In step S44, it is determined whether or not the therapeutic agent is to be administered in a predetermined first amount (for example, 15 mg). The judgment conditions are the following two: (1) gender is female, or (2) HbA1c (3m) is less than a predetermined second threshold (for example, 7.0), It is. If either of the conditions (1) or (2) is satisfied, it is determined in step S45 that the therapeutic agent is to be administered in the first amount, and then the process proceeds to step S48 to be described later. If not, the process proceeds to step S46.

  In step S46, it is determined whether or not the therapeutic agent is to be administered in a predetermined second amount (for example, 30 mg). The determination condition is that HbA1c (3m) is equal to or greater than the second threshold value (7.0), and HbA1c (6m) is less than the second threshold value (7.0). If the condition is satisfied, it is determined in step S47 that the therapeutic agent is to be administered in the second amount, and then the process proceeds to step S48 described later. If the condition is not satisfied, the process proceeds to step S48 as it is.

  In step S48, it is determined whether or not the dose of the therapeutic drug should be increased based on the progress information of the clinical data so far during the therapeutic drug administration. The criteria for determining the drug increase are, for example, that the dose of the therapeutic agent so far is the first amount (15 mg), and the administration period of the therapeutic agent in the first amount has exceeded 6 months in total. In addition, when there is no side effect such as “crus edema” in the physical findings of the subject, it is determined in step S49 that the dose of the therapeutic agent is increased to the second amount, and then the determination process in step S4 is performed. finish.

  In step S5, it is determined whether or not the process has been completed for all {hospital code, subject ID}, and the processes in steps S2 to S4 are repeated until it is determined that the process has been completed.

  If it is determined that the processing has been completed for all {hospital code, subject ID}, in step S6, the information on necessity / dose of the therapeutic agent determined in step S3 or S4 and the dose correspond to the subject ID. Then, the data is transmitted to the computer 12 corresponding to the requesting hospital code via the communication line 4.

  With the above processing, a series of dose determination processing by the determination device 31 is completed. Note that the determination process described above uses a general-purpose computer to read a computer program recorded on a computer-readable recording medium such as a hard disk or a CD-ROM, or obtain a computer program via a communication line. It can also be performed by the CPU executing it.

  As mentioned above, although this invention was demonstrated by specific embodiment, this invention is not limited to above-described embodiment.

  In the above embodiment, p22phox C242T gene polymorphism and AR-106T gene polymorphism are used as information on specific gene polymorphisms found to be related to the therapeutic effect of diabetes drugs. In addition to these two gene polymorphisms, the CD14-159T gene polymorphism may be used. The present inventor has also found that there is a single-correlated significant difference between the change in blood HbA1c level in diabetic patients with respect to CD14-159T, which is an infection defense-related gene polymorphism. Yes. When using this CD14-159T gene polymorphism for determination, after adding the presence or absence of the CD14-159T allele as an explanatory variable of the regression equation of (Equation 1), a multiple regression analysis is performed using a new regression equation, What is necessary is just to newly determine a partial regression coefficient.

  In addition, the presence / absence of the past history and the presence / absence of physical findings exemplified in step S41 or S48 of the above embodiment are merely examples, and if a new report is made on the past history or physical findings to be considered in the determination, Thus, the determination criteria may be added or changed as appropriate.

  In addition, as long as the above-described determination process can be realized, the apparatus of the present invention can be an apparatus in which other configurations are appropriately added or replaced with other configurations as necessary. For example, instead of the display unit 37 and the operation unit 36, a touch panel type configuration in which these units are integrated may be realized.

  In the above embodiment, the genetic polymorphism information and clinical data of the subject used for the determination are acquired via the communication line 4, but the data acquisition route is not limited to this, and the data used for the determination, etc. May be recorded in some recording means (for example, portable recording means such as an IC card or a memory card provided for each individual), and data or the like may be read out and used accordingly.

  In addition, the individual's genetic polymorphism information and clinical data acquired from the analysis organization are recorded in the database of the service provider in correspondence with the individual ID, and if the individual ID is notified to each individual, the individual ID By just receiving the communication, the dose determination process can be performed again using the corresponding gene polymorphism information and clinical data recorded in the database.

  Moreover, in the said embodiment, although the determination process shown in FIG. 2 and FIG. 3 is described as a process which CPU32 performs, the process which CPU32 performs is classified into each function, and a dedicated electronic circuit for every function These electronic circuits may share and execute the determination processing of FIG. 2 and FIG.

  Moreover, in the said embodiment, although the determination process shown in FIG.2 and FIG.3 is described as a process which CPU32 performs, as long as the data used for a process are visualized by paper data etc., it performs by a determination process. The calculation process and the identification process may be appropriately performed by a human.

  Hereinafter, the present invention will be described more specifically through description of experimental examples. However, the present invention is not limited to the following experimental examples.

In the following experimental examples, the relationship between pioglitazone, a therapeutic drug for diabetes, and various gene polymorphisms was investigated. Specifically, we investigated the relationship between changes in HbA1c levels in subjects after 6 months of administration of pioglitazone, an insulin sensitivity-improving drug, and various clinical data and insulin sensitivity-related gene polymorphisms. Genetic factors and clinical data affecting management effects were identified.

・ Subjects: Type 137 diabetic patients who are newly administered 15 mg to 30 mg of pioglitazone who are admitted to one hospital each in Kanagawa Prefecture and Osaka Prefecture, a total of 137 (91 men, 46 women, age 60.7 ± 10. 8 years old). The determination of patients with type 2 diabetes was performed based on the criteria of the World Health Organization (WHO). All subjects were given written informed consent after fully explaining the purpose and content of this study.

-Table 3 shows a summary of genetic polymorphism subjects for which the association was investigated . The genetic polymorphism for which the association was investigated is as shown in Table 1 in the description of the embodiment.

・ Survey results Among the various gene polymorphisms shown in Table 1, oxidative stress-related gene polymorphism p22phox C242T allele, glycation-related gene polymorphism AR (Aldose reductase) -106T allele, or infection defense-related gene polymorphism CD14 It was found that there was a single correlation significant difference between the (cluster of differentiation 14) -159T allele and the change in the blood HbA1c level in diabetic patients. The results of the survey on the relationship between CD14 gene polymorphism and clinical data are shown in Table 4, the results of the study on the relationship between p22phox gene polymorphism and clinical data are shown in Table 5, and the relationship between the AR gene polymorphism and clinical data are shown in Table 5. Table 6 shows the results of the survey on the relationship. In these Tables 4 to 6, focusing on the change value ΔHbA1c in blood HbA1c, p = 0.0097 for the CD14 gene polymorphism and p = 0.004 for the p22phox gene polymorphism. In the case of AR polymorphism, p = 0.001. In any case, the p-value is sufficiently low, and the change in the blood HbA1c value ΔHbA1c is determined to be statistically significant. It was done.

  On the other hand, PPAR-r (Pro12Ala), resistin (C-420G), PGC-1 (G1564A), IRS-1 (G3494A), and sEH (G860A) gene polymorphisms related to insulin sensitivity There was no significant association with changes in the medium HbA1c level.

  Next, referring to the results in Tables 4 and 5, in order to estimate the blood HbA1c value of the subject 6 months after pioglitazone administration, the change dHbA1c in the blood HbA1c value is obtained by multiple regression analysis. A regression equation was determined. As explanatory variables, the current blood HbA1c value of the subject, the presence or absence of the p22phox C242T allele, and the presence or absence of the AR-106T allele were used. The regression equation is as shown in (Equation 1) in the description of the embodiment, and the result of the multiple regression analysis is as shown in Table 2 in the description of the embodiment. From the amount of change dHbA1c obtained from the regression equation of (Equation 1), the estimated value of blood HbA1c after 6 months can be obtained by (Equation 3), and after 3 months by (Equation 2) The estimated value of HbA1c value could be obtained.

DESCRIPTION OF SYMBOLS 1 Hospital 2 Analysis organization 3 Service provision organization 4 Communication line 11 Blood collection means 12, 22 Computer 21 Array for gene polymorphism analysis 31 Judgment device 32 CPU
33 Memory 34 Recording unit 35 Communication interface unit 36 Operation unit 37 Display unit 38 I / O interface unit 39 Internal bus

Claims (10)

In a device comprising a calculation unit and a recording unit, a method for determining the dosage of a therapeutic agent for diabetes,
The recording unit records the obtained genetic polymorphism information and clinical data of the subject;
The operation unit identifies whether or not a specific genetic polymorphism exists in the acquired genetic polymorphism information;
A step of determining the dosage of a therapeutic agent for diabetes based on the presence / absence of the specific gene polymorphism and the clinical data;
Including
The clinical data includes blood HbA1c value of the subject, the particular genetic polymorphism, see contains the C242T polymorphism of p22phox, and 106T polymorphisms aldose reductase (aldose reductase),
The method for determining, wherein the diabetes is type 2 diabetes and the therapeutic agent for diabetes is pioglitazone . In the determining step, the calculation unit calculates an estimated value of the blood HbA1c value after elapse of a predetermined period of time for the subject using a regression equation determined in advance by multiple regression analysis,
Diagnosis patient data, wherein the regression equation uses the change in blood HbA1c value dHbA1c as an objective variable, and the subject's blood HbA1c value and the presence or absence of the p22phox C242T allele and the presence or absence of the AR-106T allele as explanatory variables The determination method according to claim 1, wherein the determination is a formula obtained by performing multiple regression analysis on the set. The clinical data further includes gender and medical history of the subject;
The step of determining comprises
A step of excluding the subject from the subject of the diabetes therapeutic agent when the arithmetic unit determines that the gender of the subject is male and the subject has a predetermined history. When,
When the calculation unit determines that the blood HbA1c value of the subject is greater than or equal to a first threshold value, a first estimated value after the first period has elapsed with respect to the blood HbA1c value and Calculating each second estimate after the second period has elapsed;
When the arithmetic unit determines that the gender of the subject is female or the first estimated value of the blood HbA1c value is less than a second threshold value, the therapeutic agent for diabetes Determining to administer a first amount;
The arithmetic unit has the first estimated value of the blood HbA1c value equal to or greater than the second threshold value, and the second estimated value of the blood HbA1c value is the second threshold value. The method according to claim 2, further comprising a step of determining that the antidiabetic agent is administered in a second amount when it is determined that the value is less than the value. History of previous SL predetermined is prostate tumor, determination method according to claim 3. The step of determining further comprises:
Whether the calculation unit increases the dose of the antidiabetic agent to the second amount based on the clinical data progress information of the subject so far during the administration of the antidiabetic agent. The determination method according to claim 3, comprising a determination step. The regression equation is
dHbA1c = a × HbA1c + b × p22phox + c × AR + d (Formula 1)
6. The determination method according to claim 2, wherein constants a, b, c, and d are partial regression coefficients determined by the multiple regression analysis. An apparatus that includes a calculation unit and a recording unit, and that determines a dose of a therapeutic agent for diabetes,
The recording unit records the obtained genetic polymorphism information and clinical data,
The arithmetic unit identifies whether a specific genetic polymorphism exists in the acquired genetic polymorphism information,
The arithmetic unit determines the dosage of a therapeutic drug for diabetes based on the presence or absence of the specific gene polymorphism and the clinical data,
The clinical data includes blood HbA1c value of the subject, the particular genetic polymorphism, see contains the C242T polymorphism of p22phox, and 106T polymorphisms aldose reductase (aldose reductase),
The determination apparatus in which the diabetes is type 2 diabetes and the antidiabetic agent is pioglitazone . A program for determining the dosage of an antidiabetic drug,
On the computer,
A function to record the acquired genetic polymorphism information and clinical data;
A function for identifying whether or not a specific genetic polymorphism exists in the obtained genetic polymorphism information;
A function of determining the dosage of a therapeutic agent for diabetes based on the presence or absence of the specific gene polymorphism and the clinical data;
Realized,
The clinical data includes blood HbA1c value of the subject, the particular genetic polymorphism, see contains the C242T polymorphism of p22phox, and 106T polymorphisms aldose reductase (aldose reductase),
A determination program in which the diabetes is type 2 diabetes and the therapeutic agent for diabetes is pioglitazone . A computer-readable recording medium storing a program for determining a dosage of a therapeutic drug for diabetes,
On the computer,
A function to record the acquired genetic polymorphism information and clinical data;
A function for identifying whether or not a specific genetic polymorphism exists in the obtained genetic polymorphism information;
A function of determining the dosage of a therapeutic agent for diabetes based on the presence or absence of the specific gene polymorphism and the clinical data;
Realized,
The clinical data includes blood HbA1c value of the subject, the particular genetic polymorphism, see contains the C242T polymorphism of p22phox, and 106T polymorphisms aldose reductase (aldose reductase),
A computer-readable recording medium recording a determination program in which the diabetes is type 2 diabetes and the antidiabetic agent is pioglitazone . A device for determining the dosage of a therapeutic agent for diabetes,
Means for recording the obtained genetic polymorphism information and clinical data;
Means for identifying whether or not a specific genetic polymorphism exists in the obtained genetic polymorphism information;
Means for determining the dosage of a therapeutic agent for diabetes based on the presence or absence of the specific gene polymorphism and the clinical data;
With
The clinical data includes blood HbA1c value of the subject, the particular genetic polymorphism, see contains the C242T polymorphism of p22phox, and 106T polymorphisms aldose reductase (aldose reductase),
The determination apparatus in which the diabetes is type 2 diabetes and the antidiabetic agent is pioglitazone .

Images