RU2293991C1 - Method for predicting genetically deterministic human diseases - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: method involves determining patient acetylation phenotype and predicting disease from table data built in advance. The table has morbidity coefficients for predicting diseases under prognosis and mortality rates caused by the diseases in groups of countries where rapid acetylators are predominant in more than 50% of population and in countries where slow acetylators are predominant in more than 50% of population in various age-specific life intervals. Prognosed diseases risks and lethal outcome risks caused by those diseases in given age intervals are determined from the values of the coefficients. The risks are predicted in the cases when said coefficient values corresponding to patient phenotype and sex are greater than the same coefficients of opposite phenotype of the same sex with authenticity level equal to or less than 0.05. Clinical course severity is additionally estimated in said age intervals depending on patient phenotype. Acetylation degree is taken into consideration.

EFFECT: high accuracy of prognosis.

6 cl, 2 tbl

Description

The invention relates to medicine and can be used to predict the genetically determined diseases of an individual person throughout his life.

The urgent task of modern biology and medicine is to establish factors of an individual's individual predisposition to various diseases. In connection with the decoding of the human genome, work has recently been intensively carried out to search for genes by mutation of which a disease prognosis can be made. Many methods have been developed for predicting various diseases based on gene mutations.

A known method for the diagnosis and prognosis of cancer based on mutations in the gene of a multifunctional tumor suppressor (MTS). By mutations in the MTS gene in the germ line, one can diagnose a predisposition to such forms of cancer as melanoma, ocular melanoma, leukemia, astrocytoma, glioblastoma, lymphoma, glioma, sarcoma, etc. [1, 2].

A known method for predicting the risk of cancer, based on the determination of coordination disorders between alleles in isolated cells compared with coordination in cells of a healthy person. [3]

The predisposition of people to various diseases is also associated with the individual activity of a genetically determined xenobiotic detoxification enzyme system. These include enzymes P-450, NAT1, NAT2, etc., varying in a wide range, due to genetic polymorphism.

A known method for the diagnosis of diseases such as cardiovascular disease, cancer, gastrointestinal diseases, inflammation, hematological diseases, neurological diseases, diseases of reproductive function and urological diseases, based on the determination of disorders of the activity of the enzyme NAT1 [4].

The advantage of these methods is the high accuracy of the forecast. However, they do not specify the age of the patient at which there is a risk of a predictable disease, the severity of the course of the disease and the possibility of death from him are unknown. This does not allow the timely implementation of preventive measures to reduce the severity of diseases and, in particular, to avoid death.

The genetically determined enzyme NAT2 (N-acetyltrasferase) takes part in the biotransformation of exogenous and endogenous substrates (lipids, hormones, neurotransmitters, immune factors, inflammation factors).

According to the activity of the genetic enzyme NAT2, all human populations are divided into two groups: with the phenotype of fast and slow acetylation (fast and slow acetylators). At the same time, no physiological advantage was found in these phenotypes. The number of fast and slow acetylators in different ethnic populations varies over a wide range.

The connection between the N-acetylation metabolism system and a person’s predisposition to a number of diseases is known. For example, patients with diabetes mellitus, eczema, adhesive disease and nephropathy have a phenotype of rapid acetylation [5], and patients with some infectious diseases have a phenotype of slow acetylation [6]. Based on this regularity by the acetylation phenotype, one can predict the patient's predisposition to these diseases in advance, as well as select a drug therapy for a particular patient.

For example, there is a method for establishing the predisposition of patients with rheumatoid arthritis to the risk of side effects when taking sulfazalazine, a well-known and widely used drug for the treatment of rheumatoid arthritis [7]. Prediction of side effects by this method is based on the determination of the patient’s NAT2 gene configuration diplotype, since it was found that side effects occur only in slow acetylators.

However, despite the fact that the connection between the acetylation phenotype and the phenotype predisposition to a number of diseases is known, there are no known methods for predicting these diseases with a clarification of the age at which there is a risk of such diseases, the prognosis of the severity of the course of the disease at different age intervals of a person’s life and the possibility of death from the predicted diseases is unknown.

The objective of the invention is the ability to predict genetically determined human diseases with the specification of the age of their development with an assessment of the severity and risk of death.

This problem is solved by the proposed method, which is carried out as follows. The patient determines the acetylation phenotype and predicts the risk of genetically determined diseases according to a previously prepared table. To compile a table according to world statistics, for example, the World Health Organization (WHO), the incidence rates of predicted diseases "a" and the mortality rates "b" from these diseases are revealed, which are given annually by WHO for different countries of the world separately for men and women, indicating the following age intervals (years): up to a year, 1-4, 5-15, 15-24, 25-34, 35-44, 45-54, 55-64, 65-74, 75 and older. Calculate the average annual values of these coefficients for the indicated age intervals, taking into account the data given for 10-20 years.

According to scientific statistics (articles, reviews), the frequency of occurrence of phenotypes of fast and slow acetylation (% of fast or slow acetylators of the total population of the country) is revealed for the same countries. Then, using the array of these data and the well-known mathematical method of statistical data processing, average annual values of these coefficients are calculated for a group of countries with a predominance of more than 50% of fast acetylators and a group of countries with a predominance of more than 50% of slow acetylators.

At the same time, the risk of each disease at the indicated age intervals and the risk of death from it are predicted if the coefficients “a” and “b” corresponding to the phenotype and gender of the patient, with a reliability equal to or less than 0.05, exceed the similar coefficients of same sex of the opposite phenotype.

The patient acetylation phenotype can be determined by methods known to those skilled in the art. In one of the methods, the phenotype is determined by the genotype of the patient. At the same time, venous blood is sampled from the patient, DNA is extracted from the nuclei of lymphocytes and the alleles of the NAT2 gene are determined using primers. When one of the alleles NAT2 * 4, NAT2 * 12A and NAT2 * 12C is detected, the rapid acetylation phenotype is established, and when two alleles are found from NAT2 * 5, NAT2 * 6, NAT2 * 7, NAT2 * 10, NAT2 * 11, NAT2 * 13 , NAT2 * 14 establish the phenotype of slow acetylation [8].

The patient acetylation phenotype can be determined by another known method [9]. In accordance with this method, in the morning on an empty stomach, the patient is given a test preparation inside, which is used as sulfadimezin at a dose of 7 mg / kg of body weight or caffeine at a dose of 4 mg / kg of body weight and its amount is determined after 6 hours in urine. In this case, the phenotype of rapid acetylation at a degree of acetylation of the test preparation is 70-100%, and the phenotype of slow acetylation at a degree of acetylation of less than 70%.

According to the claimed method, in each identified age range of predictable diseases, the severity of diseases for a particular patient is estimated taking into account the direct dependence of the parameters “acetylation degree - disease severity” for fast acetylators and the inverse relationship of these parameters for slow acetylators.

To carry out the forecast for the proposed method, the patient undergoes one or two medical procedures - taking a urine sample after administration of the test drug, or collecting peripheral venous blood to determine its acetylation phenotype.

Prepare a table in advance [1], with which forecasting will be carried out. To compile such a table from articles, reviews, scientific monographs and other scientific literature, the percentage ratio of phenotypes of fast and slow acetylation among the population of different countries of the world is revealed. Such data are presented in Table 2. For illustration, table 2 shows the phenotype ratio for 56 countries.

According to the World Health Organization (WHO Statistics), for each of these countries, they search for morbidity and mortality rates, which are published every year, by sex and age group, separately for each genetically determined disease. All data for each specific disease is subjected to statistical processing. The rates of morbidity (CV) and mortality (COP) are given in WHO in the form of standardized values of the number of diseases and deaths per 100 thousand standardized by age groups of the population. Separate data are provided for men and women. Moreover, WHO data are presented for the following age intervals (years): - up to 1, 1-4, 5-14, 15-24, 25-34, 45-54, 55-64, 65-74, 75 and older.

For example, in Japan for 1997, the following WHO data for primary liver cancer are presented:

To ef. floor Age intervals (years) Up to 1 1-4 5-14 15-24 25-34 35-44 45-54 55-64 65-74 75+ KZ M 0.86 0.96 0.41 0.42 2,5 14.8 83,2 304.6 584.8 553.6 F 0.12 0.51 0.21 0.36 0.82 3.6 12,2 66,2 189.2 292.7 The cop M 0.2 0.2 0.1 0.1 0.6 3,7 22.5 84.8 167.1 173.0 F 0,0 0.1 0,0 0.1 0.2 0.9 3.3 18,4 54.0 79.0 KZ - incidence rate KS - mortality rate

For Finland, the same data for 1997 have the following meaning:

Coef floor Age intervals (years) Up to 1 1-4 5-14 15-24 25-34 35-44 45-54 55-64 65-74 75+ KZ M 0.04 0.11 1.3 0.04 1.3 0.2 14.3 43.6 106.0 170.8 F 0,03 0.12 0.04 0.04 5.1 1,2 2,3 29.2 65.1 140.2 The cop M 0,0 0,0 0.3 0,0 0.3 0,0 3,5 10.6 27.9 48.8 F 0,0 0,0 0,0 0,0 1,2 0.3 2,3 7.4 17.6 43.9

In the same way, information about other diseases is revealed. To calculate the average annual values of the coefficients of the indicators KZ and KS use an array of data for each country for 10-20 years. As a result, a very large data set is used to compile the table, including world statistics on KZ and CS for all diseases separately for men and women in the indicated age ranges for different countries of the world and data on the same countries on the frequency of occurrence of phenotypes of fast and slow acetylation.

Using an array of these data, average annual values of the morbidity rates “a” and mortality rates “b” are calculated for the group of countries with a predominance of more than 50% of fast acetylators and the group of countries with a prevalence of more than 50% of slow acetylators. At the same time, the risk of each disease and the risk of death from it are predicted in the indicated age intervals if the coefficients “a” and “b” corresponding to the phenotype and gender of the patient, with a reliability equal to or less than 0.05, exceed the similar coefficients of the opposite phenotype of the same gender.

In the inventive method, the detected morbidity and mortality rates are the average values of these indicators for the year for each country for 10-20 years.

The patient’s acetylation phenotype can be determined by the activity of the N-acetyltransferase enzyme. In this case, a test preparation is administered to the patient on an empty stomach in the morning on an empty stomach, using sulfadimesin at a dose of 7 mg / kg body weight or caffeine at a dose of 4 mg / kg body weight after 6 hours in the urine and establish the phenotype of rapid acetylation at a degree of acetylation of the test drug 70-100%, and the phenotype of slow acetylation at a degree of acetylation of less than 70%.

In each identified age range of predictable diseases, the severity of diseases for a particular patient is assessed taking into account the direct dependence of the parameters, the degree of acetylation - the severity of the disease for fast acetylators and the inverse relationship of these parameters for slow acetylators.

The patient acetylation phenotype can be determined by its genotype. At the same time, peripheral venous blood is sampled from the patient, DNA is extracted from the nuclei of lymphocytes, and using the primers, the alleles of the NAT2 gene are determined by polymerase chain reaction and, when one of the alleles of NAT2 * 4, NAT2 * 12A and NAT2 * 12C is detected, the rapid acetylation phenotype is established, and in the presence of two alleles, NAT2 * 5, NAT2 * 6, NAT2 * 7, NAT2 * 10, NAT2 * 11, NAT2 * 13, and NAT2 * 14, the slow acetylation phenotype is established.

Having compiled such a table, forecasting by the proposed method is not particularly difficult for a specialist. To predict each disease in the table, it is enough to find the gender of the patient. Then follow the values of the coefficients “a” and “b” in the various age ranges presented for this disease, which correspond to the gender and phenotype of the patient.

In addition, it is necessary to pay attention to whether the values of the coefficients "a" and "b" corresponding to the phenotype and gender of the patient exceed the values of the same coefficients for the opposite phenotype of the same sex.

If the coefficients corresponding to this patient exceed the similar coefficients of the opposite phenotype of the same sex with a confidence (p) equal to or less than 0.05, the risk of disease and the risk of death from it are predicted.

If in any interval the reliability (p) is more than 0.05, the forecast is not carried out in it.

If necessary, the severity of the predicted disease can be estimated in the identified age-related intervals for the risk of the disease. This can be done taking into account the phenotype of the patient and specific data on the degree of acetylation of the test drug in%, obtained when establishing its phenotype. In the event that the patient is a fast acetylator, the assessment of the severity of the disease is made directly proportional to the degree of acetylation. For slow acetylators, the severity of the disease is assessed inversely with the degree of acetylation.

The reliability of the proposed forecasting method was confirmed for patients being treated in a hospital. Moreover, blood or urine was taken from patients with various diagnoses established on the basis of a comprehensive examination to establish the acetylation phenotype according to the methods described above. Then the same disease was predicted according to Table 1. For this, the same disease and coefficients “a” and “b” were found in the table for the patient’s gender and phenotype in his age range. The conclusion about the risk of the predicted disease and the risk of death from it was made if the values of the coefficients “a” and “b” corresponding to the patient significantly exceeded the same coefficients of the opposite phenotype of the same sex. After that, the severity of the disease was assessed taking into account the above patterns.

In addition, the patient made a forecast regarding the risk of other diseases with an assessment of their severity, including those that were predicted by the proposed method for an earlier age of the patient. This information was compared with the data contained in the patient's medical history.

Such predictions were made on a representative group of patients (400 people) for whom various diseases were established after a comprehensive examination in a hospital.

In all cases, the forecasts made by the proposed method coincided with the diagnoses made on the basis of data from a medical examination of patients.

Since the acetylator phenotype is genetically determined and stable throughout a person’s life, the proposed method allows predicting diseases before the onset of clinical symptoms of these diseases. Moreover, the acetylation phenotype can be determined already at an early age (up to 1 year) and entered into the patient’s medical record to use this information throughout his life.

Thus, the proposed method allows the timely prevention of predictable diseases.

In addition, the method allows for medical and genetic counseling, give dietary and pharmacological recommendations, advice on lifestyle and employment. This cannot be done by known forecasting methods, which make it possible to establish a diagnosis in the early stages of the development of the disease, when preventive measures are already useless.

The invention is illustrated by examples.

Example 1. Primary liver cancer

A 68-year-old patient G. complained of weakness, a feeling of heaviness on the right, a periodic increase in body temperature, loss of appetite, weight, nausea and vomiting, a feeling of heaviness and constant pain in the right hypochondrium, progressive deterioration. An examination of the patient revealed: the liver is enlarged, painful, dense, bumpy, its lower edge comes out of the hypochondrium. Laboratory studies found hypochromic anemia, leukocytosis, accelerated ESR, increased activity of transaminases and alkaline phosphatase. A comprehensive examination of the patient established the diagnosis of primary liver cancer.

A test drug sulfadimesin was administered to a patient on an empty stomach in a dose of 7 mg / kg body weight. 6 hours after taking the drug, a urine sample was taken from the patient and its analysis was made for the content of sulfadimezin in it. The amount of sulfadimesin in the urine was 15%. Consequently, 85% of the test preparation was acetylated. By this indicator, the patient was assigned to fast acetylators.

In addition, the established phenotype of the patient was confirmed by determining the acetylation genotype. To determine the acetylation genotype, blood was taken from a vein to isolate DNA from lymphocytes. Using the PCR reaction, the patient’s genotype was determined - NAT2 * 4 / NAT2 * 4, which determines the phenotype of rapid acetylation.

Table 1 shows the disease: primary liver cancer in men (M) and the average rates of morbidity "a" and mortality "b" in fast and slow acetylators. The table shows that the coefficients "a" and "b" of fast acetylators in all age ranges significantly exceed the coefficients of slow acetylators. The reliability of the given coefficients is analyzed in all age intervals. It can be seen that the values of the coefficients are reliable, since the p value is less than or equal to 0.05. This means that fast acetylators have a risk of developing primary liver cancer.

Therefore, the prognosis for this disease for a given patient can be made for all age intervals shown in the table.

The risk of this disease in patient G. existed at all age intervals. Patient G. at the time of prediction of 68 years, he belongs to the risk group.

Assess the severity of the course of the disease in patient G., taking into account the direct dependence of the parameter "the degree of acetylation - the severity of the disease" severity increases with increasing degree of acetylation:

Table The degree of acetylation (%) 71-80 81-90 91-100 Severity + ++ +++ Note: + - mild severity; ++ - moderate severity; +++ - severe.

The table shows that for a patient G. at the age of 68 years of AD (the degree of acetylation of 85%), the average severity of the course of the disease with primary liver cancer is characteristic. This is consistent with the clinical symptoms and laboratory findings of this patient.

In addition, to illustrate the invention for this patient, forecasting for other diseases was carried out in accordance with the proposed method, for example, atherosclerosis, phlebitis and cerebrovascular pathologies.

Table 1 shows that with phlebitis and atherosclerosis, the significantly significant morbidity and mortality rates “a” and “b” have higher values for slow acetylators than for fast acetylators, since p values are less than or equal to 0.05, in the age ranges from 45 to 75 years and older. This means that patient G. has no risk to the incidence of phlebitis and atherosclerosis, which is confirmed by the history of the disease, in which there is no information about these diseases.

With regard to the risk of morbidity and mortality from cerebrovascular pathologies from the data presented in table 1, the following can be seen. The correlation coefficients “a” and “b” are high in men of fast acetylators in the age ranges from 0 to 64 years, significantly differing from slow acetylators, which indicates a risk for this disease of fast acetylators. In the age group from 65 to 74 years, a forecast is impossible, since the values of the coefficients “a” and “b” are unreliable.

From the anamnesis data it was found that patient G., a fast acetylator, aged 50-52 years, complained of headaches, dizziness, partial loss of vision, periodic increase in blood pressure, which indicates the presence of cerebrovascular disease and is confirmed by the proposed method.

Assessment of the severity of the course of the disease with cerebrovascular pathologies of patient G. is carried out taking into account the direct dependence of the parameters "the degree of acetylation - the severity of the disease", i.e. severity increases with increasing degree of acetylation.

The table shows that for patient G. at the age of 68 years (the degree of acetylation of 85%), the average severity of the course of the disease is characteristic. This is consistent with the history and clinical symptoms of this patient.

Table The degree of acetylation (%) 71-80 81-90 91-100 Severity + ++ +++ Note: + - mild severity; ++ - moderate severity; +++ - severe.

Example 2. Primary liver cancer.

Patient "A". 47 years old complained of progressive weakness, adynamia, loss of appetite, weight, frequent nausea and vomiting, fever, feeling of heaviness and constant pain in the right hypochondrium, progressive deterioration. An examination of the patient revealed: the liver is enlarged, its lower edge is determined at the level of the navel, on palpation it is painful, dense, bumpy. Laboratory studies found hypochromic anemia, leukocytosis, accelerated ESR, increased activity of transaminases and alkaline phosphatase. Using targeted biopsy of the liver, the presence of tumor cells in the liver parenchyma was established. Based on clinical, biochemical and histological studies, a diagnosis of primary liver cancer was made.

Patient A. in the morning on an empty stomach was administered a test drug sulfadimezin at a dose of 7 mg / kg body weight. 6 hours after taking the drug, a urine sample was taken from the patient and her analysis was made for the content of sulfadimezin in it. The amount of sulfadimesin in the urine was 22%. Therefore, 78% of the test drug was acetylated. By this indicator, the patient was assigned to fast acetylators.

In addition, the patient's established phenotype was confirmed by determining the acetylation genotype. To determine the acetylation genotype, blood was taken from a vein to isolate DNA from lymphocytes. By PCR reaction, the patient’s genotype was determined - NAT2 * 4 / NAT2 * 12A, which determines the fast phenotype.

In table 1, the disease is found: primary liver cancer in women (G) and we find the average morbidity and mortality rates "a" and "b". It can be seen from the table that the coefficients “a” and “b” in all age ranges have a value for fast acetylators significantly higher than the similar values of the coefficients “a” and “b” for slow acetylators. This means that women with fast acetylators are at risk for developing primary liver cancer. The reliability of the given correlation coefficients in all age intervals is analyzed. It can be seen that the values of the coefficients are reliable, (p less than or equal to 0.05). Therefore, the prognosis for this disease for this patient can be made for all age intervals listed in the table. The risk of this disease in patient A. existed at all age intervals. Patient A. at the time of prediction of 47 years, she is a fast acetylator and refers to the age range of 45-54 years. In this interval, the coefficients “a” and “b” for fast acetylators are 13.02 and 4.94, respectively, which is 3 and 5 times greater than for slow acetylators. This indicates a risk of a patient's primary liver cancer A.

The severity of the disease of patient A., taking into account the direct dependence of the parameter “degree of acetylation - disease severity”, is estimated according to the table.

Table The degree of acetylation (%) 71-80 81-90 91-100 Severity + ++ +++ Note: + - mild severity; ++ - moderate severity; +++ - severe.

The table shows that for patient A., aged 47, AD (acetylation degree 78%), the course of the disease is characterized by primary to moderate liver cancer. This is consistent with the clinical symptoms and laboratory findings of this patient.

In addition, to illustrate the invention, for this patient, forecasting for other diseases was carried out in accordance with the proposed method, for example, phlebitis, atherosclerosis and cerebrovascular pathologies.

In table 1 find the incidence and mortality from phlebitis and atherosclerosis in women. From table 1 it can be seen that the morbidity and mortality rates “a” and “b” in women of slow acetylators significantly exceed the similar indicators for fast acetylators, (p less than or equal to 0.05), in age ranges from 55 to 75 years and older. This means that the risk of atherosclerosis is characteristic of slow acetylators (MA) from 55 years of age and older. Patient A., being a fast acetylator, is not at risk for this disease, as evidenced by her medical history.

With regard to the risk of morbidity and mortality from cerebrovascular pathologies from the data presented in table 1, the following can be seen. The morbidity and mortality rates "a" and "b" are significantly higher in women with fast acetylators in the age ranges from 0 to 64 years, compared with women with slow acetylators. This indicates a risk for women with rapid acetylators to this disease. In the age group from 65 to 74 years, a forecast is impossible, since the values of the coefficients “a” and “b” are unreliable.

Patient A., 47 years old, refers to the age range of 45-54 years, for which the coefficients “a” and “b” for fast acetylators are 113.9 and 41.1, respectively, which is 2 times more than for slow acetylators. This means that patient A., 47 years old, being a fast acetylator, has a risk of cerebrovascular disease.

From the anamnesis data, it was found that patient A., aged 40, complained of headaches, vasospasms, dizziness, periodic increase in blood pressure, which she still has at present, which indicates her predisposition to cerebrovascular pathologies. This is confirmed by the proposed method.

The severity of the disease of patient A., taking into account the direct dependence of the parameter “degree of acetylation - disease severity”, is estimated according to the table.

Table The degree of acetylation (%) BA 71-80 81-90 91-100 Severity + ++ +++ Note: + - mild severity; ++ - moderate severity; +++ - severe.

The table shows that for the patient A. at the age of 47 years (the degree of acetylation of 78%), a mild to moderate severity of the disease with cerebrovascular pathologies may be characteristic, as evidenced by the history data.

Example 3. Phlebitis.

Patient K., 45 years old, complained of a cosmetic defect in his legs, the appearance on the lower extremities of dense cords of red color, warm to the touch, painful on palpation or spontaneously, fever of the skin, diffuse pains, feeling of heaviness and bursting, night cramps of legs, swelling . The patient often feels general weakness. On examination, redness and slight swelling are determined along the affected area of the vein. On palpation, a painful seal in the form of a rosary is determined. A general blood test showed a slight leukocytosis with a neutrophilic left shift and an acceleration of ESR. On examination of patient K., varicose dilatation of the great saphenous vein and its branches was revealed. The patient was performed angiography. Diagnosis: stem lymphangitis. Surgical treatment is indicated.

Patient K. in the morning on an empty stomach was given a test drug sulfadimezin at a dose of 7 mg / kg body weight. 6 hours after taking the drug, a urine sample was taken from the patient and an analysis was made for the content of sulfadimezin in it. The amount of sulfadimesin in the urine was 72%. Therefore, 28% of the test drug was acetylated. By this indicator, the patient was assigned to slow acetylators.

In addition, the established phenotype of the patient was confirmed by determining the acetylation genotype. To determine the acetylation genotype, blood was taken from a vein to isolate DNA from lymphocytes. Using the PCR reaction, the patient’s genotype was determined - NAT2 * 7 / NAT2 * 10, which determines the phenotype of slow acetylation.

Table 1 shows the phlebitis disease in men (M) and the average morbidity and mortality rates "a" and "b" for phlebitis in men. From table 1 it can be seen that the coefficients “a” and “b” in men in the age ranges from 15 to 75+ have significantly higher values (p more than or equal to 0.05) in slow acetylators, compared with fast acetylators. This means that slow acetylators have a risk of phlebitis and a risk of death from them at these age intervals. From the data of the table it follows that patient K., aged 45, a slow acetylator, is prone to phlebitis, which is confirmed by his examination and diagnosis.

The severity of the disease, taking into account the inverse relationship between the parameter “value of the degree of acetylation - severity of the disease” for slow acetylators, increases with decreasing degree of acetylation. The severity of the disease of patient K. is evaluated according to the table.

The table shows that patient K. aged 45 years (degree of acetylation 28%) is characterized by a severe course of the disease (surgery is necessary), as evidenced by the data on his medical history.

Table The degree of acetylation (%) MA 0-30 31-50 51-70 Severity +++ ++ + Note: + - mild severity; ++ - moderate severity; +++ - severe.

In addition, to illustrate the invention for this patient, forecasting for other diseases was carried out in accordance with the proposed method, for example, atherosclerosis and cerebrovascular pathologies and primary liver cancer.

As can be seen from table 1, the risk of disease and mortality from atherosclerosis is typical for men of slow acetylators (MA), since the morbidity and mortality rates "a" and "b" for slow acetylators are significantly higher than for fast ones (p less than or equal to 0.05), in age ranges from 45 to 75 years and older. This means that the risk of atherosclerosis is characteristic of slow acetylators aged 45 years and older. A 45-year-old patient, being a slow acetylator, is at risk for the incidence of atherosclerosis.

The severity of the disease, taking into account the inverse relationship between the parameter “value of the degree of acetylation - severity of the disease” for slow acetylators, increases with decreasing degree of acetylation

The severity of the disease of patient K. is evaluated according to the table. The table shows that for the patient K. at the age of 45 years (degree of acetylation of 28%), a severe course of the disease may be characteristic.

Table The degree of acetylation (%) MA 0-30 31-50 51-70 Severity +++ ++ + Note: + - mild severity; ++ - moderate severity; +++ - severe.

Patient K., a slow acetylator, is not at risk for diseases of primary liver cancer and cerebrovascular pathologies, because the coefficients “a” and “b” for these diseases in men of slow acetylators are significantly lower than in men of fast acetylators.

Information sources

1. Pat. PU No. 2161309, cl. G 001 N 33153, published December 27, 2000, Utah University Research Foundation (US) and Miriad Genetics. INC. (US).

2. Pat. RU N 2164419, class A 61 K 48/00, published. 03/27/2001, Miriad Genetics, INC. (US).

3. WO 02/23187, cl. G 01 N 33/48, publ. 13/31/2002, UN I V RAMOT (IL) et al.

4. WO 2005040411. cl. C 12 Q 1/37, published. 05.06.2005, BAYER HEALTHCARE AG (DE) et al.

5. DAN, 2001, vol. 377, No. 1, pp. 129-131; V.K. Podymov. Lupus erythematosus. Yerevan, 1981, p. 220; K.S.Simonyan "Adhesive disease of the abdominal cavity", M. Medicine, 1966

6. Ivanova V.V. and others // Virus-bacterial infections and their role in the formation of bronchopulmonary diseases in children. Pediatrics, 1992, Vol. 4, No. 6, pp. 8-12.

7. US 20042658 16, cl. C 12 N 1/68, published. 12/30/2004.

8. Bratton & Marshall // A method for the determination of acetylator phenotype. J. Biol. Chem. (1939) 128, 537-550.

9. Wong P, Bachki A, Banerjee K, Leyland-Jones B. Identification of N-methyl-2-pyridone-5-carboxamide and N-methyl-4-pyridone-5-carboxamide as components in urine extracts of individuals consuming coffee . J Pharm. Biomed. Anal. 2002. Oct. fifteen; 30 (3): 773-80.

10. Hein D.W. Molecular genetics and function of NAT1 and NAT2: role in aromatic amine metabolism and carcinogenesis // Mutat. Res. 2002. V.506 / 507 / P / 65-77.

Table 1 Diseases Floor Age intervals 0-1 1-4 5-14 15-24 25-34 35-44 45-54 55-64 65-74 75+ Primary liver cancer M aMA 0.20 * 0.52 * 0.16 * 0.43 * 0.68 * 2.71 * 9.85 * 27.41 * 66.20 * 93.22 * aba 0.61 0.84 0.41 0.61 3.24 21,4 73.34 167.84 335.3 357.34 p 0.00 0,03 0.02 0.04 0.00 0.00 0.00 0.00 0.00 0.00 bMA 0.05 * 0.13 * 0.04 * 0.10 * 0.17 * 0.73 * 2.29 * 7.62 * 18.39 * 29.13 * bBA 0.15 0.21 0.11 0.18 0.82 5.35 21.56 52,45 90.63 111.67 p 0.00 0.02 0.01 0.01 0.00 0.00 0.00 0.00 0.00 0.00 F aMA 0.30 * 0.15 * 0.05 * 0.18 * 0.52 * 1.26 * 4.45 * 12.29 * 31.84 * 58.50 * aba 1.23 0.40 0.1 0.40 0.94 3.42 13.02 38.81 93.43 150.26 R 0.05 0,03 0.01 0.01 0.02 0.01 0.01 0.00 0.00 0.01 bMA 0.17 * 0.05 * 0.01 * 0.04 * 0.18 * 0.35 * 1.16 * 3.20 * 8.30 * 16.24 * bBA 0.13 0.09 0.04 0.11 0.29 1.34 4.94 14.70 32.63 56.07 R 0.04 0.04 0.02 0,03 0.02 0.01 0.01 0.00 0.00 0.01 Phlebitis M AMA 30.4 * 1.6 * 0.7 * 1.0 * 2.4 * 3.1 * 4.8 * 15.6 * 42.3 * 98.4 * aba 5.2 1,2 0.4 0.6 0.8 1,6 3,1 4.7 13.5 42.7 R 0.00 0.05 0,03 0.04 0.01 0.04 0.04 0.02 0.02 0,03 bMA 2.9 * 0.1 0,0 0,0 0.1 * 0.2 * 0.5 * 1.3 * 3.5 * 10.0 * bBA 0.4 0.1 0,0 0,0 0,0 0.1 0.2 0.4 1,2 3.4 R 0.01 0.06 0.05 0.05 0.01 0.05 0.04 0.02 0.04 0.04 well AMA 0.01 * 0.01 * 0.01 * 1.72 * 2.82 * 7.31 * 15.2 * 43.1 * 121.0 * 362.4 * aba 0.42 0.12 0.11 0.42 0.91 2.61 4,52 14.07 32.9 120.6 R 0.02 0.01 0,03 0.04 0.04 0.04 0.04 0.02 0,03 0.04 bMA 0,00 * 0,00 * 0,00 * 0.11 * 0.22 * 0.51 * 1.43 * 3.31 * 10.00 * 32.24 * bBA 0,03 0.01 0.01 0,03 0.06 0.17 0.38 1.01 2.88 10.73 R 0.01 0.04 0.04 0.05 0.01 0.04 0.04 0,03 0.04 0.04 Atherosclerosis M AMA 0,00 * 0.00 0.01 * 0.09 0.24 * 3.69 * 15.61 * 79.2 * 315.3 * 2072.6 * aba 0.12 0.00 0.71 0.09 0.11 1.35 7.37 24.4 91.9 701.4 R 0.01 0.05 0,03 0.06 0.04 0,03 0,03 0.04 0.04 0.04 bMA 0,00 * 0.00 0,00 * 0.01 0.03 * 0.41 * 2.23 * 9.90 * 39.41 * 241.43 * bBA 0.01 0.00 0.00 0.01 0.01 0.15 0.74 2.71 10.21 63.76 p 0.02 0.05 0.04 0.06 0.04 0.04 0,03 0.04 0,03 0.01 F aMA 0.19 * 0.001 * 0.001 * 0.002 * 0.20 * 0.81 * 4.41 * 28.3 * 176.85 * 2059.1 * aBA 0.08 0.00 0.00 0.00 0.10 0.18 2.16 5.13 38.1 587.6 p 0,03 0.05 0.04 0.05 0.04 0.02 0.05 0,03 0.04 0.01 bMA 0.02 * 0.00 0.002 * 0.001 * 0.02 * 0.09 * 0.49 * 3.14 * 19.65 * 228.77 * bBA 0.01 0.00 0.00 0.00 0.01 0.02 0.24 0.57 4.76 65.29 p 0,03 0.05 0.04 0.05 0.04 0.04 0.05 0.02 0.04 0.02 Cerebrovascular pathology M aMA 2.01 * 0.01 * 0.01 * 4.03 * 10.12 * 29.4 * 90.6 * 282.8 * 1141.2 * 4,391.5 * aBA 18,4 6.1 5.2 8.1 17.8 53,2 175.3 464.7 3260,2 3335.9 p 0.02 0.05 0.04 0.06 0.04 0.04 0,03 0.04 0.04 0.04 bMA 1.04 * 0.01 * 0.01 * 1.0 * 3.0 * 9.3 * 29.1 * 99.2 * 388.6 * 1537.6 * bBA 6.2 1,1 1,1 2.1 5.2 16,4 56.6 158.5 433.2 1234.4 p 0.01 0,03 0,03 0.05 0.04 0.04 0.04 0,03 0.05 0.04 F aMA 3.6 * 0.01 * 0.01 * 3.2 * 5.7 * 20.3 * 65.6 * 193.9 * 808.8 * 4286 * aBA 16 3,1 3.4 6.2 8.6 33,2 113.9 308.8 845.4 3248 p 0.01 0.02 0.02 0.04 0.04 0.04 0.04 0.04 0.05 0.04 bMA 1.01 * 0.01 * 0.01 * 1.03 * 2.0 * 7.2 * 21.4 * 64.5 * 275.9 * 1543.7 * bBA 4.1 1,2 1,1 2.1 3,5 12,4 41.1 105.6 313.8 1137.6 p 0.01 0.02 0.02 0.04 0.04 0,03 0.04 0.04 0.05 0.04

Table 2. The ratio of phenotypes of N-acetylation in some ethnic populations (56 populations) a country % fast acetylators % slow acetylators Thailand 93 7 Polynesia 93 7 R. Korea 89 eleven Japan 88 12 Hong Kong 85 fifteen Philippines 80 twenty Bangladezh 79 21 U.S. Indians 79 21 Sirgapur 78 22 Taiwan 78 22 Tahiti 72 28 Mexico 70 thirty Venezuela 70 thirty Chile 70 thirty Ecuador 70 thirty Australia - Aboriginal 63 37 Costa Rica 62 38 Brazil 60 40 South Africa (blacks) 59 41 Moldova 52 48 Nigeria 51 49 Tanzania 51 49 Germany 46 54 France 46 54 Spain 46 54 Belgium 46 54 Portugal 46 54 Russia 45 55 Estonia 45 55 Italy 45 55 Angola 45 55 Norway 44 56 Austria 44 56 USA 43 57 Australia 43 57 N.Zelandia 42 58 Denmark 42 58 Netherlands 42 58 Canada 41 59 Morocco 41 59 Turkey 41 59 Poland 40 60 Egypt 39 63 England 38 62 Ireland 38 62 Zimbabwe 38 62 Israel 37 63 Kuwait 37 63 Finland 36 64 Switzerland 36 64 Sudan 35 65 Greece 34 66 Sweden 32 68 Hawaii 31 59 India 26 74 Czech twenty 80

Claims (6)

1. A method for predicting a person’s genetically determined diseases in different age intervals of his life, which consists in determining the patient’s acetylation phenotype and predicting these diseases using a pre-prepared table, to compile which, according to scientific statistics, the frequency of rapid phenotypes is found for different countries of the world and slow acetylation for each country, and according to world statistics for the same countries, the values of the coefficient the incidence of predictable diseases "a" and mortality from these diseases "b" for the year in the age intervals (years) to 1, 1-4, 5-14, 15-24, 25-34, 35-44, 45-54, 55-64, 65-74, 75 and older, separately for men and women, then, using this data array, average annual values of these coefficients are calculated for the group of countries with a predominance of more than 50% of fast acetylators and the group of countries with a predominance of more than 50% of slow acetylators while predicting for the patient the risk of each disease and the risk of death from him if nts “a” and “b” corresponding to the phenotype and gender of the patient, with a confidence equal to or less than 0.05, exceed the same coefficients for the opposite phenotype of the same gender. 2. The method according to claim 1, wherein the world statistics are the World Health Organization (WHO) database. 3. The method according to claim 1, in which the detected morbidity and mortality rates are the average values of these indicators for the year for each country for 10-20 years. 4. The method according to claim 1, wherein the patient’s acetylation phenotype is determined by the activity of the N-acetyltransferase enzyme, and the test preparation is administered to the patient on an empty stomach in the morning on an empty stomach, using sulfadimesin at a dose of 7 mg / kg body weight or caffeine at a dose of 4 mg / kg of body weight, and determine its amount after 6 hours in the urine, while the phenotype of rapid acetylation is established with the degree of acetylation of the test drug 70-100%, and the phenotype of slow acetylation with the degree of acetylation of less than 70%. 5. The method according to claim 1, in which the severity of diseases for a particular patient is assessed in each identified age range of predictable diseases, taking into account the direct dependence of the parameters, the degree of acetylation is the severity of the disease for fast acetylators and the inverse relationship of these parameters for slow acetylators. 6. The method according to claim 1, wherein the patient’s acetylation phenotype is determined by its genotype, while peripheral venous blood is sampled from the patient, DNA is extracted from the lymphocyte nuclei and the alleles of the NAT2 gene are determined using primers by polymerase chain reaction and if one of the alleles NAT2 * 4, NAT2 * 12A and NAT2 * 12C establish the rapid acetylation phenotype, and if there are two alleles, NAT2 * 5, NAT2 * 6, NAT2 * 7, NAT2 * 10, NAT2 * 11, NAT2 * 13 and NAT2 * 14 phenotype of slow acetylation.