Chronic multifactorial disease. Methods for studying multifactorial diseases

Considering the various mechanisms influencing the development and course of the disease, it is not possible to trace clear patterns of transmission of the disease from generation to generation. Analysis of pedigrees for multifactorial diseases is not based on Mendel’s laws, as with monogenic traits, but on empirically obtained data. As a result of many years of observations, the following features characteristic of this form of pathology were identified.

1. The likelihood of developing the disease depends on the degree of relationship with the affected family member, as this determines the number of common genes (see Table 1).
2. The number of sick relatives determines the prognosis for the proband (Fig. 14). For example, with diabetes mellitus, the risk for the proband’s siblings, depending on the number of sick relatives, will be as follows:
   • if the parents are healthy, the probability is 5-10%;
   • if one of the parents is sick, the risk is 10-20%;
   • if both parents are sick, the risk increases to 40%. The risk for the children of the proband, depending on the extent of his parents’ involvement, will be either 10% or 20% (Fig. 15).
3. The genetic prognosis depends on the severity of the disease of the affected relative, since the severity of multifactorial diseases is determined by the total effect of several genes. Thus, a person who has received 4 genes on which arterial hypertension depends will have a more severe form of the disease and, of course, a greater likelihood of transmitting the pathological gene to offspring.
4. The degree of hereditary burden for the proband increases if his sick parent belongs to a rarely affected sex. For example, in the case of gastric and duodenal ulcers, in each family burdened with this disease, the probability of passing on genes to offspring is the same. However, the likelihood of getting sick is always greater for males and if female relatives of the proband are affected. In the pedigree presented in Fig. 16, the risk for the proband’s children to develop duodenal ulcer increases as a result of two factors: a) both of them are male (peptic ulcer refers to diseases that predominantly affect only males) and b) the proband’s mother suffers from peptic ulcer, i.e. in this case, the affected parent belongs to the less commonly affected sex.

Thus, we note that the variety of types of hereditary transmission of traits fully demonstrates the complexity of establishing the type of inheritance. A practitioner who does not have the skills to compile and analyze a pedigree should not take the liberty of making a final conclusion. He should refer the patient and his relatives for medical genetic counseling. At the same time, it should be emphasized that for a general practitioner, the most elementary use of the clinical-genealogical method (but no less effective) can be a complete collection of data from a seemingly well-known family history. Meanwhile, today many doctors underestimate the importance of family history and do not have a clear idea of ​​what to ask the subject about, how to evaluate the information received and why it is needed. Therefore, if a doctor collects family history data, he is often limited to individual random questions, noting, for example, that among relatives there were cases of pneumonia, tuberculosis, diabetes, leaving the information obtained without further analysis and evaluation.

All this is of particular importance at the present time, when Soviet healthcare is tasked with ensuring universal medical examination of the population. During clinical examination, diseases that penetrate into adulthood and old age are of particular interest. In these cases, an analysis of the family history may prompt the doctor to the need for a detailed clinical or biochemical study in order to detect early symptoms (preclinical stage) of hereditary pathology not only in a particular individual, but also in his relatives. That is why the anamnesis should contain information that allows one to assess the risk of the disease for healthy members of a hereditarily affected family. This risk may be due to varying degrees of predisposition, late penetration or low expressivity of the genotype.

Let us dwell on the minimum of questions that a doctor should ask the person being examined (the patient or during a medical examination).

During clinical examination, the majority of those examined are people who do not present any complaints. Therefore, the doctor must first of all, observing the principles of deontology, explain to the subject that the purpose of the questions is to determine the predisposition of his family members to diseases of certain systems and organs in order to prevent the possibility of their development. Here is a sample list of questions.

First, the doctor should ask the individual what chronic diseases his relatives (parents, brothers, sisters, uncles, aunts, nephews, etc.) suffered from. If a person cannot accurately name the disease, perhaps he knows the profile of the clinics (or hospital departments) in which his relatives were treated, or the main symptoms of the disease. The usual answer is to list diseases of old age and old age, and even then contains some useful information. However, the collection of anamnestic data should not be limited to information about diseases of the elderly. Equally, and sometimes even more important, are data on illnesses of relatives in adulthood, youth and childhood, including congenital physical and mental anomalies. Information about the causes of death of relatives (heart attack, stroke, malignant tumor, trauma, tuberculosis, diabetes, etc.) and their age at the time of death (young, elderly, old) may also be significant. Women are, as a rule, aware of spontaneous abortions and stillbirths among their relatives, and of certain developmental defects in their children, which is also important. Next, it should be clarified whether the cases of diseases identified in the family were isolated (sporadic) or whether they were repeated in other relatives. In this case, it is necessary to indicate the degree of relationship with the subject (father, mother, sister, uncle, nephew, etc.).

Recurrence of the disease in a family may also be due to unfavorable external factors, the role of which must be confirmed or excluded. Thus, when relatives work in the same industry, the cause of their illness may be occupational hazards. Drug effects on the fetus, as well as a number of infectious agents (especially in the early stages of development), can cause developmental defects that copy hereditary pathology - phenocopies. It is imperative to obtain answers to some specific “genetic” questions: about the consanguinity of the proband’s parents or their origin from the same area, the approximate sex ratio among sick relatives, etc. This will allow us to predict with a certain probability the type of inheritance of this pathology in the family being examined.

Let's move on to the specifics of collecting family history data from patients, the analysis of which in the future should also help characterize the general genetic background in the family, identify other diseases and predisposition to them among relatives. These features primarily include the ability to communicate with the patient’s relatives themselves, which allows one to significantly clarify the information received from him. This is especially important in cases where, guided by certain considerations, patients try to hide information known to them from the doctor. The second feature is the possibility of conducting examinations of those relatives for whom a high risk of developing a particular disease has been established. For example, if impaired glucose tolerance is detected in relatives of a patient with diabetes, it is advisable to carry out appropriate preventive measures without waiting for the clinical manifestation of the disease.

Only a geneticist can give a quantitative assessment of risk, using an arsenal of genetic techniques for this purpose, including compiling pedigrees and determining the type of inheritance. But every doctor should be able to qualitatively assess the risk as significant, moderate or small for the relatives of a sick person or a person being examined.

An objective indicator of the risk of having a pathological gene can be the degree of relationship with the patient or patients in the family. The first degree of relationship includes the parents, brothers and sisters of the subject. For hereditary diseases associated with a defect in one gene (monogenic), in this case the probability of having a pathological gene is 1/2 (50%). The second degree of relationship includes the grandfather (grandmother) of the subject, his uncles and aunts. In this case, the probability of having a pathological gene is 1/4 (25%). In the third degree of relationship (cousins) the probability is 1/8 (13%). The risk should be considered significant in cases of illness in relatives of the first and second degrees. If there are cases of the disease among third-degree relatives, the risk can be considered moderate. Isolated, sporadic cases of the disease among relatives of IV and more distant degrees of kinship indicate a low degree of risk.

In multifactorial diseases, a theoretical calculation of risk is impossible, since both the pathology itself and the possibility of its manifestation are determined by the complex interaction of many genes and environmental factors. However, here too the degree of relationship with patients and repeated cases of pathology in the family are of great importance. For example, with schizophrenia, if one of the parents is sick, the probability of the person being examined is 8-12%, and if both parents are sick - 40%.

What practical conclusions can and should a doctor make after collecting and assessing family history data?

If the risk of predisposition to family pathology is assessed as low, the doctor may recognize the history as good. But if the risk is assessed as moderate, and even more so as significant, this indicates the need for diagnostic and preventive measures. When identified, these individuals, even if they are completely healthy, should be classified as a high-risk group, registered and subsequently be under regular medical supervision. Particular attention should be paid to prevention, which should be carried out in persons who do not yet have clinical manifestations of the disease, but are “threatened” by this disease, for example, when the main “risk factors” for coronary heart disease are detected in first-degree relatives of the proband with this pathology; in persons with high levels of uric acid in members of families in which there is a patient with gout, etc. Identification of persons “at risk” for various hereditary diseases is carried out during preventive examinations of the population, during population studies as a result of total and selective screening. However, the use of the clinical and genealogical method will allow solving this problem more effectively. In this case, it is advisable, depending on the type of possible hereditary pathology, to classify people into certain risk groups (for monogenic and chromosomal diseases, for diseases with a hereditary predisposition).

RISK GROUP FOR CHROMOSOMAL PATHOLOGY

A child is at risk for chromosomal diseases in cases where:

• mother's age is over 36 years; her risk of having a child with Down syndrome increases almost 40 times compared to that of a 20-year-old woman;
• there are children in the family with chromosomal diseases;
• the mother has a burdened obstetric and family history (miscarriages, stillbirths, children with multiple malformations, with an unknown diagnosis, especially if the mother has microanomalies or congenital malformations, which may be a sign of mosaicism due to chromosomal aberration);
• the mother (father) has chromosomal mosaicism or a previously established chromosomal aberration;
• parents were in contact with mutagenic factors.

RISK GROUP FOR MONOGENIC DISEASES

A child is at risk for genetic pathology if parents, siblings or other relatives are diagnosed with a hereditary disease.

The risk group includes persons who, due to a close relationship with the proband, have an increased risk of heterozygous carriage of the mutant gene. Thus, parents and children of homozygotes for a recessive gene will be heterozygous. For example, with phenylketonuria, the patient’s parents and his future children are heterozygous carriers of this gene. In dominant diseases with incomplete penetrance, carriers of the pathological gene are all persons who have sick children and sick parents at the same time.

In diseases linked to chromosome X, all daughters of the patient (for example, hemophilia) and all mothers of patients become heterozygous “conductors”.

In the case of determining heterozygosity using the clinical genealogical method, other methods are not used, and carriers of the pathological gene must be registered. If heterozygosity is probabilistic based on genealogical analysis (for example, sister of an individual with an X-linked recessive disease), clinical and paraclinical methods must be used (Fig. 17). If possible heterozygous carriers marry, then the probability of heterozygosity of the future spouse should be determined and the family should be informed about the results of the genetic risk calculation. Possible heterozygous carriers are also advised to avoid consanguineous marriages, since this increases the risk of having an affected child.

RISK GROUP FOR MULTIFACTORIAL DISEASES

In case of multifactorial diseases, persons should be classified as high-risk, taking into account the magnitude of hereditary burden, which depends on the severity of the disease, the degree of relationship with the patient and the number of patients in the family.

Identification of risk groups using the genealogical method will make it possible to effectively carry out early treatment and preventive measures for individuals genetically predisposed to various diseases. Thus, if one of the parents has hypertension, it is necessary to monitor the child’s blood pressure and recommend a gentle regimen. In these families, it is necessary to promote as early as possible and constantly exercise, observe a work and rest schedule, and limit the consumption of table salt. If such habits develop from childhood, they can have a preventive effect. The local doctor should have close contact with the patient's family, and, apparently, the “family” approach to preventing the disease should be initiated by him. At the first detection of high blood pressure, persons with a family history should be registered at a dispensary.

Particular attention should be paid to families whose members are predisposed to diseases such as diabetes, epilepsy, schizophrenia, peptic ulcers, hypertension, etc. So, if one of the parents is sick, then the risk of having a child with diabetes is 10% . Therefore, there is a real danger of developing this disease. Members of such families must be registered with a dispensary and periodically undergo preventive examinations using additional methods.

Treatment and preventive measures can be divided into two groups:

1. prevention for persons without clinical manifestations of the disease, but with genetic risk factors, aimed at preventing the development of pathology (risk group based on family background);
2. genetic prevention - preventing cases of recurrent diseases in families.

Genetic prevention is carried out by doctors of medical genetic consultation and is aimed at preventing the birth of a sick child. The most effective method of genetic prevention is prenatal diagnosis of hereditary diseases. Currently, it is possible for all chromosomal diseases, diseases linked to chromosome X, and for some hereditary enzymopathies. If prenatal diagnosis is not possible, a genetic risk calculation is performed.

Medical-genetic consultation for multifactorial diseases is often aimed not at preventing the birth of sick children, but at preventing the disease in persons “threatened” by this disease.

Genetics for doctors General issues of medical genetics Subject and problems Hereditary pathology The role of hereditary and environmental factors in the pathogenesis of diseases General patterns of the pathogenesis of hereditary diseases Patterns of inheritance of human traits and methods of studying them Genealogical method Methodology for compiling a pedigree The procedure for collecting genealogical information. Features of collecting anamnestic data Graphical representation of the pedigree Pedigree analysis Autosomal dominant type of inheritance Autosomal recessive type of inheritance X-linked type of inheritance Multifactorial inheritance Genealogical analysis for multifactorial diseases Risk group for chromosomal pathology Risk group for monogenic diseases Risk group for multifactorial diseases Twin method Population method Chromosomes and chromosomal diseases Down disease Patau syndrome (trisomy 13) Cry of the cat syndrome Sex chromosome abnormalities Shereshevsky-Turner syndrome (X0) Triplo-X syndrome (XXX) Klinefelter syndrome (XXY) XYY syndrome

Molecular basis of hereditary pathology Enzymopathies Treatment of hereditary diseases Vitamin replacement therapy Induction and inhibition of metabolism Surgical treatment Diet therapy Efficiency of treatment of multifactorial diseases depending on the degree of hereditary burden in patients Treatment methods being developed Prevention of congenital pathology in women from high-risk groups Clinical pharmacogenetics Hereditary defects of enzyme systems identified when using drugs Atypical reactions to drugs in hereditary metabolic diseases Hereditary determination of the kinetics and metabolism of drugs Genetic basis for testing individual sensitivity to drugs Medical genetic counseling Objectives and indications for consultation Principles of counseling Stages of counseling Prenatal diagnosis of congenital malformations and hereditary diseases Medical problems psychological rehabilitation of patients with congenital diseases and members of their families Mental retardation Visual and hearing defects Anomalies of the musculoskeletal system Applications Information block N 1 - coronary heart disease Information block N 2 - diabetes mellitus Information block N 3 - peptic ulcers Information block N 4 - congenital malformations using the example of cleft lip and/or palate Literature [show] Andreev I. 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Gene diseases

Chromosomal diseases

Multifactorial diseases

All hereditary diseases are usually divided into three groups: chromosomal, caused by changes in the number or structure of chromosomes, monogenic, caused by changes in individual genes, and multifactorial, caused by the interaction of many genes and environmental factors.

The most common and well-known chromosomal disease is Down's disease, caused by the presence of an extra chromosome 21 (trisomy 21) in the set of chromosomes of each cell. In total, more than 800 chromosomal diseases are known to date. In most cases, chromosomal diseases manifest as multiple congenital malformations. Chromosomal diseases are diagnosed using special cytogenetic research methods.

In total, several thousand different monogenic diseases are known. Monogenic hereditary diseases can manifest as damage to any tissue, organ, or organ system. There are ocular, nervous, skin, skeletal, etc. monogenic hereditary diseases. However, in most cases, monogenic hereditary diseases manifest themselves in the form of syndromes, when different organ systems are affected in one patient. A special group includes hereditary metabolic diseases. Most often in this group, genes that control the synthesis of individual enzymes are changed. Diagnosis of monogenic diseases is carried out both by clinical methods, using the so-called syndromological approach, and by special biochemical and molecular genetic methods.

Multifactorial diseases include almost all common chronic human diseases, such as diabetes mellitus, bronchial asthma, coronary heart disease, etc. Multifactorial diseases also include isolated congenital malformations, for example, congenital heart defects. Multifactorial diseases are diagnosed using traditional clinical and laboratory methods.

These three main groups of hereditary diseases differ in how they are inherited. Chromosomal diseases are usually not inherited. Their cause is usually a change in the chromosome set in one sex cell, and patients with a chromosomal disease are so seriously ill that they often simply cannot leave offspring. Monogenic hereditary diseases are inherited according to the laws discovered more than 100 years ago by Gregor Mendel. There are dominant, recessive and sex-linked hereditary diseases. Dominant diseases can manifest themselves across generations. Often, in addition to a sick child, one of his parents is sick, and the patient’s brothers and sisters may be sick (50%). However, often dominant vomiting occurs in only one family member as a result of a random mutation (gene change) in one germ cell of one of the parents. In recessive diseases, the parents of a sick child are usually healthy, but each of them is a carrier of the same altered gene. Brothers and sisters of a sick child may be sick, but the probability of their illness is half as low as with dominant diseases and is 25%. With sex-linked hereditary diseases, only boys are usually affected. In the case when their mother is a carrier of an altered gene in one of the X chromosomes (this is one of the sex chromosomes), then half of the boys born to her may also be sick.

Multifactorial diseases are also characterized by familial accumulation of the corresponding disease, but it is expressed to a much lesser extent compared to monogenic diseases.

* Peptic ulcer

Peptic ulcer is a chronic relapsing disease characterized by the formation of gastric or duodenal ulcers due to disruption of general and local mechanisms of nervous and humoral regulation of the basic functions of the gastroduodenal system and trophism, as well as the development of proteolysis of the mucous membrane.

From a genetic point of view, peptic ulcer disease can be divided into four main groups:

1. Peptic ulcer disease in general is a disease with a hereditary predisposition, characteristic of multifactorial inheritance.

2. Peptic ulcer disease, which fits into a monogenic (usually autosomal dominant) type of inheritance.

3. Peptic ulcer as one of the clinical manifestations of several hereditary syndromes.

4. Ulcerative lesions of the gastroduodenal system in certain somatic diseases.

* Diabetes mellitus

Diabetes mellitus is a disease that is heterogeneous in nature, the etiology and pathogenesis of which involves both internal (genetic, immune) and external (viral infections, intoxications) factors, the interaction of which leads to disruption of carbohydrate metabolism.

The role of genetic factors in the development of diabetes mellitus:

1. Diabetes mellitus, as well as impaired glucose tolerance, is a constant component of approximately 45 hereditary syndromes.

2. The different clinical manifestations and prevalence of diabetes mellitus in ethnic groups are not always explained only by differences in environmental conditions.

3. Among patients with diabetes, there are groups of people with different dependence on insulin.

4. There is diabetes mellitus in adults, which is inherited monogenically in an autosomal dominant manner.

5. Various types of diabetes mellitus can be modeled in experimental animals.

The development of diabetes mellitus is affected by mutations in one or more genes. Formation of a pathological phenotype, i.e. The development of clinical manifestations of diabetes mellitus in the presence of a hereditary predisposition occurs with the obligatory participation of environmental factors. Various stress factors, infections, injuries, and operations are of great importance in the etiology of diabetes mellitus. For insulin-dependent diabetes mellitus, risk factors are some viral infections (rubella, chickenpox, mumps, coxsackie virus, epidemiological hepatitis), and toxic substances. For non-insulin-dependent diabetes mellitus, risk factors are excess body weight, heredity with diabetes mellitus, atherosclerosis, arterial hypertension, dyslipoproteinemia, decreased physical activity, and unbalanced diet.

High-risk groups for diabetes:

1. Monozygotic twin of a patient with diabetes mellitus;

2. A person whose one or both parents are sick or have diabetes;

3. A woman who gave birth to a child weighing more than 4.5 kg, as well as a dead child with hyperplasia of the islet apparatus of the pancreas.

Irrational drug therapy is one of the most important risk factors for the development of diabetes mellitus.

Drugs acting on carbohydrate metabolism: adrenaline, aminazine, caffeine, salbutamol, surosemide, corticosteroids, thyroxine, growth hormone, ACTH, dopegit, clonidine, trental, PAS, salicylates, butadione, sulfonamides.

Hereditary syndromes accompanied by impaired glucose tolerance or insulin resistance:

Genetic: Louis-Bar syndrome, cystic fibrosis, Fanconi anemia, glucose-6-phosphate dehydrogenase deficiency, glycogenosis type I, gout, hemochromatosis, Huntington's chorea, Lawrence-Moon-Bardet-Biedl syndrome, Prader-Willi syndrome.

Chromosomal: Down syndrome, Klinefelter syndrome, Shereshevsky-Turner syndrome.

* Coronary heart disease (CHD)

IHD occurs due to a decrease or cessation of blood supply to the myocardium due to a pathological process in the coronary vessels.

Genetically determined risk factors for IHD include:

Gender of the proband: in women, clinical manifestations occur 10-15 years later, this is due to hormonal differences and morphological features of the structure of the collateral vessels of the coronary arteries;

Body type: more often, cardiovascular diseases associated with atherosclerosis occur in individuals with a hypersthenic body type;

Personality characteristics: personality type “A” is described, in which the frequency is observed 2 times more often than with type “B”. People of type “A” are characterized by energy, an accelerated pace of work, the desire to achieve their goals, people are emotional, susceptible to stress factors;

A certain structure of the coronary vessels;

Increased levels of total cholesterol in the blood;

High levels of low and very low density lipoproteins (LDL and VLDL) in the blood;

Low concentration of high-density lipoproteins (HDL);

Low activity of LDL receptors;

Disturbances in the blood coagulation system (increased fibrinogen in the blood serum, hereditary deficiency of fibrinolytic activity);

Arterial hypertension;

Diabetes mellitus.

Monogenic forms of lipid metabolism disorders are described in section 4.

Phenocopies of hyperlipidemia associated with lipid metabolism disorders may be caused by the action of environmental factors such as:

Smoking (mortality from coronary heart disease among smokers is 2-5 times higher than among non-smokers);

Physical inactivity (the risk of death from coronary heart disease in physically inactive people is 3 times higher than in people leading an active lifestyle);

Unbalanced diet;

Impact of negative psychosocial factors;

Taking contraceptive steroids;

Change in the mineral composition of water - long-term intake of soft water, poor in mineral salts (Ca, Mg, lithium, zinc).

The main part of IHD is a multifactorial pathology, characterized by the formation of the disease through the interaction of genetic and environmental factors that lead to the direct causes of IHD:

I) spasm of the coronary arteries;

2) atherosclerosis of the coronary vessels.

The main pathophysiological mechanism of IHD is the discrepancy between the myocardial oxygen demand and the ability of the coronary blood flow to satisfy them.

Introduction

The objectivity of genetic classification of diseases is increasing with the success of molecular genetics and cytogenetics in identifying defective genes that cause specific diseases. This applies to both hereditary diseases ( Mendelian, or monogenic), and multifactorial (multifactorial) diseases (MFDs), in the occurrence and development of which both genetic and environmental factors are significant. However, the proportion of diseases that depend on known specific “pathological” genes still remains very small. In the catalog of human hereditary traits for 1992, the chromosomal localization of genes and their primary products are indicated for only 322 out of 5710 described traits (i.e., in only 5.6% of cases), and for 2.5 thousand cases only localization is indicated. The possible number of hereditary human diseases is much larger and amounts to 50–100 thousand. It is impossible to identify all such diseases and chromosomal syndromes, since disturbances in the structure of many proteins are incompatible with life and lead to early intrauterine death of the fetus; more than 3,000 of them are now known.

Thus, our knowledge of the molecular genetic basis of human diseases still concerns a relatively small number of them. At the same time, there are examples in clinical genetics that show the exceptional importance of this knowledge for diagnosis, early detection, effective treatment and prevention of specific hereditary diseases. Modern achievements of molecular genetics, or rather the “methodological revolution” of the 70s, made it possible to isolate individual genes, chemical analysis of DNA nucleotide sequences, and functional studies of gene expression and the molecular mechanisms of its regulation. All this created the prerequisites for the formation of new areas of applied molecular genetics - anatomy and pathological anatomy of the human genome, which are directly related to medical problems. These areas are being developed most consistently within the framework of the Human Genome Project. The project operates in many countries and has proven its viability and effectiveness. He paves the way into 21st century biology.

Multifactorial diseases

Monogenic (Mendelian) diseases are based on mutations of individual genes (dominant and recessive). Changes in the structure and number of chromosomes lead to chromosomal diseases. However, in many cases, human birth defects arise as a result of the simultaneous occurrence of a complex of different mutations. These are the already mentioned multifactorial diseases (MFDs), or polygenic diseases. Multifactorial (polygenic) inheritance is responsible for many congenital malformations. MDs also include such widespread diseases as diabetes mellitus, hypertension, coronary disease, bronchial asthma, etc. They are the result of a complex interaction of many genetic and environmental factors.

(hereditarily predisposed, multi-factorial, “Complex genetic disorders”) is a large and nosologically diverse group of diseases, the development of which is determined by the interaction of certain hereditary factors (mutations or combinations of alleles) and environmental factors. The etiology and pathogenesis of these diseases is complex, multi-stage and in many ways still unclear and, naturally, different for each disease.

Diseases with a hereditary predisposition occur in individuals with the corresponding genotype (combination of “predisposing” alleles) under the provoking action of environmental factors,

With a certain degree of convention, multifactorial diseases can be divided into:

1) congenital malformations,

2) common mental and nervous diseases,

3) common diseases of “middle” age.

CD of a multifactorial nature - cleft lip and palate, spina bifida, pyloric stenosis, anencephaly and cranial hernia, hip dislocation, hydrocephalus, hypospadias, clubfoot.

Bronchial asthma

Prevalence is from 4 to 8% among the entire population, in the pediatric population - up to 10%.

Bronchial asthma is a disease based on chronic allergic inflammation of the bronchi, accompanied by their hyperreactivity and periodic attacks of difficulty breathing or suffocation as a result of widespread bronchial obstruction caused by bronchoconstriction, hypersecretion of mucus, and swelling of the bronchial wall.

The main predisposing factors - atopy and bronchial hyperreactivity - are genetically determined. Recent evidence suggests that three groups of traits (level of specific IgE, level of total IgE and the presence of bronchial hyperreactivity) are inherited independently of each other. The genes that determine the production of specific IgE are localized on the short arm of chromosome 11 (11q13) and are associated with HLA class II alleles. Control of the basal level of total IgE is carried out by the gene cluster of the long arm of chromosome 5 (5q31.1). Bronchial hyperreactivity is associated with genetic markers of the same segment (5q31.1-q33). In the same area there are genes for interleukins (IL-4, IL-9, etc.), which activate mast cells, and the gene encoding the β2-adrenergic receptor.

Each of the genetic predisposition factors increases the likelihood of asthma, and their combination leads to a high risk of developing the disease with minimal participation of environmental factors. The most significant of them are the pathological course of the intrauterine period, prematurity, poor nutrition, pollutants and tobacco smoke, ARVI.

Often asthma is combined with atopic dermatitis, the main predisposing factor of which is also atopy. The risk of developing atopic disease in children (regardless of the form) is 60-80% if both parents are sick and/or have a family history; up to 50% and above - through the mother's side; 25-30% - on the father's side.

Peptic ulcer

Peptic ulcer is a chronic relapsing disease characterized by the formation of gastric or duodenal ulcers due to disruption of general and local mechanisms of nervous and humoral regulation of the basic functions of the gastroduodenal system and trophism, as well as the development of proteolysis of the mucous membrane.

From a genetic point of view, peptic ulcer disease can be divided into four main groups:

1. Peptic ulcer disease in general is a disease with a hereditary predisposition, characteristic of multifactorial inheritance.

2. Peptic ulcer disease, which fits into a monogenic (usually autosomal dominant) type of inheritance.

3. Peptic ulcer as one of the clinical manifestations of several hereditary syndromes.

4. Ulcerative lesions of the gastroduodenal system in certain somatic diseases.

Diabetes mellitus

Diabetes mellitus is a disease that is heterogeneous in nature, the etiology and pathogenesis of which involves both internal (genetic, immune) and external (viral infections, intoxications) factors, the interaction of which leads to disruption of carbohydrate metabolism.

The role of genetic factors in the development of diabetes mellitus:

1. Diabetes mellitus, as well as impaired glucose tolerance, is a constant component of approximately 45 hereditary syndromes.

2. The different clinical manifestations and prevalence of diabetes mellitus in ethnic groups are not always explained only by differences in environmental conditions.

3. Among patients with diabetes, there are groups of people with different dependence on insulin.

4. There is diabetes mellitus in adults, which is inherited monogenically in an autosomal dominant manner.

5. Various types of diabetes mellitus can be modeled in experimental animals.

The development of diabetes mellitus is affected by mutations in one or more genes. Formation of a pathological phenotype, i.e. The development of clinical manifestations of diabetes mellitus in the presence of a hereditary predisposition occurs with the obligatory participation of environmental factors. Various stress factors, infections, injuries, and operations are of great importance in the etiology of diabetes mellitus. For insulin-dependent diabetes mellitus, risk factors are some viral infections (rubella, chickenpox, mumps, coxsackie virus, epidemiological hepatitis), and toxic substances. For non-insulin-dependent diabetes mellitus, risk factors are excess body weight, heredity with diabetes mellitus, atherosclerosis, arterial hypertension, dyslipoproteinemia, decreased physical activity, and unbalanced diet.

High-risk groups for diabetes:

1. Monozygotic twin of a patient with diabetes mellitus;

2. A person whose one or both parents are sick or have diabetes;

3. A woman who gave birth to a child weighing more than 4.5 kg, as well as a dead child with hyperplasia of the islet apparatus of the pancreas.

Irrational drug therapy is one of the most important risk factors for the development of diabetes mellitus.

Drugs acting on carbohydrate metabolism: adrenaline, aminazine, caffeine, salbutamol, surosemide, corticosteroids, thyroxine, growth hormone, ACTH, dopegit, clonidine, trental, PAS, salicylates, butadione, sulfonamides.

Hereditary syndromes accompanied by impaired glucose tolerance or insulin resistance:

Genetic: Louis-Bar syndrome, cystic fibrosis, Fanconi anemia, glucose-6-phosphate dehydrogenase deficiency, glycogenosis type I, gout, hemochromatosis, Huntington's chorea, Lawrence-Moon-Bardet-Biedl syndrome, Prader-Willi syndrome.

Chromosomal: Down syndrome, Klinefelter syndrome, Shereshevsky-Turner syndrome.

This group of diseases differs from gene diseases in that they require action to manifest themselves. environmental factors. Among them, there are also monogenic ones, in which the hereditary predisposition is caused by one pathologically altered gene, and polygenic. The latter are determined by many genes, which in a normal state, but with a certain interaction between themselves and with environmental factors, create a predisposition to the onset of the disease. They are called multifactorial diseases (MFD).

Monogenic diseases with a hereditary predisposition are relatively few in number. The method of Mendelian genetic analysis is applicable to them. Considering the important role of the environment in their manifestation, they are considered as hereditarily determined pathological reactions to the action of various external factors (drugs, food additives, physical and biological agents), which are based on hereditary deficiency of certain enzymes.

Such reactions may include hereditary intolerance to sulfonamide drugs, manifested in hemolysis of red blood cells, increased temperature when using general anesthetics.

A mutation has been described in humans that causes a pathological response to air pollution, which manifests itself in the early development of pulmonary emphysema (at the age of 30-40 years). In genetically sensitive individuals, certain food components and dietary supplements may cause adverse reactions. A number of people are known to be intolerant to the milk sugar lactose. Lactose intolerance genes are widespread among the Asian population (up to 95-100%) and among American blacks and Indians (up to 70-75%). Some people have an intolerance to faba beans that they eat, causing hemolysis. A number of people cannot tolerate fatty foods and suffer from atherosclerosis at an early age, which increases the risk of developing myocardial infarction. For some people, eating cheese and chocolate triggers migraines. Specific reactions of people to alcohol have been noted. Preservatives and food colorings are not absorbed normally by some people, which also manifests itself in intolerance to these food components.

Along with chemical agents, people have an inherited pathological reaction to physical factors (heat, cold, sunlight) and factors of biological nature (viral, bacterial, fungal infections, vaccines). Sometimes there is hereditary resistance to the action of biological agents. For example, HbA HbS heterozygotes are resistant to infection by the pathogen of tropical malaria.

Diseases with a hereditary predisposition caused by many genetic and environmental factors include diseases such as psoriasis, diabetes mellitus, and schizophrenia. These diseases have a familial nature, and the participation of hereditary factors in their occurrence is beyond doubt. However, the genetic nature of the predisposition to many of them has not yet been deciphered.

Often, a predisposition to a number of diseases is observed in people with a certain combination of different genes. Thus, people with blood group II (A) are more likely to experience cancer of the stomach and intestines, uterus, ovaries and breast, as well as pernicious anemia, diabetes mellitus, coronary heart disease, cholecystitis, cholelithiasis, rheumatism, and syphilis is milder than in people with other blood groups. In people with blood group I (0), peptic ulcers of the stomach and duodenum are more common. Establishing an accurate diagnosis of a disease using various methods of genetic research, clarifying the role of heredity and environment in its development, and determining the type of inheritance in the case of hereditary diseases enable the doctor to develop methods for treating and preventing these diseases in the next generations.