Polymorphisms are not a direct and obligatory cause of the development of the disease, but may cause a greater or lesser risk of its development under the influence of various external factors.
Therefore, in the presence of polymorphisms, they inform about the increased risk of developing the disease in case of heterozygous or homozygous carriage of the polymorphism. The risk of developing a disease is measured by the odds ratio OR (odds ratio).
In Europe, clinical genetic testing of mutations in the genes: FV (Leiden), F2 (prothrombin), PAI-1, MTHFR is officially carried out.
Mutation Leiden 1691 G->A coagulation factor V (F5)
Physiology and genetics. Coagulation factor V or coagulation factor V is a protein cofactor in the formation of thrombin from prothrombin. The G1691A Leiden polymorphism (the amino acid substitution Arg (R) -> Gln (Q) at position 506, also known as the “Leiden mutation” or “Leiden”) is an indicator of the risk of developing venous thrombosis. This point (single nucleotide) mutation of the gene encoding factor V of blood clotting confers resistance to the active form of factor V to the degrading action of a specialized regulatory enzyme, C-protein, resulting in hypercoagulability. Accordingly, the risk of blood clots increases. The prevalence of the mutation in European-type populations is 2-6%.
Risk of deep vein thrombosis(DVT): 7 times higher in heterozygous carriers of the Leiden mutation of the F5 Arg506Gln gene and 80 times higher in homozygotes. Additional factors influencing the development of DVT can be divided into 3 groups.
To first A group of factors includes a change in hormonal status:
The use of oral contraceptives additionally increases the risk of developing DVT by 30 times in heterozygotes, 100 times in homozygous carriage.
Pregnancy - 16 times the risk of DVT.
Hormone replacement therapy - 2-4 times increases the risks.
Co. second a group of factors include vascular damage:
Central venous catheterization increases the risk of DVT by 2-3 times
Surgical interventions - 13 times.
To third a group of factors includes immobility: bed rest and long air flights. Here only an increase in risk is noted, but the statistics should be more complete:
Infectious and oncological diseases also increase the risk of developing DVT. The risk of ischemic stroke in women aged 18-49 years with the Leiden mutation increases by 2.6 times, and increases by 11.2 times when taking oral contraceptives.
clinical data. The presence of the Leiden mutation increases the likelihood of developing a number of pregnancy complications:
Miscarriage in the early stages (the risk increases by 3 times),
Delays in fetal development
Late toxicosis (gestosis),
Fetoplacental insufficiency.
An increased tendency to thrombus formation can lead to arterial thromboembolism, myocardial infarction and stroke. The presence of the Leiden mutation increases the risk of primary and recurrent venous thrombosis by at least 3-6 times.
The following examples illustrate the association of the mutation with various types of thrombosis and other cardiovascular diseases.
A study of more than 300 patients with venous thromboembolism (VTE) was conducted over an 8-year period at several centers, during which a 3.7-fold increased risk of VTE was found in the presence of the Leiden mutation. In another study, patients with venous thromboembolism were studied for 68 months. During this time, 14% of patients suffered a recurrent VTE. The factor V Leiden mutation results in a fourfold increase in the risk of recurrent VTE. Longer anticoagulation therapy is recommended for patients with VTE with the Leiden mutation compared to patients with normal factor V.
It should be noted that the risk of developing venous thrombosis increases significantly (8-fold increase) if the patient, in addition to the factor V Leiden mutation, also has a T mutation of the C677T polymorphism of the methyltetrahydrofolate reductase gene.
One of the most dangerous complications hormonal contraceptives are thrombosis and thromboembolism. Many women with these complications are heterozygous carriers of the Leiden mutation (G/A genotype). Against the background of taking hormonal contraceptives, the risk of thrombosis is increased by 6-9 times. Women who use hormonal contraceptives and have a homozygous Leiden mutation (genotype A/A) are more than 30 times more likely to develop cerebral sinus thrombosis (TCS) than women who do not have this mutation.
The final data of the Women's Health Initiative Estrogen Plus Progestin study on the incidence of venous thrombosis during hormone replacement therapy (HRT) were summarized. The study involved 16,608 postmenopausal women aged 50 to 79 who were followed up from 1993 to 1998. within 5 years. The presence of the Leiden mutation increased the risk of thrombosis in estrogen-progestogen hormone replacement therapy by almost 7 times compared with women without this mutation. The presence of other genetic mutations (prothrombin 20210A, methylenetetrahydrofolate reductase C677T, factor XIII Val34Leu, PAI-1 4G/5G, factor V HR2) did not affect the relationship between HRT and the risk of venous thrombosis. An analysis of more than ten independent studies showed that among patients who had myocardial infarction before the age of 55, the prevalence of the Leiden mutation was markedly higher. The average risk of developing myocardial infarction increases by 1.5 times. Moreover, the Leiden mutation leads to a 2.8-fold increase in the number of patients without severe coronary stenosis who develop myocardial infarction.
Polymorphism 20210 G->A of prothrombin
Physiology and genetics. Prothrombin (coagulation factor II or F2) is one of the main components of the blood coagulation system. During the enzymatic cleavage of prothrombin, thrombin is formed. This reaction is the first step in the formation of blood clots. The G20210A prothrombin gene mutation is characterized by the replacement of the guanine (G) nucleotide with the adenine (A) nucleotide at position 20210. Due to increased expression of the mutant gene, the prothrombin level can be one and a half to two times higher than normal. The mutation is inherited in an autosomal dominant manner. This means that thrombophilia occurs even in a heterozygous carrier of the altered gene (G/A).
Thromboembolic diseases(TE) are caused by disorders in the blood coagulation system. These disorders also lead to cardiovascular disease. The G/A genotype is an indicator of the risk of thrombosis and myocardial infarction. When thrombosis occurs, the 20210A mutation often occurs in combination with the Leiden mutation. Genotype G/A position 20210 of the prothrombin gene is a risk factor for the same complications associated with the Leiden mutation.
Heterozygous carriers of the gene are 2-3% of the representatives of the European race.
The risk of developing DVT in carriers of the mutant allele (A) of the F2 gene is increased by 2.8 times. The combination of a prothrombin mutation with a Leiden mutation further increases the risks.
According to the recommendations for obstetricians and gynecologists (UK, 2000), clinical genetic analysis of FV and prothrombin 20210 is appropriate because of the different risks of homozygotes and heterozygotes.
Distinguish between very high, high and medium degree of risk venous thrombosis in pregnant women:
- high the degree of risk in women with an individual and family history of thrombosis and homozygous for the Leiden mutation, prothrombin G20210A mutation, or a combination of these mutations. Such patients are shown anticoagulation therapy with low molecular weight heparins from the beginning to the middle of the second trimester.
- Medium the degree of risk in women with a family history of thrombosis and heterozygous for the Leiden mutation or G20210A mutation. In this case, anticoagulation therapy is not indicated.
Indications for analysis. Myocardial infarction, increased blood prothrombin level, history of thromboembolic diseases, advanced age of the patient, miscarriage, fetoplacental insufficiency, intrauterine fetal death, toxicosis, fetal growth retardation, placental abruption, patients preparing for major abdominal operations (uterine fibroids, cesarean section, ovarian cysts, etc.), smoking.
Clinical Data. A study of 500 patients with myocardial infarction and 500 healthy donors showed a more than five-fold increase in the risk of myocardial infarction in patients with the 20210A genotype younger than 51 years. Genetic analysis of the group of patients with the first myocardial infarction (age 18-44 years) showed that the 20210A variant occurs four times more often than in the healthy group, which corresponds to a 4-fold increase in the risk of myocardial infarction. The likelihood of heart attack was especially high in the presence of other risk factors for cardiovascular disease. For example, smoking in the presence of the 20210A genotype increases the risk of myocardial infarction by more than 40 times. The 20210A mutation is a significant risk factor for early myocardial infarction.
In a study of patients with a family history of venous thrombosis and a control group of healthy donors, it was found that the 20210A mutation leads to a three-fold increase in the risk of venous thrombosis. The risk of thrombosis increases for all ages and for both sexes. This study also confirmed a direct relationship between the presence of the 20210A mutation and elevated blood prothrombin levels.
In therapeutic hospitals, where patients with cardiovascular diseases predominate, TE in the form of pulmonary embolism occurs in 15-30% of cases. In many cases, TEs are the direct cause of death, especially in postoperative and cancer patients. It has been established that among cancer patients in the presence of TE, mortality increases several times, while the number of TEs exceeds the average values. The reasons for the growth of TE in cancer patients, perhaps, should be sought in the ongoing therapy, inconsistent with the genetic predisposition of the patient. This doesn't just apply to cancer patients. According to post-mortem reports, 60% of patients who die in general hospitals show signs of thromboembolic disease.
Knowledge of the genotypic characteristics of the patient will allow not only to assess the risk of developing life-threatening conditions, but also to correctly determine the methods for their prevention and treatment, as well as the possibility of using certain drugs.
Thermolabile variant A222V (677 C->T) of methylenetetrahydrofolate reductase
Physiology and genetics. Methylenetetrahydrofolate reductase (MTHFR) plays a key role in folic acid metabolism. The enzyme catalyses the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. The latter is the active form of folic acid necessary for the formation of methionine from homocysteine and further - S-adenosylmethionine, which plays a key role in the process of DNA methylation. Deficiency of MTHFR promotes not only teratogenic (damaging the fetus), but also mutagenic (damaging DNA) effects. In this case, inactivation of many cellular genes, including oncogenes, occurs. This is one of the reasons why oncologists are interested in genetic variants of MTHFR. The amino acid homocysteine is an intermediate in the synthesis of methionine. Violations of the MTHFR enzyme lead to excessive accumulation of homocysteine in the blood plasma - hyperhomocysteinemia.
The MTHFR gene is located on chromosome 1p36.3. About two dozen mutations of this gene are known to disrupt the function of the enzyme. The most studied mutation is a variant in which the nucleotide cytosine (C) at position 677 is replaced by thymidine (T), which results in the replacement of an alanine amino acid residue with a valine residue (position 222) at the folate binding site. Such an MTHR polymorphism is referred to as a C677T mutation. In individuals homozygous for this mutation (T/T genotype), MTHFR thermolability and a decrease in enzyme activity to about 35% of the mean value are noted. On the whole, in the world population, the 677T mutation of the MTHFR gene is quite widespread among representatives of the European (Caucasian) race. The frequencies of two major mutations (C677T and A1298C) were studied in the US population. The presence of homozygous T/T was shown in 10-16% of Europeans and 10% of persons of Spanish origin, and heterozygous carriers of this gene were, respectively, 56 and 52% of the examined persons, i.e. the presence of the 677T variant (C/T or T/T genotypes) was observed in 62-72% of cases. Similar results were obtained for European population samples. The C677T polymorphism is associated with at least four groups of multifactorial diseases: cardiovascular disease, fetal defects, colorectal adenoma, and breast and ovarian cancer.
Indications for analysis. Elevated levels of blood homocysteine (hyperhomocysteinemia), cardiovascular diseases (in particular, coronary heart disease (CHD) and myocardial infarction), atherosclerosis, atherothrombosis. antiphospholipid syndrome. Cancer chemotherapy before or during pregnancy. Family predisposition to pregnancy complications leading to congenital malformations: defects in the nervous system of the fetus, anencephaly, deformities of the facial skeleton (cleft palate, cleft lip), prenatal death of the fetus. Intestinal polyposis, colorectal adenoma with alcohol consumption, rectal cancer. Family predisposition to cancer, the presence of mutations in the BRCA genes. Cervical dysplasia, especially in combination with papillomavirus infections.
Clinical Data. Defects in this gene often lead to various diseases with a wide range of clinical symptoms: mental and physical retardation, prenatal death or fetal defect, cardiovascular and neurodegenerative diseases, diabetes, cancer, and others. Carriers of C/T heterozygotes experience folic acid deficiency during pregnancy, which can lead to neural tube defects in the fetus. Smoking enhances the effect of the mutation. Carriers of two T/T alleles (homozygous state) have a particularly high risk of developing side effects when taking drugs used in cancer chemotherapy.
Hyperhomocysteinemia (HH) is an independent risk factor for atherosclerosis and atherothrombosis (independent of hyperlipidemia, hypertension, diabetes mellitus, etc.). It has been established that 10% of the risk of developing coronary atherosclerosis is due to an increase in the level of homocysteine in the blood plasma. In a study of a group of patients with HH and a group of healthy donors, the homozygous form 677T was found in 73% of patients with HH and only in 10% of healthy donors. The presence of the homozygous form 677T leads to an almost 10-fold increase in the risk of HH. Patients with HH also had lower levels of folic acid and vitamin B12, consumed more coffee, and smoked more frequently than healthy donors. Normally, the level of homocysteine is 5-15 µmol/l, a moderately elevated level is 15-30 µmol/l. In severe HH, a 40-fold increase in homocysteine levels is possible. Researchers attribute the cause of severe forms of HH to other mutations and factors - a homozygous mutation of the Cb S gene, I278T and G307S are considered the most common, although the frequency of their manifestation varies greatly in different countries, much less often the causes of severe HH are MTHFR T/T genotype, methionine synthetase deficiency and impaired methionine synthetase activity due to genetic disorders of vitamin B12 metabolism. Correction of HH can be carried out by the intake of cofactors necessary for the metabolism of homocysteine (folic acid, vitamins B12, B1 and B6 (features of HH therapy with vitamins). In carriers of the T/T MTHFR genotype, with optimal folate intake, the level of homocysteine is moderately elevated (up to 50%). Although a combination of 2.5mg folic acid, 25mg vitamin B6 and 250mcg daily vitamin B12 is known to reduce the progression of atherosclerosis in severe HH (measured by carotid plaque), it remains to be confirmed whether homocysteine-lowering therapy prevents significant vascular complications in individuals with moderate HH.
The importance of the problem of HH is evidenced by the fact that the US Department of Health in 1992 recommended that women who can become pregnant take 400 micrograms of folic acid per day. The US Food and Drug Administration requires folic acid fortification in cereals at levels that can provide an additional 100 micrograms per day. However, the daily dose of folic acid required to maximize homocysteine reduction is 400 micrograms, so higher doses of folate supplementation may be justified.
The pathogenesis of congenital neural tube defects includes, in particular, genetic and dietary factors. In a study of 40 children from Southern Italy with a congenital neural tube defect and healthy donors, it was shown that the 677C genotype in the homozygous state (C/C) leads to a twofold increase in the risk of developing defects, while the homozygous T/T mutant corresponds to an almost tenfold decrease in risk. . In a study of a sample of the population of Ireland (395 patients and 848 healthy controls), it was found that the occurrence of the T variant is increased in patients with a congenital neural tube defect. It is difficult to say whether these conflicting research results are due to population changes or other risk factors are not taken into account. Therefore, it is not yet possible to determine whether the T variant is protective or, conversely, a pathogenic factor for this disease. An increase in the frequency of the 677T genotype was noted not only in late toxicosis (preeclampsia), but also in other pregnancy complications (placental abruption, fetal growth retardation, prenatal fetal death). The combination of the 677T mutation with other risk factors leads to an increased likelihood of early miscarriage. When studying the relationship between the 677T mutation and cardiovascular disease, it was found that the homozygous 677T mutation occurs much more often in patients with cardiovascular disease than in healthy donors. In young patients with arterial ischemia, homozygous T/T occurs 1.2 times more often.
A statistical analysis of 40 independent studies (meta-analysis) of patients with coronary artery disease, summarizing data on 11162 patients and 12758 healthy donors, showed an increase in the risk of developing coronary artery disease by 1.16 times in the presence of homozygous T/T. The low degree of risk is associated with the heterogeneity of the analyzed population samples. When studying homogeneous population samples (individual studies, not meta-analyses), risk estimates are much higher. Thus, the difference in the frequencies of T/T homozygotes in patients and healthy donors corresponded to a 3-fold increase in the risk of cardiovascular diseases at an early age. The presence of the 677T mutation in the MTHFR gene in patients with antiphospholipid syndrome correlates with the recurrent course of thrombosis.
A definite, albeit complex, relationship has been found between MTHFR variants and the development of precancerous and cancerous conditions in the colorectal region. A significant group of patients with polyposis of the large intestine was studied. Erythrocyte folate levels were determined, along with an assessment of the C/T MTHFR genotype. Previous results have shown an association between low folate levels and the risk of developing adenomatosis. Multivariate analysis showed that smoking, folate status, and MTHFR genotype are significant components of a high risk of adenomatosis. This risk turned out to be very high in individuals with low folate levels and the carriage of the 677T allele in the homo- or heterozygous form. These data showed a strong interaction of dietary and genetic factors in the development of precancerous conditions.
Similar assumptions were put forward by scientists who examined a large cohort of patients with colon cancer and showed a significant relationship between the risk of developing cancer, age of patients, age-related folate deficiency and T/T MTHFR genotype. A study of 379 patients with colorectal adenoma and 726 healthy donors showed that male carriers of the T/T genotype who consumed a lot of alcohol had a 3.5 times higher risk of developing adenoma. However, some researchers believe that without alcohol consumption as one of the risk factors, the 677T mutation is a protective factor.
Thus, a study of patients with proximal colorectal cancer showed that the presence of a homozygous T/T in a patient leads to a 2.8-fold decrease in the risk of developing colorectal cancer. These findings require verification for other populations. Most likely, the significance of the inactive mutant MTHFR can be considered aggravating against the background of the other listed risk factors, since this gene defect can reduce the stability of the genome due to DNA hypomethylation. C677T polymorphism affects the effectiveness of cancer chemotherapy. Fluorouracil is widely used for chemotherapy in colorectal cancer. The probability of positive dynamics in response to chemotherapy for colorectal adenocarcinoma in a patient with the 677T genotype increased by almost three times. The results suggest that genotyping for the C677T polymorphism will allow the development of more effective chemotherapy courses. However, a study of small samples (up to 50) of breast cancer patients showed that in the presence of a T/T homozygote, the risk of side effects when using methotrexate (an antimetabolite whose action is associated with inhibition of MTHFR enzyme activity) increases tenfold.
There are few studies of the MTHFR genotype in gynecological cancers. The C677T polymorphism of the MTHFR gene was studied in a large group of Jewish women with breast and ovarian cancer, including hereditary forms associated with mutations in the BRCA genes. With such an unfavorable genetic background, the presence of the T/T genotype in patients turned out to be a significant factor in aggravating the disease. The frequency of the T/T genotype was 2 times higher (33% versus 17%, P=0.0026) among women with bilateral breast cancer and ovarian cancer compared with the main group of patients. Women with a heterozygous C/T genotype had a double oncological risk, and in patients with a homozygous T/T genotype, the risk was three times higher than in the control group. At the same time, reduced dietary folate increased the genetic risk by up to five times that of controls. The authors also confirmed the fact that infection with HPV (papilloma virus) in patients is the most important risk factor for the development of cervical dysplasia. At the same time, the special significance of the combination of HPV infection with the T/T variant of MTHFR is emphasized.
Polymorphism Arg353Gln (10976 G->A) of coagulation factor VII (F7)
Physiology and genetics. In the active state, factor VII interacts with factor III, which leads to the activation of factors IX and X of the blood coagulation system, that is, coagulation factor VII is involved in the formation of a blood clot. The 353Gln (10976A) variant leads to a decrease in the productivity (expression) of the factor VII gene and is a protective factor in the development of thrombosis and myocardial infarction. The prevalence of this variant in European populations is 10-20%.
Indications for analysis. The risk of myocardial infarction and fatal outcome in myocardial infarction, the level of coagulation factor VII in the blood, a history of thromboembolic diseases.
clinical data. High levels of coagulation factor VII in the blood are associated with an increased risk of death from myocardial infarction. These data on the clinical significance of the mutation are confirmed by studies in other European populations. In particular, the presence of the 10976A variant corresponded to a reduced risk of fatal outcome in myocardial infarction.
In a study of patients with coronary artery stenosis and myocardial infarction, it was found that the presence of the 10976A mutation leads to a decrease in the level of factor VII in the blood by 30% and a 2-fold decrease in the risk of myocardial infarction, even in the presence of noticeable coronary atherosclerosis.
In the group of patients who did not have myocardial infarction, there was an increased incidence of hetero- and homozygous 10976A genotypes, respectively G/A and G/G.
Polymorphism -455 G->A fibrinogen
Physiology and genetics. When blood vessels are damaged, fibrinogen passes into fibrin, the main component of blood clots (thrombi). The -455A fibrinogen beta (FGB) mutation is accompanied by increased production (expression) of the gene, which leads to an increased level of fibrinogen in the blood and increases the likelihood of blood clots. The prevalence of this variant in European populations is 5-10%.
Indications for analysis. Elevated plasma fibrinogen levels, high blood pressure, history of thromboembolic disease, stroke.
Clinical Data. An increased tendency to thrombosis can lead to thrombosis and cardiovascular disease. The level of fibrinogen in the blood is determined by a number of factors, including medication, smoking, alcohol intake, and body weight. However, the G and A genotypes also correspond to a noticeable difference in blood fibrinogen levels (10-30% according to various studies).
In a study of a group of healthy donors, it was found that the -455A mutation leads to an increased content of fibrinogen in the blood. In the large-scale EUROSTROKE study, it was found that the risk of stroke (ischemic or hemorrhagic) increases 2-3 times with an increase in blood fibrinogen content. The risk is further increased with elevated systolic pressure (>160 mmHg). These data are supported by studies of non-European populations.
With increased blood pressure, the presence of the -455A genotype increases the risk of ischemic stroke.
Stroke patients with the -455A genotype are characterized by multifocal lesions: they may have three or more lacunar infarcts of cerebral vessels, on average, the risk of stroke increases by 2.6 times.
With increased blood pressure in patients with a mutation, the risk of multifocal stroke increases by more than 4 times (Finland).
Polymorphism - IIeMet (66 a-g) Mutation of methionine synthetase reductase
Physiology and genetics. The MTRR gene encodes the enzyme methionine synthase reductase (MCP), which is involved in a large number of biochemical reactions associated with the transfer of a methyl group. One of the functions of MCP is the reverse conversion of homocysteine to methionine. Vitamin B12 (cobalamin) is involved as a cofactor in this reaction.
The I22M A->G polymorphism is associated with an amino acid substitution in the MCP enzyme molecule. As a result of this replacement, the functional activity of the enzyme is reduced, which leads to an increased risk of fetal developmental disorders - neural tube defects. The effect of polymorphism is exacerbated by vitamin B12 deficiency. When the I22M A->G polymorphism of the MTRR gene is combined with the 677C-> T polymorphism in the MTHFR gene, the risk increases.
The I22M A->G polymorphism of the MTRR gene also exacerbates hyperhomocysteinemia caused by the 677C->T polymorphism in the MTHFR gene. The A66G (Ile22Met) polymorphism in the MTRR gene in both heterozygous (AG) and homozygous (GG) variants significantly increases the concentration of homocysteine only when combined with the MTHFR 677TT genotype.
MTRR 66 A-G polymorphism increases the risk of having a child with Down syndrome by 2.57 times. The combination of polymorphisms in the MTHFR and MTRR genes increases this risk to 4.08%.
Polymorphism - 675 5G/4G Plasminogen activator inhibitor (PAI) mutation 1
Physiology and genetics. This protein (also known as SERPINE1 and PAI-1) is one of the main components of the thrombolytic plasminogen-plasmin system. PAI-1 inhibits tissue and urokinase plasminogen activators. Accordingly, PAI-1 plays an important role in predetermining susceptibility to cardiovascular disease. The homozygous variant of the 4G polymorphism -675 4G/5G is a risk factor for the development of thrombosis and myocardial infarction. The prevalence of the homozygous form of this variant in Caucasian populations is 5-8%. The PAI-1 gene differs from all known human genes in its maximal response to stressful influences. The association of the 4G mutant allele with an increased risk of DVT has been analyzed in many studies, but their results are conflicting.
According to Russian researchers (St. Petersburg), the risk of developing cerebral thrombosis increased in persons with a family history of cardiovascular diseases in the presence of the 4G allele by 6 times. The association of carriage of 4G polymorphism with recurrent miscarriage was shown.
Clinical aspects. The 4G variant results in increased expression of the gene and hence an increased level of PAI-1 in the blood. Consequently, the thrombolytic system is inhibited and the risk of thrombosis increases.
In a study of large population samples (357 patients and 281 healthy donors), it was found that the 4G/4G variant increases the risk of developing thrombosis by an average of 1.7 times. The increased risk was much higher for the subgroups of patients with portal vein thrombosis and splanchnic thrombosis. However, no statistically significant correlations were found for subgroups of patients with deep vein thrombosis, cerebral or retinal thrombosis. The 4G variant was associated with an increased risk of myocardial infarction. In the presence of the 4G variant in PAI-1 and L33P in the ITGB3 gene, the average statistical risk of developing myocardial infarction increased by 4.5 times; in men, the risk increased by 6 times in the presence of these two variants.
A study of 1179 healthy donors and their close relatives showed the 4G variant to be associated with a family history of coronary artery and/or heart disease. In this large population study, the mean increased risk in the presence of homozygotes was 1.6-fold. Variants of the 4G/5G polymorphism correlate especially markedly with mean blood levels of PAI-1 in the presence of obesity. It has been suggested that the effect of the 4G variant is related to central rather than peripheral obesity. Since patients with central obesity are particularly at risk for cardiovascular disease, the effect of polymorphism on blood PAI-1 levels may lead to an additional increase in risk.
Indications for analysis polymorphism. Portal vein thrombosis, visceral thrombosis, myocardial infarction, family history of myocardial infarction, coronary artery/heart disease, blood PAI-1 level, obesity.
It is customary to call polymorphic genes that are represented in a population by several varieties - alleles, which determines the diversity of traits within a species.
Genetic polymorphism (Gr. genetikos- related to birth, origin; Greek polys- many and morphe- appearance, form, image) - a variety of allele frequencies of homozygotes. Differences between alleles of the same gene, as a rule, lie in minor variations in its "genetic" code. A large proportion of genetic polymorphism is made by substitutions of one nucleotide for another and changes in the number of repetitive DNA fragments that occur in all structural elements of the genome: exons, introns, regulatory regions, etc. The scale of genetic polymorphism in humans is such that between DNA sequences two people, unless they are identical twins, there are millions of differences. These differences fall into four main categories:
a) phenotypically not expressed (for example, polymorphic DNA regions used to identify a person by molecular genetic methods);
b) cause phenotypic differences (eg, in hair color or height) but not predisposition to the disease;
c) playing some role in the pathogenesis of the disease (eg, in polygenic diseases);
d) playing a major role in the development of the disease (eg, in monogenic diseases).
Although most of the known polymorphisms are expressed either in substitutions of a single nucleotide or in a change in the number of repeated DNA fragments, nevertheless, variations affecting the coding fragments of genes and affecting the amino acid sequence of their products are relatively rare and are not related to the analyzed specific problem, for which First of all, the possible consequences of the polymorphism of nitrones and 5'-terminal non-coding sequences are important. The analysis of this phenomenon largely depends on how variable the intrinsic functions of the protein encoded by different alleles are, which is also true for the enzymes of formation and metabolism of steroid hormones, about which further will be discussed.
A locus is said to be polymorphic if two or more alleles of that locus exist in a population. However, if one of the alleles has a very high frequency, say 0.99 or more, then there is a high probability that no other allele will be present in a sample drawn from a population unless the sample is very large. Thus, a locus is usually defined as polymorphic if the frequency of the most common allele is less than 0.99. Such a division is very conditional, and other criteria for polymorphism can be found in the literature.
One of the simplest ways to measure the degree of polymorphism in a population is to calculate the average ratio of polymorphic loci and divide their total number by the total number of loci in the sample. Of course, such a measure largely depends on the number of individuals studied. A more accurate indicator of genetic variability within a population is MEAN EXPECTED HETEROSYGOSSITY or GENE DIVERSITY. This value can be obtained directly from gene frequencies and is much less affected by the effects of sampling error. Gene diversity at a given locus is defined as follows:
M h = 1 - SUM x i * i=1 where SUM is the sum, x i is the frequency of allele i and m is the total number of alleles of the given locus.
For any locus, h is the probability that two alleles randomly selected in a population will be different from each other. The average over all h for each studied locus, H, can be used as an estimate of the degree of genetic variability within a population.
The degrees of genetic diversity h and H have been widely used for electrophoretic and restriction enzyme data. However, they may not always be suitable for data obtained from the study of DNA sequences, since the degree of diversity at the DNA level is extremely high. Especially when long sequences are considered, it is likely that each will differ from other sequences in one or more nucleotides. Then both h and H will be close to 1 and therefore will not differ between loci or populations, thus being non-informative.
When working with DNA, a more acceptable measure of polymorphism in a population is the average number of nucleotide substitutions per position between two randomly selected sequences. This assessment is called nucleotide diversity (Nei M., Li W.-H., 1979) and is denoted by p:
P = SUM (x * x * p) i,j i j ij where x i and x j are the frequencies of sequences of the i-th and j-th types, and p ij is the proportion of nucleotide differences between the i-th and j-th types of sequences.
Currently, there are several works on the study of nucleotide diversity at the level of DNA sequences. One such work was done for the locus encoding D. melanogaster alcohol dehydrogenase (Adh) (Nei M., 1987) .
11 sequences with a length of 2.379 nucleotides were studied. Ignoring deletions and insertions, nine different alleles were identified, one of which was represented by three, and the other eight by one sequence. Thus, the frequencies x 1 - x 8 were equal to 1/11, and x 9 =3/11. Forty-three positions were polymorphic. First, the proportions of nucleotide differences for each pair of sequences were calculated, shown in the table:
For example, the 1-S and 2-S alleles differed in three positions out of 2.379, hence n 12 = 0.13%. The value of n obtained using formula 3.20 turned out to be 0.007.
Genetic polymorphism and hereditary diseases.
In 1902, Garrod suggested that metabolic disorders, such as alkaptonuria, are the extreme expression of the chemical individuality of the organism. The true breadth of genetic diversity first became apparent when cell extract electrophoresis (without prior enzyme purification) showed the existence of several structural isoforms for many proteins. The presence of isoforms is due to the existence of multiple gene variants (alleles) of this protein in the population. Alleles have identical localization in homologous chromosomes.
Most genes in every organism are represented by two alleles, one inherited from the father and the other from the mother. If both alleles are identical, then the organism is considered homozygous, if different - heterozygous.
In the course of evolution, different alleles have occurred as a result of mutations from a single precursor allele, most often they differ from each other by replacing one nucleotide (missense mutations). Typically, proteins encoded by different alleles of the same gene have the same functional properties, that is, the amino acid substitution is neutral or almost neutral from the point of view of natural selection.
The presence of certain alleles is often judged on the basis of an analysis of the amino acid sequence of the corresponding proteins. For many genes (for example, the gene for the beta chain of globin), it is possible to isolate the normal allele - the most common in the population, which occurs much more often than others. Sometimes among the alleles there is not one that could be considered normal. Extremely high polymorphism is characteristic, for example, of the apoprotein (a) gene and the haptoglobin alpha chain gene. A gene is considered polymorphic if its most common allele occurs in less than 99% of people. This definition reflects only the prevalence of different alleles, not their functional differences.
The concept of polymorphism expanded with the discovery of the extraordinary variability of DNA sequences. In the genomes of different people, 1 out of 100-200 base pairs differs; this is consistent with heterozygosity at 1 in 250-500 base pairs. Modern methods make it possible to identify substitutions of individual nucleotides in coding regions, which may be non-sense or cause a change in the amino acid sequence. DNA polymorphism is even more pronounced in non-coding regions of the genome, whose influence on gene expression is small or non-existent.
In addition to the replacement of individual nucleotides, DNA polymorphism is based on insertions, deletions, and changes in the number of tandem repeats. There are (long) tandem repeats varying in number (minisatellite DNA) and short (tetra-, tri-, di- or mononucleotide) tandem repeats (microsatellite DNA).
The scale of DNA polymorphism is such that there are millions of differences between the DNA sequences of two people, unless they are identical twins. These differences fall into four broad categories:
Phenotypically not expressed (for example, polymorphic DNA sections used to identify a person by molecular genetic methods);
Causing phenotypic differences (for example, in hair color or height), but not predisposing to the disease;
Playing some role in the pathogenesis of the disease (for example, in polygenic diseases);
Playing a major role in the development of the disease (for example, with
) two or more different hereditary forms that are in dynamic equilibrium over several and even many generations. Most often, G. p. is caused either by varying pressures and vectors (orientation) of selection under different conditions (for example, in different seasons), or by increased relative viability of heterozygotes (See Heterozygote). One of the types of polymorphism, balanced polymorphism, is characterized by a constant optimal ratio of polymorphic forms, a deviation from which is unfavorable for the species, and is automatically regulated (an optimal ratio of forms is established). Most of the genes are in a state of balanced G. p. in humans and animals. There are several forms of G. p., the analysis of which makes it possible to determine the effect of selection in natural populations.
Lit.: Timofeev-Resovsky N. V., Svirezhev Yu. M., On genetic polymorphism in populations, "Genetics", 1967, No. 10.
Great Soviet Encyclopedia. - M.: Soviet Encyclopedia. 1969-1978 .
See what "Genetic polymorphism" is in other dictionaries:
genetic polymorphism- Long-term existence in a population of two or more genotypes, the frequencies of which significantly exceed the probability of the occurrence of the corresponding repeated mutations. [Arefiev V.A., Lisovenko L.A. English Russian explanatory dictionary of genetic terms ... ... Technical Translator's Handbook
Genetic polymorphism genetic polymorphism. Long-term existence in a population of two or more genotypes, the frequencies of which significantly exceed the probability of the occurrence of the corresponding repeated mutations. (Source: "English Russian sensible ... ...
genetic polymorphism- genetinis polimorfizmas statusas T sritis ekologija ir aplinkotyra apibrėžtis Genetiškai skirtingų dviejų ar daugiau vienos rūšies formų egzistavimas populiacijoje, kurio negalima laikyti pasikartojančiomis mutacijomis. atitikmenys: engl. genetic ... Ekologijos terminų aiskinamasis žodynas
genetic polymorphism- genetinis polimorfizmas statusas T sritis augalininkystė apibrėžtis Ilgalaikis buvimas populiacijoje dviejų ar daugiau genotipų, kurių dažnumas labai viršija pasikartojančių mutacijų radimosi tikimybę. atitikmenys: engl. genetic polymorphism … Žemės ūkio augalų selekcijos ir sėklininkystės terminų žodynas
Genetic polymorphism- long-term existence in a population of two or more genotypes, the frequencies of which significantly exceed the probability of the occurrence of the corresponding repeated mutations ... Dictionary of Psychogenetics
Polymorphism in biology, the presence within one species of individuals that are sharply different in appearance and do not have transitional forms. If there are two such forms, the phenomenon is called dimorphism (a special case is sexual dimorphism). P. includes a difference in appearance ... ...
I Polymorphism (from the Greek polýmorphos diverse) in physics, mineralogy, chemistry, the ability of certain substances to exist in states with different atomic crystal structures. Each of these states (thermodynamic phases), ... ... Great Soviet Encyclopedia
Unique event polymorphism unique event polymorphism/UEP in genealogy DNA means a genetic marker corresponding to one extremely rare mutation. It is believed that all carriers of such a mutation inherit it from ... ... Wikipedia
Discontinuous variability for homologous alleles of the same gene locus on which population stability is based. The sensitivity of organisms to various environmental factors is differentiated, genotypically determined, ... ... Ecological dictionary
polymorphism polymorphism. Existence in a crossing group (in a population) of genetically different individuals; P. may have a non-genetic (modification) character, for example, depending on the density of the population (see.
Genetic diversity or genetic polymorphism is the diversity of populations according to traits or markers of a genetic nature. One of the types of biodiversity. Genetic diversity is an important component of the genetic characteristics of a population, group of populations or species. Genetic diversity, depending on the choice of genetic markers under consideration, is characterized by several measurable parameters:
1. Average heterozygosity.
2. Number of alleles per locus.
3. Genetic distance (to assess interpopulation genetic diversity).
Polymorphism happens:
Chromosomal;
Transition;
Balanced.
Genetic polymorphism occurs when a gene is represented by more than one allele. An example is blood group systems.
Chromosomal polymorphism - between individuals there are differences in individual chromosomes. This is the result of chromosomal aberrations. There are differences in heterochromatic regions. If the changes do not have pathological consequences - chromosomal polymorphism, the nature of the mutations is neutral.
Transitional polymorphism is the replacement in a population of one old allele with a new one that is more useful under given conditions. A person has a haptoglobin gene - Hp1f, Hp 2fs. The old allele is Hp1f, the new one is Hp2fs. Hp forms a complex with hemoglobin and causes aggregation of erythrocytes in the acute phase of diseases.
Balanced polymorphism - occurs when none of the genotypes benefits, and natural selection favors diversity.
All forms of polymorphism are very widespread in nature in populations of all organisms. In populations of sexually reproducing organisms, there is always polymorphism.
Invertebrates are more polymorphic than vertebrates. The more polymorphic the population, the more evolutionarily plastic it is. In a population, large stocks of alleles do not have maximum fitness in a given place at a given time. These stocks occur in small numbers and are heterozygous. After changes in the conditions of existence, they can become useful and begin to accumulate - transitional polymorphism. Large genetic stocks help populations respond to their environment. One of the mechanisms that maintain diversity is the superiority of heterozygotes. With complete dominance, there is no manifestation; with incomplete dominance, heterosis is observed. In a population, selection maintains a genetically unstable heterozygous structure, and such a population contains 3 types of individuals (AA, Aa, aa). As a result of natural selection, genetic death occurs, which reduces the reproductive potential of the population. The population is falling. Therefore, genetic death is a burden for the population. It is also called genetic cargo.
Genetic load - part of the hereditary variability of the population, which determines the appearance of less adapted individuals that undergo selective death as a result of natural selection.
There are 3 types of genetic cargo.
1. Mutational.
2. Segregation.
3. Substitutional.
Each type of genetic cargo correlates with a certain type of natural selection.
The mutational genetic load is a side effect of the mutational process. Stabilizing natural selection removes harmful mutations from a population.
Segregation genetic load - characteristic of populations that use the advantage of heterozygotes. Weaker adapted homozygous individuals are removed. If both homozygotes are lethal, half of the offspring die.
Substitutional genetic load - the old allele is replaced by a new one. Corresponds to the driving form of natural selection and transitional polymorphism.
genetic polymorphism creates all the conditions for ongoing evolution. When a new factor appears in the environment, the population is able to adapt to new conditions. For example, insect resistance to various types of insecticides.
Genetic polymorphism is a condition in which there is a clear diversity of genes, but despite this, the frequency of the least common gene in the population will be more than 1%. The maintenance of polymorphism occurs due to the constant recombination and mutation of genes. According to the results of recent studies conducted by genetic scientists, genetic polymorphism is very widespread, because the combination of a gene can reach several million.
Mutation of genes
In real modern life, genes are not so permanent, once and for all life. Genes can mutate at different rates. Which, in turn, can cause the appearance of any previously unknown signs, which are far from always useful.
All mutations are usually divided into the following types:
gene - leading to changes in the DNA nucleotide sequence in any individual gene, which also leads to changes in RNA and in the protein encoded by this gene. Gene mutations are also classified into 2 categories recessive and dominant. This type of mutation can lead to the development of new traits that support or suppress the vital activity of a living being.
generative mutation affects germ cells and is transmitted through sexual contact;
somatic mutation does not affect germ cells, in animals and humans it is not transmitted from parents to children, and in plants it can be inherited in the case of vegetative reproduction;
genomic mutation is reflected in the change in the number of chromosomes in the cell karyotype;
chromosomal mutation directly affects the process of rearrangement of the structural structure of chromosomes, changes in the positions of their sections, occurring due to breaks or loss of individual sections.
The following components of modern life can lead to gene mutation, and, therefore, to an increase in the prevalence of ailments of a hereditary nature:
Technogenic catastrophic incidents;
Environmental pollution (use of pesticides, extraction and use of fuel, use of household chemicals);
The use of drugs and food additives that affect DNA and RNA;
Eating genetically modified foods;
Long-term, constant, or especially strong short-term radiation.
Mutation of genes is a highly unpredictable process. This is due to the fact that it is almost impossible to predict in advance which gene, how and in which direction it mutates. Mutation of genes proceeds by itself, changing hereditary factors and, using the example of such a genetically determined disease as thrombophilia, it is quite obvious that these transformations are far from always beneficial.
Types of polymorphism
Among genetic scientists, it is customary to distinguish between transient and balanced gene polymorphism. Transient polymorphism is noted in a population if there is a replacement of an allele that was previously common with other alleles that endow their carriers with a higher level of fitness. In the course of transient polymorphism, a directed shift (calculated in%) of various genotypic forms is noted. This type of gene polymorphism is the main path of the evolutionary process. An example of transient polymorphism is the industrial mechanism process. Thus, as a result of the deterioration of the ecological state in a number of the largest megacities of the world, more than 80 species of butterflies have darker colors. This happened due to the constant contamination of tree trunks and the subsequent destruction of lighter butterflies by insectivorous birds. Later it turned out that the darker color of the body in butterflies appeared due to a gene mutation caused by environmental pollution.
Balanced gene polymorphism is explained by the absence of a shift in the numerical ratio of various forms and genotypes among populations living in unchanging environmental conditions. However, the percentage of forms either remains unchanged, or may vary around some unchanging value. Unlike transient gene polymorphism, balanced polymorphism is an integral part of the ongoing evolutionary process.
Gene polymorphism and health status
Modern medical research has proven that the process of intrauterine development of a child can significantly increase the likelihood of thrombogenic changes. This is especially expected if a woman has a predisposition or suffers from a genetic disease herself. In order for the pregnancy and the process of the birth of the long-awaited baby to pass without serious complications, doctors recommend raising their pedigree to see if close or more distant relatives of the expectant mother suffered from hereditary diseases.
To date, it has become known that the genes of such a hereditary disease as thrombophilia contribute to the development of thrombophlebitis and thrombosis during childbearing, labor and the postpartum period.
In addition, polymorphic changes in the prothrombin factor FII genes can cause incurable infertility, the development of hereditary malformations, and even intrauterine death of an infant before birth or shortly after birth. In addition, this gene transformation significantly increases the risk of developing such ailments as: thrombophlebitis, thromboembolism, atherosclerosis, thrombosis, myocardial infarction and ischemic damage to the heart vessels.
Gene polymorphism of the FV Leiden factor can also significantly complicate the process of pregnancy, as it can provoke a habitual miscarriage and contribute to the development of genetic disorders in an unborn child. In addition, it can cause a heart attack or stroke at a young age or contribute to the development of thromboembolism;
Mutation of the PAI-1 genes reduces the activity of the anti-clotting system, for this reason it is considered to be one of the most important factors in the normal course of the blood coagulation process.
The development of such ailments as thrombosis or thromboembolism is very dangerous during pregnancy. Without professional medical intervention, they often lead to death during childbirth for both mother and child. In addition, childbirth in the presence of these ailments in most cases is premature.
When is it necessary to donate blood in order to detect genetic disorders?
It is recommended that every person have some information about predisposition to certain genetic diseases, even if he does not plan pregnancy. Such knowledge can be invaluable in the prevention and treatment of accelerated thrombosis, heart attacks, strokes, PE and other ailments. However, today the value of information about one's genetic fund plays a huge role in the treatment of cardiological ailments and in obstetrics.
Thus, where the appointment of an analysis to detect thrombophilia and hemophilia plays a special role in the following cases:
When planning a pregnancy;
In the presence of pathological complications during pregnancy;
Treatment of diseases of blood vessels, heart, arteries and veins;
Finding out the causes of miscarriages;
infertility treatment;
In preparation for planned operations;
In the treatment of oncological neoplasms;
In the treatment of hormonal disorders;
Obese persons;
In the treatment of endocrinological diseases;
If necessary, take contraceptive formulations;
Persons engaged in especially hard physical labor, etc.
The timely development of medicine makes it possible to detect genetic abnormalities in advance, determine their polymorphism and possible predisposition to the development of genetic diseases by conducting a complex blood test. Although this analysis may be costly when performed at paid medical centers, such an analysis can greatly facilitate the treatment or prevent the development of many genetic disorders.
