All primary DLPs have a genetically determined nature. However, it is necessary to differentiate the classical family forms of HCV or DLP (monogenic GLP)and such forms of HCV or DLP that are associated only with a hereditary predisposition to this pathology (polygenic DLP). The development of the latter largely depends on environmental factors – nutritional conditions, physical activity, certain concomitant diseases (metabolic syndrome, diabetes, obesity, etc.).
Classical family forms of DLP (monogenic), as a rule, appear from childhood, when one or both parents bear the “main” mutant gene for this pathology. A similar gene plays a leading role in the “ensemble” of genes involved in the exchange of lipoproteins. These genes are designed to regulate the production and structure of one of the core lipoproteins (LP) or the structure and function of specialized lipoprotein receptors, or protein transporters, sometimes enzymes that perform their synthesis or cleavage.
The mutant gene is often transmitted from one of the parents, i.e. , the defect is of a heterozygous character . Much less common are cases where a mutant gene is inherited from both parents, that is , the defect has a homozygous nature. In this case, the pathology manifests itself in early childhood and proceeds very hard.
To understand the laws of inheritance, one must imagine that for some genetic defects, dominant inheritance is characteristic , for others – recessive. Passed to the heir, the dominant gene sooner or later will manifest itself, although it is inherited from one of the parents. The recessive gene manifests itself as a violation in full force if it is inherited from both parents. If the recessive gene is transmitted to the offspring only from one of the parents, then the heir becomes only the carrier of the pathological gene. For such a gene to manifest itself clinically, a “conjugal meeting” of this person with another carrier (carrier) of the same recessive gene is necessary. Only then in a part of their descendants the disease manifests itself clinically. Homozygous “heirs” in such families are born with a frequency of 25 %, heterozygous – (carriers of one mutant gene) – with a frequency of 50 %, finally, 25 % of offspring in such a marriage can not get a pathological gene and does not differ from individuals from a healthy population.
We present figure 2 (schematic diagram of the hereditary transmission of familial HCV), which shows the path of transmission of a heterozygous dominant mutation (male faces are designated by squares, female faces are circles). Carriers of the mutant gene of the family HCS in this figure have a two-color characteristic.
In families where one of the parents has a dominant mutant gene (causing HCS), and the second parent has a healthy set of genes, the probability of inheriting a pathological dominant gene, as mentioned, is 50 %. In other words, half of the descendants in such a marriage can expect the birth of ” heterozygotes ” with family HCV.
So, primary DLP can be caused by one “main” mutant gene (monogenic family DLP), and the mutations of this gene may be different, that is , they are heterogeneous.
In most cases, birefringence is the primary consequence of the interaction of several nucleotide polymorphisms in the ensemble of secondary polygenes , involved in the regulation of lipid metabolism. it polygenic DLP in families with a hereditary predisposition to DLP, to which unfavorable environmental factors (for example, excess animal fats and cholesterol in the diet, etc.) or aggravating co-morbidities (metabolic syndrome, diabetes, obesity) are added.
If the appearance of DLP with monogenic family inheritance is unavoidable, the development of DLP with the inheritance of nucleotide polymorphisms does not necessarily occur.
Monogenic (Family) WCT
Let us first consider specific types of monogenic DLPs.
For our latitudes, the most common family HCS is due to deficiency or defect in LDL receptors in liver and other somatic cells or their low functional activity (due to structural defect). The consequence of this is the accumulation of LDL particles, the main carriers of cholesterol, in the circulating blood.
With relatively frequent heterozygous forms of familial HCV (1 case per 500 population), the blood cholesterol level in these individuals usually ranges from 8-10 mmol / l (350-500 mg / dl ). In rare cases of homozygous familial HCV (1 case per 1 million inhabitants), the blood cholesterol level reaches 15-20 mmol / l (650-1000 mg / dL ).
The nucleotide chain of the gene for the LDL receptor consists of approximately 45,000 nucleotides. It is necessary to assume that in its construction the probability of “error” or mutation is quite high, and these “failures” can occur in different parts of the nucleotide chain, are able to “fix” and be inherited. About 1500 variants of mutations leading to familial HCV and causing disruption of the activity of LDL receptors are described.
One of the variants of this mutation is quite widespread among the Eastern European Jews – “Ashkenazi”, whose ancestors were from Lithuania, because of what the mutation was called “Lithuanian”. Interestingly, among the Jews of Spanish descent – long-established inhabitants of the Mediterranean ( Sephardic Jews ) – a “Lithuanian” mutation is not found.
Among French-Canadians and residents of South Africa with Dutch roots, the frequency of this disease is very high (1 case per 100-300 people), which was called the “effect of the founder.” This is explained by the fact that in a relatively limited population there are mainly only “internal” marriages, that is , this ethnic group almost does not mix with the wider population, which increases the chance of genetically determined pathology.
Mutations of familial HCV associated with a defect in the gene for LDL receptors arise in one of the genetic loci of the 19th chromosome.
Another variant of familial HCG is characterized by a breakdown in the structure of apoprotein B-100, a key protein of LDL. In this case, normal LDL receptors poorly recognize LDL and bind to them poorly, since apo B-100 is a ligand (linker) of LDL receptors. The gene that controls the structure of apo B-100 is located in the 2 nd chromosome. The mutation of this gene entails a defect apo B-100, which will lead to a bad evacuation of LDL from the circulating blood. This is another version of the family HCH. This type of mutation is most often found among peoples inhabiting the countries of Western Europe.
Both described variants of familial HCC have the character of dominant mutations.
A third (rare) species of familial HCV is described, which is autosomal recessive (ARH). The mutation was discovered in one Lebanese family and was called “Lebanese”. The mutation is localized in one of the genes of the 1 st chromosome. This gene is “responsible” for the synthesis of the transport protein that carries the LDL + LDL receptor complex from the surface of the hepatic cells inwards to the organoids that must be utilized for LDL. If the transport protein is not capable of transferring the LDL + LDL receptor complexes into the cell, they accumulate on the membrane and block further LDL binding. A consequence of this will be a delay in LDL in peripheral blood, i.e. HCS.
Recently opened one more – the 4th – type of monogenic autosomal dominant mutation, also leading to familial HCV. This is the result of a mutation in one of the genes of the 1 st chromosome, which controls the synthesis of the enzyme ” subtilisin-kexin- type 9 -protein-convertase ,” designated as PCSK-9. Depending on the nature of its structure, this enzyme can either inhibit or stimulate the activity of LDL receptors. In the case where PCSK-9 is produced with increased affinity for LDL receptors, the activity of these receptors will be inhibited, which will lead to HCS.
Interestingly, the mutation of this enzyme may also be directly opposite to that described above. As a result, the affinity of PCSK-9 for LDL receptors will decrease, they (LDL receptors) will be very active, which will cause a decrease in the level of LDL and cholesterol. In this case, we can talk about a mutation with a positive sign, which will provide resistance to the development of atherosclerosis.
There is also a monogenic mutation associated not with GLP, but with dyslipidemia (DLP) without HCS, leading to widespread atherosclerosis due to the very low content of anti-atherogenic fraction – HDL in blood plasma. This rare endemic disease is the Tangier disease, which is common in one of the islands in the Western Atlantic. The disease develops as a result of a homozygous mutation of a gene located in the 9th chromosome and encoding the synthesis of the transport protein ABCA-1. This protein serves as a specialized intracellular carrier of free cholesterol to the key apoprotein of HDL – apo A1. If an ABCA deficiency occurs in the body, the formation of mature, functionally active forms of HDL is blocked. In addition to the shortage of transport protein (ABCA-1), the content of the A-1 and A-II apoproteins , the key HDL proteins, is also significantly reduced when Tangier disease , without which their synthesis is impossible.
Deficiency of HDL-3 and HDL-2 dramatically reduces the reverse transport of cholesterol from the surface of peripheral cells to the liver. Cholesterol is delayed in tissues, including accumulation in the vascular wall, which leads to the formation of atherosclerotic plaques, although HCS does not develop in this case.
In the literature, other homozygous mutations associated with defects in other sterol transport proteins are described , such as ABCG-5, ABCG-8. With the broken structure of these proteins, the release of sterols from cells is greatly hindered [K. Berge et al ., 2000].
As a rule, such defects are accompanied by increased absorption of plant sterols [J. Horton et al ., 2002], which leads to sitosterolemia , although HCS is absent. Since the necessary protein carriers of sterols are small, the ability of the sterols to be released in the body, which gradually accumulates in the liver, is impaired. This entails suppressing the synthesis of LDL receptors, which in the future can also cause HCS.
Dyslipidemic states characterized by a selective decrease in HDL level (without HCV and without GTG) are quite common in all regions of the world, although they are not related to Tangier disease. When heterozygous carriers of the defective gene ABCA-1 Tangier disease does not develop, but the HDL-fraction content is clearly reduced, which makes these people vulnerable to atherosclerosis [MU Mandelstam, VB Vasiliev, 2008]. Even one pathological allele of the gene that controls the synthesis of the protein ABCA-1 can have a negative effect on this transport protein and make it insufficiently functional.
In some cases, the deficit of HDL is developed as a result of an anomaly in the structure of the genes controlling the synthesis of lecithin-cholesterol acyltransferase (LHAT), the participation of which is necessary for the esterification of free cholesterol. This defect arises as a result of polygenic pathology with a combination of several functionally significant nucleotide polymorphisms (in several genetic loci).
Another monogenic (genetically determined) recessive defect is the cause of a rare form of dyslipidemia – abetalipoproteinemia . In this type of DLP, the synthesis of apoprotein B is disrupted , the formation of LDL particles is sharply inhibited and the level of cholesterol and blood TG is reduced. Although in this case the soil for the development of atherosclerosis disappears, serious violations from the central and peripheral nervous system develop, since the extreme deficiency of LDL primarily affects trophic nerve cells and their processes.
Of the other little-known monogenic defects associated with the development of DLP, one can point to a mutation in the gene controlling the production of the scavenger- receptors. The function of these cell formations of the liver is to capture the HDL-returning HDLs loaded with cholesterol, which they brought from the periphery. If the function of the scavenger- receptors is disrupted, HDL – PI poorly penetrate the liver, their concentration in the peripheral blood rises, but the function is paralyzed, since they are loaded with cholesterol up to the limit and can no longer perform their anti-atherogenic mission [D. Osgood et al ., 2003]. The level of total cholesterol is increased. Thus, sometimes you have to deal with patients who have a lot of HDL, but functionally they are inactive. In other words, there are individuals with a high content of HDL particles, and their protection from atherosclerosis is at a very low level.
A similar situation occurs with genetically determined triglyceridylase deficiency , which does not cleave TG, does not release HDL from them, which greatly inhibits the anti-atherogenic function of these particles [R. Hegele et al ., 1991].
The poor performance of HDL can be associated not only with their deficiency, but with the genetically determined pathology (deficiency) of transport proteins transporting lipids. For example , if transport protein such as CETP lacks (carries cholesterol esters and TG), it is difficult to mobilize esterified cholesterol from HDL, these particles are enlarged, overloaded with cholesterol, and instead of acceptors, cholesterol becomes its donors [ILLUMINATE, 2006]. The concentration of cholesterol in the peripheral blood is up to 70 mg / dl (1.8 mmol / l) and higher. Again, with this example, one can ascertain that the not always high content of the antiatherogenic fraction of lipoproteins (HDL) in The circulating blood guarantees protection against atherosclerosis. We observed one such patient.
We quote our observation:
Patient S., 65 years old (1995 ). In March 1995 , the patient suffered an acute myocardial infarction on the anterolateral wall of the left ventricle. When examined at home 3 days after a heart attack (the patient refused hospitalization), the patient’s condition is satisfactory, the pulse is 60 beats / min, BP = 140/80 mm Hg. Art. In the anamnesis – many years of hypertension, irregularly taking antihypertensive drugs. In 1980 (at the age of 50) suffered a first myocardial infarction. In May 1995 , when the blood lipid profile was studied, the total CH = 308 mg / dl (7.9 mmol / L), CT = 185 mg / dl (2.1 mmol / L), HDL-CI = 91 mg / dl (2 , 3 mmol / l), LDL cholesterol = 180 mg / dL (4.6 mmol / L), the atherogenicity coefficient is 2.4 units.
SUMMARY. Despite the very high level of HDL cholesterol (91 mg / dl ) and the normal coefficient of atherogenicity , the patient suffered myocardial infarction twice. There is every reason to assume that the HDL particles in this patient do not fulfill their intended role. These particles are many, but they are functionally, apparently, inferior.
There are other forms of genetically determined dyslipidemia , for example, combined hyperlipidemia , in which the level of both cholesterol and TG is increased. This type of DLP (HLP) results from the mutation of a gene that controls the synthesis of transcriptional DNA, which is described as the Upstream Stimulatory Factor (USF-1). It is also a monogenic mutation, in which the elimination of VLDLP, and hence the TG, from the circulating blood is mainly disturbed. For the first time, this mutation was identified in Finland and, in its heterozygous variant, apparently causes THG in individuals with a metabolic syndrome. The authors who described this mutation [P. Pajukanta et al ., 2004], consider USF-1 as a regulator of the work of other genes, which by means of RNA encodes the synthesis of a number of proteins participating in the exchange and transport of apoproteins A-2, C-3, E, ABCA-1, etc.
Special attention is required to assess the genetic determination of apoprotein E. According to researchers from South Korea [N. Oh et al ., 2008], several isoforms of apoE ( apo E-2, apo E-3, apo E-4) have been identified , which can occur in different combinations, depending on the genetically determined genotype. It was found that in the majority of practically healthy individuals who do not have DLP, the genotype E-3 / E-3 (homozygous) or the E-3 / E-2 or E-3 / E-4 (heterozygous) alleles is usually found. In some cases (due to the presence of certain nucleotide polymorphisms in some genes) genotypes E-2 / E-2 or E4 / E4 are formed, at which defective apoproteins E [D. Betteridge & J. Morrell , 2003]. In some cases, there is a predisposition to the development of severe combined hyperlipidemia , close to type III according to Fredrickson’s classification . In the future (with age) in persons with similar disorders, there is a high probability of developing dementia or conditions close to Alzheimer’s syndrome.
At the 79th congress of the European Society for the Study of Atherosclerosis in Sweden (2011), Spanish researchers [M. Solancs et al .] Reported two mutations that they found in 9 patients with type III HLP (they designated them as R136S and AL149).
Of the monogenic mutations, one often encounters familial HCV associated with deficiency of LDL receptors or disorders in the structure of the LDL particles themselves.
Population surveys aimed at detecting dyslipidemic conditions primarily identify primary DLPs that are polygenic, that is , caused by genetically determined nucleotide polymorphisms that create a hereditary predisposition to these conditions.
A survey of adults in cities in the European part of Russia revealed 15-20 % of individuals with such disorders, which are realized in conditions of additional unfavorable environmental factors, for example, it can be a diet containing many animal fats, sugary products; sedentary lifestyle; smoking; stress, etc.
Admittedly, controlling the lipid composition of blood with diet and medications is much easier with polygenic DLP, whereas monogenic DLPs are more difficult to treat therapeutically.
As for the manifestations of polygenic DLP, it is most often a moderate HCS or hypertriglyceridemia (THG in the range 2.0-2.5 mmol / l).
If the pathological significance of HCS is not in doubt at present, there is no single point of view regarding the harmful effect of a moderate increase in blood TG levels. In the modern literature, more and more works in which the pathological significance of postprandial THG is attached , ie , an increase in the concentration of TG in the blood plasma after 1-2 hours after eating. It should be borne in mind that the main carriers of TG are VLDL, which are the main substrate for LDL production, the main culprit in the process of lipid infiltration into the vascular wall after its modification.
Reciprocal relationships between TG and VLDLP, on the one hand, and HDL, on the other, have been established. The higher the VLDL level, the lower the HDL content. It’s not for nothing that the latest guidelines on lipidology suggest that we talk not so much about LDL cholesterol as an indicator of the risk of atherosclerosis, but about cholesterol not related to HDL. This cholesterol is calculated as the difference between the total cholesterol and the amount of cholesterol-VLDL, intermediate-density lipoprotein cholesterol (LDL), and LDL cholesterol. It is even easier to calculate this atherogenic cholesterol index as the difference between total cholesterol and HDL cholesterol [ESC / EAS Guidelines , 2011]. It is this cholesterol that is the reference criterion for assessing the pathological significance of HCV.
Clinical manifestations of dyslipidemia
The most severe homozygous monogenic forms of hypercholesterolemia usually begin to appear from the age of 5-7 when the child develops yellowish spots that rise above the skin – xanthomas – on the extensor surfaces of the hands, in the region of the elbows, and sometimes in other parts of the skin, for example, in the gluteal region . In the older age tendon xanthomas are formed in the area of metacarpophalangeal joints and Achilles tendons
There is also a deposition of cholesterol-containing formations in the eyelid region, which are known as ” xanthelasm “. Already in childhood have homozygotes with hypercholesterolemia observed lipoid arc of the cornea, which can be seen at the edge of the iris in the form of rings or poluduzhek top, sides, or bottom, being provided between the arc or semicircle cholesterol ringlet and the edge of the iris can be seen free from cholesterol rim (Fig. 3 ). All these are typical “tags” of congenital monogenic HCV.
Determination of total cholesterol in the blood plasma reveals extremely high rates – 15-20 mmol / l (600-800 mg / dL ). By the age of 15, such an adolescent often has a systolic murmur in the aortic aortic cavity, less often a carotid artery, as the cholesterol deposits begin to enter the vascular wall and atherosclerotic plaques form.
We give a rare example of family number 2, in which heterozygous GLP IIa type was in both parents (not related by kinship). The youngest daughter inherited a mutant gene from one of the parents, that is , it can be characterized as a heterozygote for a family HCV, the eldest son obtained mutant genes from both the mother and the father, ie , became the owner of a homozygous HCV.
A patient, K., born in 1935 , who underwent two myocardial infarctions, who had a high HCV (446 mg / dL ), was proband for this family, and his sister, Valentin P., was invited to the survey r. She had no complaints about her health, but the bright circular lipoid arches of the cornea attracted attention . A study of blood lipids found HCS (480 mg / dL ). The husband of Valentina – EP, 1939 b. also had lipoid arches of the cornea and was treated for intermittent claudication; the His blood cholesterol was determined at 450 mg / dl. He died suddenly, at the wheel of a car, at the age of 52. At the son – Konst . P., 1965 b. – There were large xanthomas on elbows, in the area of metacarpophalangeal articulations and Achilles tendons, and lipoid arches of the cornea. On the aorta, a rough systolic murmur was heard, as in the stenosis of the aortic orifice.
His blood cholesterol fluctuated within the “astronomically” high values: 1500-2000 mg / dL (more than 25 mmol / l!). At the age of 18, the young man suddenly died. Autopsy revealed widespread atherosclerosis of the aorta and coronary arteries.
Daughter – Nat . P., 1975 b. had no clinical markings of HCV (it did not have either xanthoma or lipoid arches of the cornea), total blood cholesterol = 274 mg / dL (7.0 mmol / l). She developed normally, got married, gave birth to a healthy child. At mother Konst . and Nat . Valentine P., despite the very high level of blood cholesterol, up to 70 years of age, the state of health remained quite satisfactory.
SUMMARY . A unique family is represented here, in which husband and wife, not being relatives, had a heterozygous HCV. In the family, two children were born, of whom the son was a homozygote for the family HCS, the daughter – a heterozygote . At the son the level of HS of blood reached an incredibly high level, which gave clinical symptoms from childhood in the form of multiple xanthomas , lipoid arches of the cornea, early-formed aortic stenosis and coronary atherosclerosis. It is not surprising that this young man had a lethal outcome at the age of 18. These data are confirmed by a pathoanatomical study.
The daughter of this family, although the concentration of cholesterol in the blood plasma was elevated, the level of HCS was much lower than that of both parents and the brother, so that until the adulthood, she did not have any clinical manifestations of HCV.
It is noteworthy that men in this family (both son and father) passed away at a young age, whereas women, despite the HCV, exist quite safely and have no serious complications. The example of this family demonstrates the importance of the gender factor for the prediction of patients with heterozygous HCV, although this is not always the case. This is in part true only for heterozygous forms of HCV.
It has already been pointed out that in a certain percentage of cases where both parents have a heterozygous form of HCV, healthy children (without a pathological gene) may be born, but the probability of having children with a heterozygous form of HCS is higher (less high with a homozygous form of HCV).
It is better to learn that the child has inherited the mutant gene of HCS from an early age to start preventive activities since childhood. For this purpose, in families where one of the parents (especially both parents) has HCS, one must take the umbilical cord blood of a newborn baby to study the lipid spectrum.
If it is a heterozygous HCV, clinically it most often manifests itself after 20 years (in women – much later). In heterozygous children in such families, there are usually no typical typical HCV labels, mentioned above ( xanthoma , lipoid arches of the cornea), but they can appear in adulthood. The level of blood cholesterol in these cases varies in the range of 8-10 mmol / l. Clinical signs of developing atherosclerosis in the aorta, in the vessels of the heart, in the carotid arteries in these individuals begin to be detected by the age of 35 (with homozygous forms of HCS – from childhood).
Occasionally there are such monogenic forms of hyperlipidemia , in which not HCS acts, but other disorders, for example, GTG or hyperchylomicronemia ( CGM ).
We give an example:
In the 1980s, we observed a girl with GXM, whose parents were practically healthy, but both of them appeared to be carriers of the recessive gene of CGM. The daughter inherited from both her mother and her father one recessive gene from the CGM. The disease manifested itself from early childhood. The serum of the girl’s blood was turbid, contained a thick layer of XM, which was biochemically expressed in extremely high Tg levels, which reached several thousand mg / dl (25-30 mmol / l). Already at the age of 2, the child had acute pancreatitis, because of which children’s surgeons performed laparotomy. The girl was on a special diet, took a set of digestive enzymes and for some time felt satisfactory. When palpating the abdominal cavity, there was a significant increase in the liver and spleen. The further destiny of the girl (after 14 years) is unknown to us.
SUMMARY. The parents, each of which was the carrier of only one recessive mutant gene (heterozygous carriers of the gene), had no clinical manifestations of the disease. But their daughter inherited 2 recessive mutated GKM gene (that is, it turned out to be a homozygote for a mutant gene), so that the disease manifested itself in full force and led to repeated acute pancreatitis, hepatolienna syndrome and disability .
In cases with genetically determined STT type IV, the first clinical manifestations usually occur by the age of 40 when tolerance to carbohydrates is violated and type 2 diabetes mellitus develops, and then signs of cerebral or coronary artery atherosclerosis appear.