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Dysregulation of adipose tissue functions makes a significant contribution to the pathogenesis of metabolic syndrome, one of the most common diseases in recent years. Adipose tissue is an organ that secretes at least several dozen signaling molecules, adipokines. One of the most studied and at the same time mysterious adipokines is adiponectin. The latter is due to the lack of clear ideas about the biological role of this adipokine, the presence of its several molecular forms with different activity and several types of receptors to this adipokine localized in almost all cells of the body. The purpose of this review is to summarize and analyze the available information about the molecular mechanisms of the effect of adiponectin on metabolism of carbohydrates, lipids and lipoproteins. The literature search was conducted by the keywords "adiponectin" and "metabolic syndrome" in the Pubmed and Elibrary.ru databases for the period from 1995 to 2021.According to the results of the literature analysis, it is assumed that adiponectin is involved in energy metabolism as a «satiety» hormone that promotes the utilization and storage of energy-rich substrates, fatty acids and glucose, which prevents the development or mitigates the already developed insulin resistance. This reduces the amount of plasma triglycerides and increases the level of high-density lipoproteins in the plasma. Adiponectin affects metabolic processes by activating the AdipoR1-APPL1-LKB1-AMPK, AdipoR1-APPL1-p38, AdipoR2-PPARa cascades, and possibly by activating the ceramidase and phosphoinositide pathways and insulin signaling. In addition to the AdipoR1/2 receptors, the adhesion molecule T-cadherin may be involved in the transduction of the adiponectin signal in endothelial and muscle cells. The mechanisms of signal transduction from T-cadherin, as well as from AdipoR2, remain unclear. Studies on the mechanisms of the action of individual molecular forms of adiponectin are extremely rare. The analysis shows the complex nature of adiponectin signaling, many of the mechanisms of which remain undiscovered, and it is possible that the near future will bring us significant progress in this area.

Features of the heart rate variability at patients with acute disorder of cerebral circulation depending on the type of hemodynamics were studied in acute period of disease and in a condition of relative functional rest. Surveyed men and women (121 patients, 3055 years old) were divided into 3 groups according to the type of hemodynamics that was defined at the first day of their disease: the groups of patients with hyper-, hypo- and normodynamic types of hemodynamics were selected. The integral rheography of the body was carried out again on the 7th day of hospitalization of the patients. And according to the received data all examined individuals were divided into subgroups. The evaluation of indicators of the heart rate variability at patients during acute period of disease showed the significant increase of activity of the sympathetic link of regulation among people with hyperdynamic type of hemodynamics: the indices of tension and vegetative balance also as the standard deviation of NN intervals (SDNN) were rather law. The sam e patients examined on the 7th day of their disease demonstrated the reduction of the indices of tension and vegetative balance and the increase of the mean square difference between the duration of adjacent R-R intervals (RMSSD). These changes were regarded as gradual weakening of the sympathetic influences on cardio-vascular system in stabilization period. At examination of patients in a week from the moment of their hospitalization transformation of the type of hemodynamics was revealed among many of the surveyed. The indices of tension and vegetative balance were the lowest among patients with acute disorder of cerebral circulation and initially hyperdynamic type of hemodynamics and newly formed hypodynamic type of blood circulation. While patients with acute disorder of cerebral circulation and constantly hyperdynamic type of blood circulation showed the maximal tension in operation of the regulatory systems.

Management of variability of the cardiac rhythm (VCR) is widely applied as a marker of psycho emotional state in educational institutions. This approach is suitable for testing properties of the pupils for the detection of vocal signals. The aim of the study was a comparative analysis of VCR as an objective parameter corresponded with psycho-emotional tension and acoustic perception of the speech in youngsters under sophisticated condition of the competition between vocal signals pronounced by different individuals. Methods. VCR was measured in 44 male and female youngsters 1316 years old with the comparison of identification of competing acoustic signals random sequences of words simultaneously pronounced by male or female voice. VCR analysis provided distinction the prevalence of sympathetic versus parasympathetic tone reflecting high or moderate level of psycho-emotional tension. Results. Identification of target words pronounced by female voice in subjects with prevalence of sympathetic or parasympathetic tone was correct in 96% and 87% respectively. Target words pronounced by the male voice were correctly identified in 88% cases in both groups. It is suggested that in primary schools where women compose majority of teachers, the developing juvenile brain imprints the corresponding acoustic wave band. Under the conditions of psycho-emotional tension these links are realized with maximal effectiveness.

Features of the heart rate variability at patients with acute disorder of cerebral circulation depending on localisation of ischemic damage and type of hemodynamics were studied in acute period of disease and in a condition of relative functional rest. Surveyed men and women (30–55 years old) were divided into 3 groups: patients with ischemic damage to the area of the left average brain artery, right average brain artery and with ischemia in vertebro-basilar department. According to indicators of the integral rheography of the body which was carried out in the acute period of a disease, patients of each group were divided into subgroups depending on hemodynamics type – with hyper dynamic, hypo dynamic and normo dynamic type of blood circulation. It was revealed that the highest activity of sympathetic link of regulation and also higher values of the index of tension and the index of vegetative balance characterized patients with ischemia in the area of right average brain artery and hyper dynamic type of blood circulation. The indicator of activity of regulatory systems characterized “overstrain of regulatory mechanisms” and also “exhaustion of mechanisms of regulation” at patients of this group in the acute period. However upon repeated examination 7 days later revealed the significant reduction of the values of the indicator of activity of regulatory systems. Similar indicators of the heart rate variability were found at patients with ischemic damage in the area of right average brain artery and normo dynamic type of blood circulation. Thus, it was detected that the greatest disorders of regulation of the cardiovascular system were characteristic of patients with ischemia in the area of right average brain artery both hyper dynamic and normo dynamic blood circulation types. Activation of parasympathetic and suppression of sympathetic link of regulation were noted in all patients on the seventh day of hospital stay regardless of localisation of ischemic damage and type of hemodynamics.

The review is devoted to discussion the data regarding involvement of the adipocytes’ secreting protein, adiponectin, in atherogenesis. The questions relating the structure of its molecular forms, mechanisms of its production and signaling are also considered. Based on analysis of clinical studies and the results obtained in animals and cell cultures it is thought that adiponectin has both antiatherogenic and proatherogenic properties.

Summary. Female rats after the vital stress caused by experience of the circumstances of the death of a partner from the actions of the predator showed long-lasting behavioral disturbances, such as decreased locomotor activity, exploratory activity, increased anxiety and aggression. Indicators of lipid metabolism of rats were altered in comparison with control at different time after exposure. These changes through two months later a single stress and right after second psychogenic trauma were characterized by reduced total cholesterol and cholesterol of high density lipoproteins in serum and increased triglycerides in the liver. The severity of behavioral disorders and deviations from the control values of indicators of lipid metabolism in female rats depended on the phases of the estrous cycle. The revealed deviations are discussed in terms of post-traumatic stress disorder.

The study included 79 patients with coronary artery disease, 25 individuals with preclinical atherosclerosis and 59 healthy controls. Key lipid parameters were examined in all the participants. Levels of antibodies (Abs) against (IgG and IgM) LDL modified by malondialdehyde (MDA), acetic anhydride and hypochlorite, were determined by the enzyme-linked immunosorbent assay (ELISA). Abs specificity was tested by competitive ELISA. Circulating immune complexes (CIC) were isolated by precipitation in polyethylene glycol. Abs to hypochlorite-modified low density lipoprotein (hypochlorite-LDL) were detected in the serum samples. These Abs did not demonstrate cross-reactivity with MDA-modified LDL (MDA-LDL) and acetylated LDL (acetyl-LDL). Patients with coronary artery disease had increased levels of CIC (p0.0001) and decreased levels of Abs (IgM) to hypochlorite-LDL, compared with healthy controls and patients with preclinical atherosclerosis (p=0.006). A correlation between the levels of Abs (IgG) to the hypochlorite-LDL and Abs to MDA- and acetyl-LDL was found. There was a correlation between the content of the Abs (IgM) to MDA- and acetyl-LDL and the concentration of CIC-cholesterol. Lipid parameters did not correlate with Abs levels.59 prakticheski zdorovykh lits. U vsekh patsientov byli opredeleny kliuchevye lipidnye pokazateli. Urovni antitel (AT) klassov IgG i IgM k LPNP, modifitsirovannym malonovym dial'degidom (MDA), uksusnym angidridom i gipokhloritom, opredeliali metodom immunofermentnogo analiza. Spetsifichnost' AT proveriali metodom konkurentnogo immunofermentnogo analiza. Tsirkuliruiushchie immunnye kompleksy (TsIK) vydeliali metodom osazhdeniia v poliétilenglikole s posleduiushchim opredeleniem v nikh soderzhaniia kholesterina énzimaticheskim metodom. V syvorotke krovi obsledovannykh lits byli obnaruzheny AT k LPNP, modifitsirovannym gipokhloritom (gipokhlorit-LPNP), kotorye perekrestno ne vzaimodeĭstvovali s modifitsirovannymi MDA (MDA-LPNP) i atsetilirovanymi LPNP (atset-LPNP). Po sravneniiu so zdorovymi litsami i patsientami s doklinicheskim aterosklerozom u bol'nykh IBS byl povyshen uroven' kholesterina TsIK (KhS-TsIK) (p0,0001) i snizhen (p=0,006) uroven' AT (IgM) k gipokhlorit-LPNP. Obnaruzhena korreliatsiia mezhdu urovniami AT (IgG) k gipokhlorit-LPNP i urovniami AT k MDA- i atset-LPNP. Takzhe nabliudalas' korreliatsiia mezhdu soderzhaniem AT (IgM) k MDA- i atset-LPNP i kontsentratsieĭ kholesterina TsIK (KhS-TsIK). Sviazi mezhdu urovniami AT i lipidnymi pokazateliami ne vyiavleno.

Peculiarities of hemodynamics in dependence of individual psycho-physiological features are examined among patients with acute disorders of cerebral circulation and healthy volunteers remaining in the situation of emotional stress. It was demonstrated that formation of “negative” emotional balance (prevailing of personal anxiety on reactive anxiety) promoted occurrence of the excessive tension and/ or overstrain of the adaptive mechanisms. It was either revealed that “negative” emotional balance facilitated the appearance of signs of the adaptive systems overexertion regardless of the type of the initial hemodynamics. It was detected that the psycho-physiological parameters, the peculiarities of hemodynamics and the level of tension of adaptive mechanisms in patients with acute disorders of cerebral circulation were comparable with the similar indices of healthy volunteers characterized by “negative” emotional balance in the situation of the emotional stress.

Bradykinin B2 receptor is involved in many processes, including the regulation of blood pressure and smooth muscle contraction, vasodilation, inflammation, edema, cell proliferation, and pain. This receptor attracts special attention as one of the factors that have cardioprotective and infarct-limiting effects. Certain genetic variants of the coding and noncoding regions of the bradykinin B2 receptor gene (BDKRB2) may play a role in modulating its expression. The 3′-untranslated region of BDKRB2 exon 3 harbors a minisatellite repeat (B2-VNTR), which affects the mRNA stability. Hence, it is of interest to study a possible association of B2-VNRT alleles with various forms of coronary heart disease (CHD). In our work the allele and genotype frequency distributions of B2-VNTR were compared between healthy individuals and patients with CHD (angina pectoris or myocardial infarction (MI)) of the Russian ethnic group. Based on its length polymorphism, B2-VNTR was classed with low-polymorphic non-hypervariable minisatellites. Three B2-VNTR alleles, which consisted of 43, 38, and 33 repeats, were observed in all investigated cohorts. The alleles with 43 and 33 repeats were the most prevalent. The allele and genotype frequencies of B2-VNTR did not significantly differ between males and females in control group, and also between healthy males and males with angina pectoris or MI. Thus, B2-VNTR length polymorphism was not associated with these clinical forms of CHD in males. However, we do not exclude the possibility of an association of the short B2-VNTR alleles (38 and 33 repeats) with a cardioprotective effect in females with CHD. This hypothesis requires further investigation.

The antiatherogenic role of high-density lipoproteins (HDL) was demonstrated by numerous experimental, clinical and epidemiological studies. The mechanism underlying the antiatherogenic potential of HDL is based on their involvement in reverse cholesterol transport (RCT) from peripheral tissues into the liver. Transmembrane transporter ABCG1 is a key RCT protein. Its function is to remove cholesterol from cells and transfer it to HDL. The role of ABCG1 transporter in the development of atherosclerosis in humans remains unexplored. The goal of our study was to investigate the expression of ABCG1 gene in patients with atherosclerosis. Real-time PCR was applied to study ABCG1 mRNA content in leukocytes, monocytes, and macrophages activated with macrophage colony-stimulating factor (M-CSF) from patients with atherosclerosis and healthy people. The amount of ABCG1 protein in monocytes and macrophages of patients and healthy donors was assayed by immunoblotting. It was found that the level of ABCG1 mRNA (p < 0.001) and ABCG1 protein (p < 0.05) was lower in macrophages of patients with atherosclerosis. The level of ABCG1 mRNA in monocytes of patients with artery occlusion was lower than in patients with features of lesser stenosis and the control group (p < 0.05). No correlation was found between ABCG1 gene expression and total and HDL cholesterol levels in the blood plasma. It can be concluded that reduced ABCG1 gene expression in monocytes and macrophages may be critical for the atherosclerosis progression.

Aim of the studyThis study is dedicated to evaluation of the prevalence of metabolic syndrome and its components in patients with schizophrenia in Russia.Subject or material and methods138 patients with schizophrenia who received antipsychotic medication and 138 mental healthy subjects from 1,561 bank employees cohort matched to schizophrenic patients by sex, age and body mass index were enrolled to the study. Fasting blood plasma levels of glucose, lipids, insulin, cortisol, prolactin concentrations were determined.ResultsIn comparison with control group patients had significantly higher frequency of metabolic syndrome and abdominal type of obesity (according to NCEP ATP III and IDF criteria). In spite of lesser level of plasma glucose and total cholesterol, plasma insulin and triglycerides concentrations were higher in patients with schizophrenia. High density lipoprotein cholesterol concentration was lower in patients while arterial blood pressure level didn’t differ between groups. Cortisol and prolactin levels were elevated in the patient group, but these hormones correlated neither with metabolic syndrome nor with any metabolic parameters studied.DiscussionThe study conducted in Russia revealed the increased frequency of metabolic syndrome in schizophrenic patients in comparison with mental healthy cohort. The main disorders found in the patient group were abdominal obesity, insulin resistance and dyslipidemia.ConclusionsResults obtained in this study should be taken into account when developing of medical treatment of patients with schizophrenia.

Interrelationship between total, multimer (MM) and oligomer (OM) adiponectin blood concentrations with some metabolic parameters has been investigated in 49 men and 49 women (mean age of 57.3 ± 10.1 years). We have found negative correlations between total blood adiponectin and its MM form content with body mass index, waist circumference, the insulin resistance index HOMA, with blood concentrations of insulin, glucose, free fatty acids, triglycerides and also positive correlations with high density lipoprotein cholesterol content. There was a poor correlation between OM adiponectin concentration with any parameter studied. According to the regression analysis, concentration of total adiponectin but not its MM form was an independent determinant of the HOMA index in women and free fatty acid concentration in men. In the group of men with the low level of adiponectin its MM form but not total adiponectin reversely correlated with the HOMA index and was its independent determinant. Thus, correlation between blood adiponectin concentration and metabolic parameters is associated with its MM rather than OM form. Study of the role of adiponectin in development of metabolic disorders may be limited to determination of total blood adiponectin concentration except a group of male patients characterized by a low level of this adipokine. In these patients concentrations of the MM form should be determined.

ABCA1 transporter is known to play an important role in cholesterol transport from peripheral tissues. However, its contribution to atherosclerosis development remains obscure. Using Real Time PCR, we detected a significant reduction of ABCA1 mRNA level in leukocytes of patients with atherosclerosis compared to control. Mean ABCA1 expression levels in leukocytes from the group of patients and from the control group were 0.57 ± 0.28 and 0.93 ± 0.14 (p = 0.02). At the same time, we revealed a significant increase of ABCA1 mRNA level in macrophages of patients compared to control. Mean ABCA1 expression levels in macrophages from the group of patients and from the control group were 1.32 ± 0.10 and 0.90 ± 0.14 (p = 0.014). In summary, we suggest that the expression level of ABCA1 gene may regulate atherosclerosis development.

The purpose of the study was to reveal a possible role of adipokines, biologically active adipose tissue proteins (leptin and adiponectin) and nonesterified fatty acids in generating insulin resistance (IR). One hundred and fifty-seven patients (90 females and 67 males) aged 57.5±9.2 years were enrolled in the study. According to the HOMA index for IR, the patients were divided into 3 equal groups. The examinees with a high HOMA index were found to have elevated levels of fatty acids, leptin and decreased concentrations of adiponectin. At the same time according to the linear regression analysis, all these indices are its independent determinants. However, analysis of the data in the groups of patients with different body weight revealed that the increased concentrations of fatty acids and leptin may play a role in the development of IR in subjects with obesity while the higher level of fatty acids and lower adiponectin may be involved in patients without noticeable obesity. Thus, it may be assumed that leptin, adiponectin and nonesterified fatty acids may affect the development of IR; however, their contribution depends on the degree of adiposity.

Examination of low-density lipoprotein (LDL) receptor gene, its promoter, and most of exon-intron boundaries from 74 probands with familial hypercholesterolemia (FH) of St. Petersburg revealed 34 mutations and 8 widely spread polymorphisms at this locus. Only four mutations were considered neutral, while the other 30 are likely to cause familial hypercholesterolemia (FH). Mutations in the LDL receptor gene, causing the disease, were identified in 41 (55%) out of 74 families with FH. Mutation R3500Q in apolipoprotein B (APOB) gene was not detected in all probands. Therefore in the families lacking mutations hypercholesterolemia was caused by mutations in the introns of the LDL receptor gene or by other genetic factors. Nineteen mutations causing disease progression were described in St. Petersburg for the first time, while 18 of them are specific for Russia. Among Ashkenazi Jews, predominant mutation G197del was detected in 30% (7 out of 22) of patients with FH. In the Slavic population of St. Petersburg, no predominant mutations were detected. Only five mutations were identified in two Slavic families, while 24 were found in unique families. These data are indicative of the lack of a strong founder effect for FH in the St. Petersburg population.

Aim The role of adipose tissue hormones, adipokines, in formation of metabolic disorders in schizophrenia is not fully understood. The aim was to investigate the association of leptin and adiponectin plasma levels with metabolic parameters in antipsychotic treated patients with schizophrenia and in the group of age, gender and body mass index matched mental healthy persons. Methods One hundred patients with diagnosis of schizophrenia, who took antipsychotic medication, and equal number of control subjects, were enrolled for cross-sectional evaluation. Fasting blood plasma levels of glucose, lipids, insulin, adiponectin, leptin concentrations and insulin resistance HOMA index were determined. Results In both groups plasma leptin concentration positively correlated with body mass index, insulin plasma level and HOMA index, while adiponectin level had negative correlations with adiposity measures and positive associations with high density lipoprotein cholesterol content. At the same time, in schizophrenia group, but not in control subjects, leptin level positively associated with cholesterol and triglycerides concentrations and adiponectin negatively correlated with plasma insulin content, HOMA index and triglycerides levels. After controlling for confounders significant correlations remained for leptin concentration with HOMA index and plasma triglycerides level in schizophrenic patients and for adiponectin concentration with plasma high density lipoprotein cholesterol concentrations in both studied groups. Conclusions Both adipokines associate with metabolic parameters in antipsychotic treated patients with schizophrenia. Leptin can play more specific role in pathogenesis of metabolic syndrome in schizophrenic persons than in mental healthy subjects.

Using PCR-single-strand conformation polymorphism analysis, followed by sequencing of the abnormal samples, two novel point mutations in the 5' end of the fourth exon of the low-density lipoprotein receptor gene were found in two Russian families with familial hypercholesterolemia. These missense mutations consist of C127W and C139G transitions and result in a loss of one of three disulfide bonds in the fourth cysteine-rich repeat of the ligand-binding domain of the low-density lipoprotein receptor. Hypercholesterolemia segregated with the identified mutations.

We used polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) analysis to detect LDL receptor gene defects in the St. Petersburg population. We have found a deltaG197 mutation in several patients of Jewish origin. The mutation named is shown to be responsible for one-third (7/23) of familial hypercholesterolemia (FH) cases in St. Petersburg Jews and absent in patients of Russian descent. The prevalence of a deltaG197 mutation in St. Petersburg Jews is consistent with its origin in Lithuania or Poland. The deltaG197 mutation can be easily detected in polyacrylamide minigels because of formation of specific heteroduplexes during PCR with DNA of heterozygous patients. Taken together with high prevalence of the mutation in St. Petersburg Jews, this observation provides an opportunity for DNA diagnostics of FH in this ethnic group. Hum Mutat 12:255–258, 1998. © 1998 Wiley-Liss, Inc.

The cytopathogenic effect of various modified lipoproteins on cultured peritoneal macrophages was studied in vitro. After minor peroxide modification lipoproteins induced apoptosis of macrophages. Immune complexes containing oxidized lipoproteins caused cell necrosis.

Female rabbits fed cholesterol-rich diet during pregnancy and/or lactation developed hypercholesterolemia and their progeny had higher lipid levels than the progeny of normolipidemic females. The weight of rabbits born from or fed by females with alimentary hypercholesterolemia was lower than normal during the entire observation period (40 weeks). After weaning (at the age of 6 weeks), serum concentrations of cholesterol and triglycerides in the progeny were higher than in audlt animals.

Apolipoprotein B-containing lipoproteins injected parenterally to CBA mice exhibit immunomodulatory activity. This activity depends on the class (very low or low density lipoproteins) and origin (syngeneic or xenogeneic) of injected lipoproteins. Lipoproteins also modulate phagocytic activity of neutrophils.In vitro lipid peroxidation impairs the immunomodulatory activity of lipoproteins.

The concentration of high-density lipoprotein cholesterol and triglycerides in rat serum sharply decreased after psychic trauma caused by life hazard. The content of these substances remained unchanged for not less than 1 week after trauma. The concentration of high-density lipoprotein cholesterol was low, while serum content of triglycerides increased 6 weeks after trauma. The concentration of high-density lipoprotein cholesterol significantly decreased after repeated psychic trauma. These changes were accompanied by a sharp increase in the concentration of triglycerides in the serum. Total cholesterol concentration in the liver decreased under these conditions.

Specific autoantibodies against acetylated, maleylated and malonic dialdehyde-(MDA)-modified lipoproteins are detectable in human plasma. Immunization of rabbits with autologous, correspondingly modified low-density lipoproteins (LDLs) did induce autoantibodies against acetylated, maleylated and MDA-modified lipoproteins. In atherosclerotic lesions from hyman aorta, the epitopes have been detected that were recognized by the antibodies to acetylated, maleylated, and MDA-modified LDLs. Such antigens were detected at all atherogenesis stages, beginning with the earliest lesions (lipid spots), and their deposition pattern was quite variable. Rabbit and human autoantibodies against acetylated, maleylated and MDA-modified lipoproteins recognized antigens in human atherosclerotic aorta. Modified proteins were localized both intra- and extracellular in tectum, superficial and deep layers of the atherosclerotic lesions. The most typical mode of depositions for all modified proteins si represented by extracellular deposits in the cap of lipid streaks and fibrous plaques, especially in transitional “shoulder” area. The intimal deposits of modified proteins shared similar features with distribution of apo-B-containing lipoproteins, like as of lipids detectable by Oil Red staining. The areas where modified proteins and apo-B-containing lipoproteins were revealed did often coincide with foci of IgG deposits. Modified proteins were not detectable in the non-affected segments of aortic intima.

Familial hypercholesterolemia (FH), a monogenic disease known to be caused by low-density lipoprotein receptor (LDLR) gene mutations, results in the development of premature atherosclerosis and coronary artery disease in affected individuals. The spectrum of LDLR gene mutations in Russia is poorly known. Using polymerase chain reaction (PCR)-single-strand conformational polymorphism (SSCP) analysis, followed by DNA sequencing, we have screened selected exons of the LDLR gene in 80 unrelated St. Petersburg FH patients for the presence of mutations. Two new LDLR gene mutations, 347delGCC and E397X, were characterized among individuals with familial hypercholesterolemia in St. Petersburg. The carriers of both mutations possessed highly elevated blood serum cholesterol. Cosegregation of E397X mutation and LDLR gene RFLP haplotypes with hyperlipidemia was demonstrated by family study. Both mutations seem to be specific to Slavic patients.

Background Familial hypercholesterolemia is a human monogenic disease caused by population-specific mutations in the low density lipoprotein (LDL) receptor gene. Despite thirteen different mutations of the LDL receptor gene were reported from Russia prior to 2003, the whole spectrum of disease-causing gene alterations in this country is poorly known and requires further investigation provided by the current study. Methods Forty-five patients with clinical diagnosis of FH were tested for the apolipoprotein B (apoB) mutation R3500Q by restriction fragment length analysis. After exclusion of R3500Q mutation high-sensitive fluorescent single-strand conformation polymorphism (SSCP) analysis and automatic DNA sequencing were used to search for mutations in the LDL receptor gene. Results We found twenty one rare sequence variations of the LDL receptor gene. Nineteen were probably pathogenic mutations, and two (P518P, T705I) were considered as neutral ones. Among the mutations likely to be pathogenic, eight were novel (c.670-671insG, C249X, c.936-940del5, c.1291-1331del41, W422X, c.1855-1856insA, D601N, C646S), and eleven (Q12X, IVS3+1G>A, c.651-653del3, E207X, c.925-931del7, C308Y, L380H, c.1302delG, IVS9+1G>A, V776M, V806I) have already been described in other populations. None of the patients had the R3500Q mutation in the apoB gene. Conclusions Nineteen pathogenic mutations in the LDL receptor gene in 23 probands were identified. Two mutations c.925-931del7 and L380H are shared by St.-Petersburg population with neighbouring Finland and several other mutations with Norway, Sweden or Denmark, i.e. countries from the Baltic Sea region. Only four mutations (c.313+1G>A, c.651-653del3, C308Y and W422X) were recurrent as all those were found in two unrelated families. By this study the number of known mutations in the LDL receptor gene in St.-Petersburg area was increased nearly threefold. Analysis of all 34 low density lipoprotein receptor gene mutations found in St.-Petersburg argues against strong founder effect in Russian familial hypercholesterolemia.

The development of atherosclerosis is closely associated with an increase in plasma LDL and VLDL concentrations. These lipoproteins probably acquire autoantigenic properties. Some authors (Beaumont 1970; Lewis and Robertson 1974; Noseda et al. 1972) have identified autoimmune complexes containing LDL as antigens and IgA or IgM as antibodies in plasma of atherosclerotic patients. It is also known that a specific immunologic lesion of the arterial wall induces or aggravates the development of atherosclerosis as has been shown by Minick and Murphy (1973). On the other hand, sensitization to structural antigens of the vessel wall, desequestered in the course of degenerative changes on the sites of atherosclerotic lesions, probably enhances the pathologic process. This trend is being successfully studied by Gero et al. (1975).