[Show abstract][Hide abstract] ABSTRACT: Ischemic heart disease (IHD) develops in patients with familial hypercholesterolemia (FHC) 15-20 years earlier than in general population. However age of onset of the disease, its clinical manifestations are variable and not completely determined by cholesterol level and class of low density lipoprotein receptor mutations.
To elucidate associations of some auxiliary genetic factors -- such as C151565T, C677T, R353Q polymorphisms of glycoprotein IIIa (GPIIIa), methylenetetrahydrofolate reductase (MTHFR) and coagulation factor VII genes, respectively, -- with the presence of IHD in patients with FHC.
Patients with clinical diagnosis of heterozygous FHC (n=198) with (n=106) and without (n=92) IHD.
Patients with compared with those without IHD had similar frequency of T-allele of MTHFR gene (p=0.519), more often had T-allele of GPIIIa gene (23 and 12.5%, respectively, p=0.009), and less often -- Q-allele of factor VII gene (13 and 21%, respectively, p=0.048). Multifactorial analysis showed that risk of IHD was higher in patients with TT compared with CC genotype of the GPIIIa gene (OR 1.53, 95%CI 1.12-2.3), and lower in patients with RQ and QQ compared with RR genotype of factor VII gene (OR 0.41, 95%CI 0.19-0.75).
In patients with FHC polymorphisms in factor VII and GPIIIa genes but not C677T polymorphism of MTHFR gene were associated with the presence of IHD.
[Show abstract][Hide abstract] ABSTRACT: One of most widely spread causes of hypertrophic cardiomyopathy (HCMP) is mutation in cardiac beta-myosin heavy chain gene. Data on contribution of this mutation to development of HCMP in Russian patients are very limited. We conducted screening of beta-myosin heavy chain gene for the presence of mutations in 116 patients with confirmed HCMP (probands). DHPLC was used with subsequent sequencing of DNA fragments. Genetic defects of beta-myosin heavy chain were found more than in every 10-th patient. These defects were represented by 13 mutations (Ala729Pro mutation was found twice). Phenotypes of majority of known mutations in Russian population did not differ substantially from their phenotypes in other populations. Six mutations had not been previously described; most of them were associated with especially severe clinical and hemodynamic signs and relatively unfavorable course of the disease. Thus beta-myosin heavy chain gene mutation play important role in etiology of HCMP in patients in Russia.
[Show abstract][Hide abstract] ABSTRACT: Low density lipoprotein receptor (LDLR) gene mutations cause familial hypercholesterolemia which is associated with elevated risk of ischemic heart disease.
To define LDLR gene mutations in unrelated patients with heterozygous familial hypercholesterolemia in Russia.
PCR- single-strand conformation polymorphism analysis, automated DNA sequencing, and test for the presence of the apolipoprotein (apo) B-3500 mutation known to induce hereditary defect in apo-B-100.
We found 6 novel mutations of LDLR gene designated E8X, 230insG, 671_679dupGACAAATCT, W422R, D461Y, and V698L. We also identified three missense mutations - C139G, E207K and R395W, which were previously described in FH patients from western populations. None of the studied persons had apo-B-3500 mutation.
These findings broaden knowledge on mutations responsible for development of familial hypercholesterolemia and confirm molecular heterogeneity of this disease in Russia.
[Show abstract][Hide abstract] ABSTRACT: Analysis of genes of apolipoprotein E (apoE), LDLP receptor and methylentetrahydrofolate reductase (MTHFR) in a female patient with mixed hyperlipoproteinemia (HLP) and early ischemic heart disease (IHD).
A patient with a mixed form of HLP and 5 her relatives were examined genetically. The genotype of apoE and MTHFR was determined using a restrictive analysis of PCR fragments. Conformation of one chain DNA was used to analyse gene of LDLP-receptor with following sequencing of anomalous DNA.
The proband had changes in all examined genes: nucleotide replacement of A370T gene of LDLP receptor, nucleotide replacement of MTHFR gene C677T and epsilon 2/epsilon 2-genotype of apoE. None of the relatives carried more than one polymorphism by the studied genes.
Early IHD in females can be caused by combination of polymorphisms of genes associated with development of atherosclerosis.
No preview · Article · Feb 2003 · Terapevticheskii arkhiv
[Show abstract][Hide abstract] ABSTRACT: The expression level of two new lipoprotein-binding proteins p105 and p130 was maximal in inactive VSMC and could be suppressed by activators of proliferation. Both proteins were detected by antisera against three synthetic fragments of T-cadherin and were rendered soluble by GPI-specific phospholipase C. The findings suggest that the 105 kDa lipoprotein-binding protein is T-cadherin whereas p130 is a partially processed GPI-anchored precursor of T-cadherin.
No preview · Article · Aug 1999 · Rossiĭskii fiziologicheskiĭ zhurnal imeni I.M. Sechenova / Rossiĭskaia akademiia nauk
[Show abstract][Hide abstract] ABSTRACT: Potential antigenic determinants of the atypical lipoprotein-binding proteins T-cadherin (p105) and its precursor (p130) from cells of human smooth muscles were synthesized by the solid phase method according to the Fmoc-scheme. These corresponded to the 51-61, 140-160, 161-179, 260-271, 340-352, 350-362, and 370-385 sequences of p130 and were chosen on the basis of computer analysis of its antigenic structure. The conjugates of the peptides with horseradish peroxidase were used for the immunization of mice and rabbits. Antisera against the peptides corresponding to the 140-160, 161-179, and 260-271 sequences of p105 were shown by immunoblotting to react with p105, which we isolated from the vascular cells of smooth muscles and earlier identified as T-cadherin. These antisera inhibited the binding of low density lipoproteins with p105 in a dose-dependent manner. These results confirmed the identification of the p105 protein as T-cadherin and demonstrated the fundamental possibility of studying the interaction of this protein with low density lipoproteins by using antipeptide antibodies that inhibit binding.
No preview · Article · Apr 1999 · Bioorganicheskaia khimiia
[Show abstract][Hide abstract] ABSTRACT: Lipoprotein-binding sites on cultured human omental vascular smooth muscle cells have been investigated. Two sites specifically binding low density lipoprotein (Kd1 = 1 microgram/ml and Kd2 = 50 micrograms/ml) were found. The properties of the high affinity site are similar to those of the previously described "classical" apo B,E-receptor. The nature of the second site is not clear. Binding to this low affinity site is saturable at physiological concentrations of LDL, is reversible and demonstrates a significant selectivity for LDL as compared to HDL3. In contrast with the apo B,E-receptor, the interaction of LDL with the low affinity site is not heparin-sensitive, does not require the presence of bivalent cations and is not abolished after modification of lysine residues of apo B. The kinetic characteristics of the LDL interaction with the low affinity site are in good correlation with the parameters of activation of second messenger systems. The Kd2 value of LDL binding is close to the LDL concentration inducing a half-maximal elevation of inositol phosphates and cytoplasmic Ca2+ level. Acetylation or carbamylation of apo B does not influence the ability of LDL to activate cell-signalling systems. Also, LDL-induced activation of the phosphoinositide turnover is not sensitive to heparin and EDTA. The data obtained support the hypothesis that the low affinity LDL-binding site mediates lipoprotein-induced activation of second messenger systems in human vascular smooth muscle cells.
No preview · Article · Oct 1994 · Biokhimii͡a (Moscow, Russia)