"Finnish" mutations in LDL receptor gene: a rare cause of familial hypercholesterolemia in St. Petersburg and Petrozavodsk.

The search for two mutations, FH-Helsinki and FH-North Karelia, in LDL receptor gene was carried out in patients with familial hypercholesterolemia from St. Petersburg (80 families) and Petrozavodsk (80 families) using allele-specific PCR and analysis of single-stranded DNA fragment conformation polymorphism (SSCP analysis) with subsequent sequencing. The FH-North Karelia mutation was found in one family in St. Petersburg and in one family in Petrozavodsk, while FH-Helsinki mutation was not detected in any of the samples. Hence, the two "Finnish" mutations together responsible for 2/3 familial hypercholesterolemia cases in Finland were extremely rare in the Russian regions neighboring Finland.

[Family and polygenic hypercholesteremia: similarities and differencies according to long-term clinical observations].

AIM: Detection and analysis of similarities and differences in patients with family and polygenic hypercholesterolemia (FHCE and PHCE). MATERIAL AND METHODS: The study included 100 patients with FHCE and 80 PHCE patients with LD-LP cholesterol level at least 4.3 mmol/l (170 mg/dl). RESULTS: The patients differed by age, gender, severity of hypercholesterolemia, clinical symptoms. Half of PHCE patients had myocardial infarction, 18% had angina pectoris, 29% cerebrovascular events. The disease was asymptomatic in 19% FHCE patients, 33% had myocardial infarction, 15%--angina pectoris, 12%--cerebrovascular events, 9%--aortic problems. Total mortality in both groups was similar--32 and 33%. Long-term treatment with statins reduced lethality twice both in FHCE and PHCE. Adequate statin therapy prolonged life of the patients by 11 years, on the average. CONCLUSION: Regular treatment of patients with hypercholesterolemia reduces lethality and prolong their life span.

[Familial hypercholesterolemia in St. Petersburg: diversity of mutations argues against a strong founder effect].

Examination of low-density lipoprotein (LDL) receptor, its promoter, and major exon-intron boundaries from a sample of patients with familial hypercholesterolemia (FH) from 74 probands of St. Petersburg revealed 34 mutations and 8 widely spread polymorphisms at this locus. Only four mutations were considered silent, while the other 30 are likely associated with familial hypercholesterolemia (FH). Mutations in the LDL receptor gene, inducing 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 induced 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, major mutation G197del was detected in 30% (7 out of 22) of patients with FH. In the Slavic population of St. Petersburg, no major mutations were detected. Only five mutations were identified in two families, while 24 were found in isolated families. These data are indicative of the lack of a strong founder effect for FH in the St. Petersburg population.

[About dyslipidemic states characteristic for various forms of ischemic heart disease and cerebrovascular damages].

We examined 4 groups of patients younger than 70 years with atherosclerosis of coronary and/or cerebral arteries. In 98 patients the disease began as acute myocardial infarction, 65 patient from the very beginning suffered from angina of effort, 33 had ischemic cerebral stroke, and in 26 dyscirculatory encephalopathy was diagnosed. Among patients with ischemic heart disease (IHD) and cerebrovascular damages (CVD) 87 and 89%, respectively, had dyslipidemia (DLP). Disorders of lipid composition of the blood with pronounced hypercholesterolemia prevailed in patients with IHD and elevated level of triglycerides or selective decrease of antiatherogenic fraction of lipoproteides - in patients with CVD (especially in patients with stroke). When treatment is prescribed to patients with IHD and CVD at the background of DLP it is necessary to take into consideration DLP variants in order to obtain most effective action of statins and fibrates.

[Atherogenic changes of blood lipids and their components in patients after ischemic stroke]. / Aterogennyi sdvig lipidnogo spektra krovi i ego sostavliaiushchie u bol'nykh, perenesshikh ishemicheskii insul't.

The aim of the study is to analyze frequency and character of blood lipids abnormalities in patients after ischemic stroke (IS). Blood lipids were studied in 54 patients who survived ischemic stroke at 38-70 years. Atherogenic dyslipidemia was found in 49 (90.7%) patients, 37% had a selective low level of HDL cholesterol (< 37 mg/dl). Patients with dyslipidemia, IV type, (27.8%) showed a high level of triglycerides (413 +/- 72mg/dl) and patients with IIa or IIb types--LDLP cholesterol (223 +/- 12.5 mg/dl). A complete analysis of blood lipids allows detecting atherogenic dislipedimia in the majority of patients who survived ischemic stroke (90.7%), which can be treated with statins or fibrates. An adequate therapy of such patients may significantly improve prognosis for those who survived ischemic stroke and, in some cases, prevent its development.

[Localization of vessel lesions in arteriosclerosis and blood lipid composition]. / Lokalizatsiia sosudistykh porazhenii pri ateroskleroze i osobennosti lipidnogo sostava krovi.

AIM: To investigate correlations between composition of plasmic lipid fractions in patients with ischemic heart disease (IHD) and those with cerebrovascular insufficiency (CVI) caused by atherosclerosis. MATERIAL AND METHODS: 75 patients were divided into three groups; 26 patients with IHD free of CVI (group 1), 22 patients with CVI free of IHD (group 2), 27 patients with IHD and CVI (group 3). Blood lipids were measured by a standard mesiautomatic method using Technicon-AA-2 unit (USA). RESULTS: Hyperlipidemia (HLE) type II was most frequent in group 1 while HLE type IV or hypoalphalipoproteinemia without rise in cholesterol or triglycerides--in groups 2 and 3. CONCLUSION: In IHD without CVI dyslipidemia in most cases was associated with one of the additional risk factors (hypertension, smoking, diabetes mellitus) while in CVI it combined with two or three additional risk factors.

[Identification of novel missense mutation G571E, novel silent mutation H229H, nonsense mutation C74X, and four single nucleotide polymorphisms in the low-density lipoprotein receptor in patients with familial hypercholesterolemia from St. Petersburg]. / Identifikatsiia novoi missens-mutatsii G571E, novoi molchashchei mutatsii H229H, nonsens-mutatsii C74X i chetyrekh odnonukleotidnykh polimorfizmov v gene retsptora lipoproteinov nizkoi plotnosti u patsientov s semeinoi giperkholesterinemiei Sankt-Peterburga.

Novel missense mutation G571E (c.1775 G > A), novel silent mutation H229H (c.750 C > T), and nonsense mutation C74X (c.285 C > A), earlier described in Japan but unknown in Russia, were identified in the low-density lipoprotein (LDL) receptor gene in St. Petersburg familial hypercholesterolemia in patients. The analyzed group of patients was shown to be polymorphic in many positions of the LDL receptor gene, namely: c.1171 G/A, c.1773 T/C, c.2177 C/T, and c.2231 G/A.

[Four new mutations and polymorphic variants of the low density lipoprotein receptor in patients with familial hypercholesterolemia in Saint Petersburg]. / Chetyre novye mutatsii i polimorfnye varianty gena retseptora lipoproteinov nizkoi plotnosti u patsientov s semeinoi giperkholesterinemiei Sankt-Peterburga.

In a collection of DNA samples from 100 unrelated patients with clinical features of familial hypercholesterolemia (FH), a search for mutations of exons 4 and 10 of the low-density lipoprotein (LDL) receptor gene was performed using heteroduplex and single-strand conformational polymorphism (SSCP) analyses followed by sequencing of amplified DNA fragments. Four new mutations of the LDL receptor gene were identified: C146R (c.499 T > C), A130P (c.451 G > C), G128G (c.477 T > C), and C188Y (c.626 G > A). Mutation A130P was assigned to the same chromosome with allele variant 447C. Two polymorphic sites in exon 10 of the LDL receptor gene (1413G/A and 1545C/T) were found in the Russian population for the first time. Based on the data obtained, familial hypercholesterolemia was confirmed in seven patients.

[Search for frequently encountered mutations in genes predisposing to breast cancer]. / Poisk chasto vstrechaiushchikhsia mutatsii v genakh predraspolozhennosti k raku molochnoi zhelezy.

DNA of oncological patients, including Ashkenazi Jews and Slavs, living in St. Petersburg was collected, and the resultant collection was screened for three common mutations of genes BRCA1 and BRCA2 by means of heteroduplex analysis. The mutation 5382insC in exon 20 of the BRCA1 gene was found in four unrelated patients, including three Slavs and one Ashkenazi Jew, with a positive family history of breast cancer. The mutations 185delAG and 6174delT in the BRCA1 and BRCA2 genes, respectively, which are typical of Ashkenazi Jewish patients with breast cancer, were not found in the patients of either ethnicity living in St. Petersburg, although the 6174delT mutation was found in the control group of Ashkenazi Jews. A new 12-nucleotide duplication g.71741ins12nt found in intron 20 of the BRCA1 gene was described. The high frequency of the 5382insC mutation in the BRCA1 gene in patients with familial breast cancer in both St. Petersburg and Moscow indicates that Russian families with the history of breast cancer should be primarily tested for this mutation.

[An epidemiological assessment of ischemic heart disease and mortality in men over 70 in the population of Saint Petersburg]. / Epidemiologicheskaia otsenka ishemicheskoi bolezni serdtsa i smertnosti u muzhchin starshe 70 let v populiatsii Sankt-Peterburga.

AIM: To analyze prevalence of ischemic heart disease (IHD), main IHD risk factors and mortality in the population of males aged 70-79 and over 80 years. MATERIALS AND METHODS: The study included 209 males aged 70-79 years and 96 males over 80. All the males were examined for IHD and 3 main risk factors: blood hypertension, hyperlipidemia and smoking. RESULTS: Incidence of IHD was about similar in both age groups. For 3.5 years of follow-up in the group of 80-year-olds mortality was 2 times that of the group of 70-79-year-olds. The presence of IHD in the groups was directly related to the presence of 2 or 3 risk factors, especially in the group aged 70-79 years. In the group of 80-year-olds and older combination of IHD with affection of cerebral vessels was a poor prognosis sign. CONCLUSION: Factors deteriorating prognosis in males over 70 were: macrofocal myocardial infarction in anamnesis, atherosclerosis of the coronary and cerebral arteries.

[The characteristics of the hypolipidemic effect of Mevacor with its permanent multiyear use]. / Osobennosti gipolipidemicheskogo éffekta mevakora pri ego permanentnom mnogoletnem primenenii.

Changes in blood lipids were assessed in the course of 4 years in 29 patients with cholesterol (CS) levels at least 300 mg/dl (hyperlipidemia). Of these, 20 received mevacor, 9 were controls. Taking mevacor in a dose 20-40 mg/day for 6 months reduced CS in the study group by 20% and by 10% more within the next 6 months. CS in controls changed unnoticeably. Lowering of the dose to 10-20 mg/day or mevacor discontinuation at the moment CS fell to 250 mg/dl or greater did not entail a rerise of total blood CS within subsequent 4-6 months.

[The clinico-genetic aspects of familial hypercholesterolemia and their applied significance]. / Kliniko-geneticheskie aspekty semeinoi giperkholesterinemii i ikh prikladnoe znachenie.

Clinico-biochemical, genealogical evidence was compared to molecular-genetic findings on LDLP receptor gene in 4 families with a history of high blood cholesterol. It was found that members of the same family carrying the anomalous gene can demonstrate varying atherogenic shift in blood lipid fractions suggesting involvement of other endo- and exogenic factors. Molecular-genetic examination of subjects with family hypercholesterolemia discovered a family with structural derangement of the gene, two families with spot defects and a family in which the proband's hypercholesterolemia seemed unrelated to changes in the gene, but probably related to the gene controlling synthesis of apoB-protein.

[Molecular heterogeneity of familial hypercholesterolemia in the St. Petersburg population]. / Molekuliarnaia geterogennost' semeinoi giperkholesterinemii v populiatsii zhitelei Sankt-Peterburga.

Inheritance of Taq I, BstE II, and Nco I restriction fragment length polymorphisms (RFLP) in three families from St. Petersburg with familial hypercholesterolemia (FH) was studied. In two of these families, polymorphic markers of the low density lipoprotein receptor (LDLR) gene cosegregated with the disease. This data confirmed FH diagnosis based on the analysis of blood plasma lipid levels. Three different RFLP haplotypes were associated with the disease, suggesting the presence of at least three point mutations in the LDLR gene in the population studied, i.e., suggesting molecular heterogeneity of FH in the St. Petersburg population.

[A multiexon deletion in the human low density lipoprotein receptor gene as a reason for familial hypercholesterolemia]. / Mul'tiékzonnaia deletsiia v gene retseptora lipoproteinov nizkoi plotnosti cheloveka kak prichina semeinoi giperkholesterinemii.

Inheritance of Taq I, BstE II, and Nco I restriction fragment length polymorphisms (RFLP) in three families from St. Petersburg with familial hypercholesterolemia (FH) was studied. In two of these families, polymorphic markers of the low density lipoprotein receptor (LDLR) gene cosegregated with the disease. This data confirmed FH diagnosis based on the analysis of blood plasma lipid levels. Three different RFLP haplotypes were associated with the disease, suggesting the presence of at least three point mutations in the LDLR gene in the population studied, i.e., suggesting molecular heterogeneity of FH in the St. Petersburg population.

[Psychophysiological approaches to assessing patients with painful and painless forms of ischemic heart disease]. / Psikhofiziologicheskie podkhody k otsenke bol'nykh s bolevoi i bezbolevoi formoi IBS.

By the results of bicycle ergometry test 28 coronary heart disease (CHD) patients were divided into 2 groups: with a pronounced anginal syndrome (group 1) and coronary insufficiency evident on ECG (group 2). Vegetative and psychophysiological parameters obtained in the examinees (heart rate, arterial pressure, pain threshold, personality profile) demonstrated that increased pain sensitivity, anxiety, predisposition to neurotic reactions were more typical for patients of group 1. Therapeutic response was achieved after psychophysiological correction by means of creation and activation of artificial stable functional connections of the brain.

[Hyperlipidemia as a factor of myocardial damage (experimental study)]. / Giperlipidemiia kak faktor povrezhdeniia miokarda (éksperimental'noe issledovanie).

To elucidate the assumed direct negative effect of huperlipidemia (HL) on the myocardium, histological and electron microscopic studies of the myocardia of rabbits with alimentary hypercholesterolemia which were on an atherogenic diet for 30 days and underwent transesophageal pacing tests were conducted. An experimental group comprised 7 rabbits with HL, a control one included 4 animals. In HL rabbits, the cardiac pacing test caused irreversible myocardial histomorphological changes. In normolipidemic rabbits this caused only myocardial functional overload and histological changes were moderate and reversible. The findings suggest that HL contributes to myocardial hypoxic damage due to impaired microcirculation and tissue diffusion of oxygen with higher myocardial oxygen demand.

[An evaluation of the hypolipidemic effects of lovastatin in primary hypercholesterolemia. A multicenter study]. / Otsenka gipolipidemicheskikh éffektov lovastatina pri pervichnoi giperkholesterinemii. Mnogotsentrovoe issledovanie.

In the multicenter trial, the hypolipidemic efficacy and adverse event profile of lovastatin were estimated in 294 patients with primary hypercholesterolemia. The mean baseline (on placebo) lipid and lipoprotein values were: total serum cholesterol (TC) 313 mg/dl, triglycerides (TG) 168 mg/dl, low density lipoprotein cholesterol (LDL-C) 235 mg/dl, high density lipoprotein cholesterol (HDL-C) 44.9 mg/dl. Lovastatin was begun with 20 mg/day, the dose being doubled after 4 and 8 weeks if the target reduction of TC < 200 mg/dl was not reached at those moments. At the end of the treatment the mean TC decreased by 29.5% (p) as compared with the baseline level, TG by 14% (p). The normal target level of TC was reached in 106 patients (36%), the borderline levels (200-240 mg/dl) in 123 (42%), high TC (240 mg/dl) remained in 65 patients (22%). LDL-C decreased by 38% (p), HDL-C increased by 7.8% (p), whereas LDL-C/HDL-C ratio decreased by 40% (p). The treatment was well tolerated by patients: mild clinical side effects were noticed in 2.7% of patients and asymptomatic transient deviations of laboratory tests in 8.2%. The authors conclude about high hypolipidemic efficacy and low adverse event profile of lovastatin in patients with primary hypercholesterolemia.