Molecular characterization of Polish patients with familial hypercholesterolemia: novel and recurrent LDLR mutations.

Autosomal dominant hypercholesterolemia (ADH) is caused by mutations in the genes coding for the low-density lipoprotein receptor (LDLR), apolipoprotein B-100 (APOB), or proprotein convertase subtilisin/kexin type 9 (PCSK9). In this study, a molecular analysis of LDLR and APOB was performed in a group of 378 unrelated ADH patients, to explore the mutation spectrum that causes hypercholesterolemia in Poland. All patients were clinically diagnosed with ADH according to a uniform protocol and internationally accepted WHO criteria. Mutational analysis included all exons, exon-intron boundaries and the promoter sequence of the LDLR, and a fragment of exon 26 of APOB. Additionally, the MLPA technique was applied to detect rearrangements within LDLR. In total, 100 sequence variations were identified in 234 (62%) patients. Within LDLR, 40 novel and 59 previously described sequence variations were detected. Of the 99 LDLR sequence variations, 71 may be pathogenic mutations. The most frequent LDLR alteration was a point mutation p.G592E detected in 38 (10%) patients, followed by duplication of exons 4-8 found in 16 individuals (4.2%). Twenty-five cases (6.6%) demonstrated the p.R3527Q mutation of APOB. Our findings imply that major rearrangements of the LDLR gene as well as 2 point mutations (p.G592E in LDLR and p.R3527Q in APOB) are frequent causes of ADH in Poland. However, the heterogeneity of LDLR mutations detected in the studied group confirms the requirement for complex molecular studies of Polish ADH patients.

Differences in risk factors for dementia with neurodegenerative traits and for vascular dementia.

In 229 patients with dementia and in 144 control subjects, polymorphisms of apolipoprotein E (ApoE), low-density-lipoprotein (LDL)-receptor-related protein, alpha(2)-macroglobulin, interleukin (IL) 1beta, angiotensin-converting enzyme and of methylene tetrahydrofolate reductase genes were investigated. In plasma, antibodies against Chlamydia pneumoniae and lipids were determined. Dementia was classified as probable Alzheimer's disease (AD), probable dementia of vascular origin (VaD) and mixed dementia (MD). An association of the disease with ApoE and IL-1beta polymorphism and increased levels of LDL cholesterol were observed in AD and in MD but not in VaD.

[Determination of lipoprotein (a) [Lp(a)] in patients with ischemic stroke. Preliminary communication]. / Oznaczanie lipoproteiny (a) [Lp(a)] u pacjentow z niedokrwiennym udarem mozgu. Doniesienie wstepne.

The aim of this work was the determination of apolipoprotein(a) [Lp(a)] in the patients three months after the onset of ischaemic stroke. A group of 56 patients was investigated. Stroke was diagnosed as caused by atherosclerotic changes in main cerebral arteries in 32 patients and in 11 by changes in cervical arteries. In 13 persons a lacunar stroke was recognised. The mean Lp(a) level and the median value were significantly higher in the group of patients after stroke as compared with 45 controls. A more frequent occurrence of Lp(a) level over 30 mg/dl considered as pathological was observed more often in the patients. No correlation was seen between Lp(a) and the resistance of LDL to oxidation nor between Lp(a) and the amount of products of LDL oxidation in vitro.

Apolipoprotein E genotype, lipid levels and coronary heart disease in a Polish population group.

Genotype of apolipoprotein E has been identified in a group of randomly selected Polish subjects participating in a cross-sectional study performed within the POL-MONICA Program, the part of international study WHO-MONICA Project. The investigated group consisted of 170 persons, 92 males and 78 females aged 41-69 years (mean age 62.0+/-5.11). The observed frequency of apolipoprotein E alleles was: epsilon2 - 7.6%, epsilon3 - 81.8% and epsilon4 - 10.6%, which was similar to frequencies in the neighbouring European countries. Statistically significant lower means of total cholesterol (TC) and of low density lipoprotein cholesterol (LDL-C) levels in epsilon2 carriers and higher means of TC, of LDL-C and of triglycerides in epsilon4 carriers were observed as compared with noncarriers of respective alleles. Some nonlipid cardiovascular risk factors (hypertension (HT) and obesity) and coronary heart disease (CHD) showed a tendency to lower prevalence in the epsilon2 allele carriers as compared to noncarriers. In the epsilon4 allele carriers a tendency to higher prevalence of HT, but not of CHD was observed as compared to noncarriers of this allele.

Familial defective apolipoprotein B-100 in a group of hypercholesterolaemic patients in Poland. Identification of a new mutation Thr3492Ile in the apolipoprotein B gene.

The prevalence of the familial defective apolipoprotein B-100 (FDB) Arg3500Gln mutation in 525 unrelated hypercholesterolaemic Polish subjects was evaluated. DNA samples were screened for FDB mutation using SSCP method. Presence of mutation was confirmed using a mismatch MspI PCR strategy. Plasma lipid levels and clinical characteristics of 13 patients identified as carriers of the mutation and of their 23 affected relatives were analysed and compared with non-affected ones. In the affected individuals a variable expression of lipid concentrations and of atherosclerosis symptoms were observed. The prevalence of FDB Arg3500Gln mutation in hypercholesterolaemic Polish subjects (3.7%) seems to be similar to the frequency reported in other Caucasian hypercholesterolaemic populations. The estimated prevalence of the mutation in general Polish population is relatively high being 1/250. The same haplotype at the apoB locus in the carriers of this mutation in Poland as in other populations from Western Europe suggests its common origin. In one hypercholesterolaemic subject a non-hitherto described mutation was identified. It consisted in C-->T transition in apoB codon 3492 leading to threonine to isoleucine substitution in 3492 position of apoB gene (Thr3492Ile).

Apolipoprotein E genotype and lipid and lipoprotein levels in dementia.

In 64 individuals with dementia (26 Alzheimer type, 34 of vascular origin and 4 other types of dementia) apolipoprotein E genotype was identified. Frequency of epsilon4 allele was 36.5% in Alzheimer patients and 32.4% in vascular dementia ones. In a group of 39 nondemented individuals of the same age the epsilon4 frequency was 11.5%. In demented patients, carriers of epsilon4, a tendency to higher plasma levels of atherogenic lipids (total cholesterol and low-density lipoprotein cholesterol) as compared with noncarriers was observed. It is possible that the epsilon4 form may aggravate the course of dementia through a moderate influence on the atherogenic lipoprotein level. The results showed that both Alzheimer disease and vascular dementia shared the same risk factors which is consistent with current opinion about a link existing between these two types of dementia.

Apolipoprotein E in alcoholics.

In 31 alcohol addicted patients entering detoxication treatment and in 14 social drinkers apolipoprotein E (Apo E) was assayed by radial immunodiffusion in the whole serum and after phosphotungstate Mg2+ precipitation. Serum Apo E level in the intoxicated individuals was increased compared with the controls. The Apo E increase was mostly due to the very low and low density (VLDL + LDL) fraction. The Apo E/cholesterol ratio in this fraction was increased. It is possible that increased Apo E concentration in VLDL contributes to their enhanced uptake by the liver.

[Effect of bezafibrate on serum lipid, lipoprotein and apoprotein levels in patients with hyperlipoproteinemia type II and IV]. / Wplyw bezafibratu na lipidy, lipoproteiny i apoproteiny surowicy u chorych z II i IV typem hiperlipoproteinemii.

The effect of six months' treatment with bezafibrate (400-600 mg daily) on serum lipids, lipoproteins and apolipoproteins concentrations was investigated in 32 patients with primary hyperlipoproteinemia (HLP) type IIa, IIb and IV. In all types of HLP the reduction of serum cholesterol (CH), triglycerides (TG), very low density lipoprotein (VLDL) fraction and increase in high density lipoprotein (HDL) cholesterol, HDL3-CH and apolipoprotein AI concentrations was observed. In type IIa and IIb HLP low density lipoprotein (LDL) cholesterol and apolipoprotein B levels decreased while in type IV increased. The greatest fall of serum CH concentrations was observed in type IIb while of serum TG level--in type IV. In 15 (46.9%) patients the side effects were noted. They were: abdominal pain, skin rash, myalgia, moderate increase in CPK and aminotransferase activities. Most of there side effects disappeared spontaneously without treatment cessation.

[Comparative studies on the effects of propranolol and acebutolol on blood pressure, serum lipids and lipoproteins in patients with primary hypertension]. / Porównawcze badania nad wplywem propranololu i acebutololu na cisnienie tetnicze oraz lipidy i lipoproteiny surowicy w nadcisnieniu tetniczym pierwotnym.

A comparative studies on the effect of propranolol and acebutolol on blood pressure, cardiac function, blood serum lipids and lipoproteins were carried out in 48 patients with the primary hypertension double-blind method was applied. Tested drugs were given for 12 weeks. It was found, that both drugs are potent and comparable hypotensive agents normalizing blood pressure in the majority of treated patients. No significant difference in the effect on heart rate and adverse reactions has been noted. Acebutolol did not change lipid metabolism parameters whereas propranolol slightly but statistically significantly increased serum triglycerides.