Haplotype analysis of the low density lipoprotein receptor (LDLR) gene was performed in Norwegian subjects heterozygous for familial hypercholesterolemia (FH). Southern blot analysis of genomic DNA, using an exon 18 specific probe and the restriction enzyme NcoI, showed that two out of 57 unrelated FH subjects had an abnormal 3.6 kb band. Further analyses revealed that this abnormal band was due to a 9.6 kb deletion that included exons 16 and 17. The 5' deletion breakpoint was after 245 bp of intron 15, and the 3' deletion breakpoint was in exon 18 after nucleotide 3390 of cDNA. Thus, both the membrane-spanning and cytoplasmatic domains of the receptor had been deleted. A polymerase chain reaction (PCR) method was developed to identify this deletion among other Norwegian FH subjects. As a result of this screening one additional subject was found out of 124 subjects screened. Thus, three out of 181 (1.7%) unrelated Norwegian FH subject possessed this deletion. The deletion was found on the same haplotype in the three unrelated subjects, suggesting a common mutagenic event. The deletion is identical to a deletion (FH-Helsinki) that is very common among Finnish FH subjects. However, it is not yet known whether the mutations evolved separately in the two countries.
BACKGROUND: Guidelines for treating overweight and obesity have been suggested by the World Health Organization and other expert groups. We asked whether most men and women targeted in obesity guidelines would already be included in existing clinical recommendations for the prevention of coronary heart disease (CHD) or whether a new group of patients would be added to current workloads. SUBJECTS AND METHODS: In 1997 the Norwegian National Health Screening Service examined CHD risk factors in subjects aged 40-42 y living in three counties. We studied 6911 men and 7992 women who did not report treatment for diabetes, hypertension or the presence of cardiovascular disease. Estimated 10 y risk of CHD was calculated using the Framingham equation. RESULTS: The prevalence of single risk factors (systolic blood pressure > or =160 mmHg, diastolic blood pressure > or =95 mmHg, total cholesterol level > or =7.8 mmol/l and nonfasting glucose > or =11.1 mmol/l) ranged between 0 and 11% among subjects with body mass index > or =25 kg/m2. Adding low HDL cholesterol ( or =10%). Sensitivities and specificities of using body mass index (BMI) or BMI and waist circumference as a screen for elevated CHD risk ranged between 22 and 91%. Screening for 10 y CHD risk of > or =10% or one or more risk factors among men and screening for one or more risk factors among women gave positive predictive values of 19-50%; however, the positive predictive value of screening for 10 y CHD risk of > or =10% was only 1-2% among women. Compared with men with BMI
Dietary antioxidants such as vitamin E, vitamin C, beta carotene and flavonoids may retard atherosclerosis by preventing low density lipoprotein oxidation. Observational epidemiological studies, including ecological correlations, case control and prospective studies, indicate that high vitamin E levels may be associated with decreased cardiovascular disease. Beta carotene may be protective among smokers and the elderly. Few studies have been able to show that vitamin C has a protective effect. A handful of intervention studies have examined the effects of vitamin E and beta carotene with mixed results. While few side effects of antioxidant supplementation are known, the results of current, large-scale studies in primary intervention must be awaited before recommendations can be made. Increased intake of fruits and vegetables that are rich in antioxidants is recommended.
Familial hypercholesterolaemia is an autosomal dominant disorder characterized by hypercholesterolaemia, xanthomas and premature coronary heart disease. Treatment of hypercholesterolemia is effective and consists of dietary changes and lipid lowering drugs. Only a minor proportion of familial hypercholesterolaemia patients are adequately treated, however. One explanation for this is assumed to be the relatively vague clinical diagnostic criteria applied. Because familial hypercholesterolaemia is caused by a mutation in the gene encoding the low density lipoprotein (LDL) receptor, mutation analysis of this gene could form the basis for specific diagnosis. 29 different mutations in the LDL receptor gene have been found to cause familial hypercholesterolaemia among Norwegian patients, and a total of 681 patients from 322 unrelated families have been provided with a molecular genetic diagnosis. We conclude that the use of molecular genetic analysis is feasible, and should be used clinically.
Familial hypercholesterolemia causes premature cardiovascular disease. Genetic screening of patients' relatives who have already been diagnosed has proved to be more efficient than screening in a general population. Privacy laws in Norway forbid physicians to directly contact persons with genetic disorders who are not their own patients. We examined attitudes towards this type of screening in a representative sample of the Norwegian population and a group of patients with familial hypercholesterolaemia. In both groups the majority showed a positive attitude towards physicians contacting relatives directly to detect individuals with familial hypercholesterolaemia. In both groups the majority wanted to know whether, based on the diagnosis of relatives, they might also be affected. Both groups wanted this information regardless of the risk of their being affected. We conclude that the privacy laws should be amended to conform with the attitudes of the population and the patients, thus enabling physicians to contact relatives directly.
Three founder mutations have been discovered among individuals with familial hypercholesterolemia (FH) in Norway: FHElverum and FHSvartor, predicted to be null alleles, and FHC210G, predicted to disrupt the secondary structure of the ligand-binding domain. To clarify the effect of these and other mutations on lipid levels and parental history of premature cardiovascular disease, we examined 164 boys and girls ages 6 to 16 years with heterozygous FH. Among all children, serum cholesterol levels of the FH parent, percent body fat, pubertal stage, and serum cholesterol levels of the non-FH parent, but not apo E polymorphism, were significant determinants of LDL cholesterol levels in a stepwise multiple regression equation and explained 40% (95% confidence interval [Cl], 25% to 55%) of the variance in LDL cholesterol. Among boys, percent body fat, dietary sucrose, and apo E genotype determined 31% (95% CI, 14% to 49%) of the variance in triglyceride levels; whereas among girls, only percent body fat was associated with triglyceride levels. Percent body fat was not associated with LDL cholesterol or triglyceride levels in the FHC210G group. The children's and FH parents' lipid levels and premature cardiovascular disease among parents were similar among the null-allele and defective-protein groups and in those with an undetected mutation. These data confirm that the phenotypic expression of FH in childhood is influenced by modifiable lifestyle characteristics and by genetic factors other than the underlying mutation and raise the possibility that body fatness may interact with genotype in determining lipid levels.
Though severe hyperlipidaemia (total cholesterol level > or = 13 mmol/l in this study) is uncommon, it is important to make a precise diagnosis. We examined 57 patients with isolated severe hypercholesterolaemia. Of these, four were homozygotes for familial hypercholesterolaemia, 48 were heterozygotes for familial hypercholesterolacmia and one had sitosterolemia. The heterozygotes carried 15 different LDL receptor mutations, with no one mutation predominating. When the diagnosis is made, relatives should be given the opportunity to be tested. Combined severe hyperlipidaemia is usually due to a secondary cause, at our clinic, the most common cause is diabetes mellitus. The underlying disease should be treated first. However, many patients will require additional lipid-lowering drugs because the underlying disease may be associated with an increased risk of cardiovascular disease. With the exception of fish oil capsules, drugs that reduce serum triglyceride levels substantially are not registered in Norway at present.
BACKGROUND: Dietary treatment plays an important role in prevention of coronary heart disease. In Norway as in other European countries, patients with established coronary heart disease are advised to follow a cholesterol-lowering diet. However, epidemiological observations have suggested that Mediterranean and other diets may have cardioprotective characteristics beyond their effects on serum total and LDL cholesterol levels. MATERIAL AND METHODS: We describe the results of randomised, controlled clinical trials that have investigated the effect of diet on secondary prevention of coronary heart disease. RESULTS: Diets characterised by high contents of oleic acid (18: 1n-9), alpha-linolenic acid (18: 3n-3) and fish or fish oil and near-vegetarian diets have reduced cardiovascular morbidity and mortality in patients with coronary heart disease. INTERPRETATION: Several characteristics of the Mediterranean diet seem to have additional anti-atherothrombogenic effects beyond those observed with the usually recommended cholesterol-lowering diet. We ask whether Norwegian dietary recommendations for secondary prevention, should emphasise more strongly the type of fat used and fruit and vegetable intake, in line with the principles of the Mediterranean diet. Such dietary advice should be incorporated into the medical treatment given to all patients with coronary heart disease, regardless of their lipid profile.
Apo B is the exclusive protein constituent of LDL and is ligand on LDL, recognized and bound by the LDL receptor. Several restriction fragment length polymorphisms (RFLPs) of the apo B gene have been shown to be associated with variation in serum lipid levels in different populations. In this study we sought to determine the frequency of XbaI, EcoRI, and MspI polymorphisms and the haplotypes generated by these three polymorphic sites of the apo B gene and their influence on lipid levels in a sample of Norwegian subjects at risk of atherosclerosis and healthy control subjects.
108 White Norwegians at risk of atherosclerosis (cases) and 64 healthy individuals (controls) were examined for possible association between the alleles at the XbaI (X), EcoRI (R), and MspI (M) polymorphic restriction sites of the apolipoprotein B gene and serum lipid levels. The frequency of the M allele (absence of restriction site) was significantly higher in cases with high total cholesterol (TC), high low-density lipoprotein cholesterol (LDLC), and high apolipoprotein B (apo B) than in controls with normal TC, LDLC, and apo B (P