Victor Wynn

Apolipoprotein B gene variants are involved in the determination of serum cholesterol levels: a study in normo- and hypelipidaemic individuals☆

We have investigated the frequencies of 3 restriction fragment length polymorphisms (RFLPs) of the apolipoprotein B (apo B) gene in normo- and hyperlipidaemic individuals. In individuals with type III hyperlipidaemia, the allele frequency for the RFLP detected with XbaI was significantly different from the allele frequency in normolipidaemic individuals and in those with other types of hyperlipidaemia. No significant difference in allele frequency was found among these groups for the RFLPs detected with MspI or EcoRI. Within a sample of 62 normolipidaemic individuals, homozygotes for the X2 allele (cutting site) of the XbaI RFLP had a significantly higher serum cholesterol level than homozygotes for the XI allele, with individuals of the genotype X1X2 having an intermediate value (X2X2 mean 5.71 mmol/l, X1X1 mean 4.81 mmol/l, X1X2 mean 5.30 mmol/l). There were also significant differences in serum triglyceride levels in individuals with different XbaI genotypes. In these normolipidaemic individuals there was no correlation between the EcoRI and MspI RFLP genotypes and levels of any serum lipid variable. Information from the XbaI and EcoRI RFLPs was used in conjunction to define apo B haplotypes. These haplotypes are a more precise measure of the genotypic variation, and they explain a greater fraction of the serum cholesterol and triglyceride levels than the single-site polymorphisms considered separately. This study suggests that variations in the gene for apo B are associated with the determination of serum cholesterol and triglyceride levels both in patients with type III hyperlipidaemia and in the normal population.

Effect of duration of low-dose oral contraceptive administration on carbohydrate metabolism

Two hundred and ten healthy young women volunteered to take a combined oral contraceptive (OC) and to have glucose tolerance in insulin secretion measured in a projected 3-year study with roughly annual investigations. Although the dropout rate was high, glucose tolerance was noted to deteriorate progressively and insulin secretion to rise initially, but thereafter they remained constant. Eventually, insulin levels were lower than would have been expected from the prevailing glucose values. This combination of steroids produced marked insulin resistance to which the pancreas could respond by further insulin secretion. It is suggested that levonorgestrel is too strong a progestin for routine use in the combined OC, and it is recommended that its dose be reduced further or that weaker progestins such as norethindrone be used.

Identification of a deletion in the low density lipoprotein (LDL) receptor gene in a patient with familial hypercholesterolaemia.

SummaryDNA samples from 60 unrelated UK patients with familial hypercholesterolaemia (FH) were screened by Southern blot hybridisation to detect gross alterations in the low density lipoprotein (LDL) receptor gene. One patient was found to have a 2kb deletion in the 3′ part of the gene. The deletion cosegregates with the FH phenotype in his family. This finding is compatible with the deletion being the cause of FH in this case and makes a presymptomatic test based on DNA analysis available for this family. The defects in most of the other patients are likely to be due to point mutations.

THE ALIMENTARY ABSORPTION OF SOME ENTERIC‐COATED SODIUM AND POTASSIUM CHLORIDE TABLETS

The alimentary absorption of sodium chloride and potassium chloride tablets covered with a new enteric coating, has shown their absorption to be satisfactory. Of three other brands, one has been found to be only poorly absorbed, producing diarrhoea in some subjects; a second brand was poorly absorbed in 1 out of 5 patients, while the third proved moderately satisfactory. Samples of all the brands of enteric‐coated tablets passed the in vitro tests for disintegration specified by the British Pharmacopoeia (1958, Appendix 21B).

The use of polymorphic DNA and protein markers for the third complement component for determining linkage of familial hypercholesterolaemia

We have used DNA and protein polymorphisms for the third complement component (C3) to assess the potential of DNA markers in the diagnosis and study of familial hypercholesterolaemia (FH), and to confirm the reported linkage between FH and C3. The inheritance of FH and the C3 gene has been studied in 10 families by combining information from both the protein and DNA polymorphisms. Our results confirm that the C3 gene is loosely linked to the gene causing FH (lod score maximum of 2.0) at a recombination distance of 0.15. When these results are combined with previously published data the overall lod score maximum is 4.75 at a recombination distance of 0.2, meaning that the two genes will be inherited together in only about 80% of children. These results confirm that the gene that causes familial hypercholesterolaemia is linked to C3 and is therefore on chromosome 19, but C3 is not close enough to be used as a diagnostic marker.

Low-Density Lipoprotein Metabolism by Cultured Human Fibroblasts: Relationship with Aging and Atherosclerosis

22 male subjects aged 21-55 years with normal plasma lipid concentrations were divided into two groups on the basis of the presence or absence of proven coronary artery disease and/or peripheral vascular disease. The rates of uptake and degradation of low-density lipoprotein (LDL) by fibroblast cultures obtained from each subject were assessed using 125I-labelled LDL, and an attempt was made to relate them to the presence or absence of atherosclerosis and to the age of the subject. Atherosclerosis was found to be significantly correlated with elevated rates of LDL uptake and degradation. On the other hand, aging was shown to be associated with a significant reduction in cellular LDL metabolism.

Low density lipoprotein metabolism by cultured skin fibroblasts from atherosclerotic patients

The aim of this study was to determine whether an abnormality in low density lipoprotein (LDL) metabolism could be demonstrated in fibroblasts cultured from normolipidaemic subjects with atherosclerosis. Seventeen male subjects aged 30-55 years with normal plasma lipid concentrations were divided into 2 groups on the basis of the presence or absence of proven coronary artery and/or peripheral vascular disease. LDL metabolism was assessed in cultured fibroblasts obtained from each of these subjects. After 6 h incubation with 125I-labelled LDL, it was found that binding, uptake and degradation of the lipoprotein were all significantly higher in cells from the atherosclerotic group of subjects than the controls. Variations in cellular LDL metabolism were also correlated with 4 risk factors for cardiovascular disease. Plasma LDL concentration in the atherosclerotic subjects was found to be inversely related to LDL binding and degradation. Subject age was inversely related to LDL degradation in both groups of subjects. No association was demonstrated in either group of subjects between LDL metabolism and glucose intolerance, or between LDL metabolism and cigarette smoking. It is concluded from these results that cellular LDL binding may constitute a factor in determining the rate of atheroma formation, which is independent of other cardiovascular risk factors.