Lipoprotein(a) and coronary heart disease.
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Apolipoproteins A↗
Biomedical subjects
M Seed
Publications and source records attributed to M Seed.
Lipoprotein Lp(a) levels are reduced by danazol, an anabolic steroid.
Serum levels of lipids, lipoproteins and apolipoproteins were measured in 26 premenopausal women with endometriosis both before and after six months therapy with the anabolic steroid danazol (600 mg/day) and in 15 untreated women who acted as controls. No changes were seen in the control group over six months. In women treated with danazol, mean levels of low density lipoprotein (LDL) cholesterol increased by 36% while those of high density lipoprotein (HDL) cholesterol decreased by 46%, changes characteristic of androgenic steroids. In contrast to this potentially detrimental lipoprotein profile, lipoprotein(a) [Lp(a)] levels were reduced by 78.6% +/- 24.0% (mean +/- S.D.) in women taking danazol. These dramatic changes in Lp(a) levels correlated with baseline Lp(a) levels but not with changes in LDL or HDL. Anabolic steroids such as danazol appear to be powerful modulators of serum Lp(a) concentrations. This could be due to direct effects on Lp(a) metabolism, or secondary to the effects of these steroids on insulin metabolism or on the coagulation and fibrinolysis system.
Adolescent↗
Lipid and lipoprotein (a) concentrations in renal transplant patients.
Lipid and lipoprotein concentrations, including lipoprotein (a), were measured in 67 clinically stable renal allograft recipients and compared with age- and sex-matched controls. Median lipoprotein (a) concentrations were significantly elevated in the transplant group (P = 0.048), with the distribution of apoprotein (a) isoforms being similar between the two groups. The transplant group also demonstrated significant elevations in cholesterol (P less than 0.0001), triglycerides (P = 0.0007) and low-density lipoprotein cholesterol (P less than 0.0001). There was no significant difference in high-density lipoprotein cholesterol concentrations between the groups although there was the expected tendency for higher values in females. Lipoprotein abnormalities are common following renal transplantation and these patients also demonstrate elevated lipoprotein (a) values. This unique lipoprotein is known to be atherogenic and may contribute to the development of vascular disease, which is a common mode of death in these patients.
Adolescent↗
Characterization of deletions in the LDL receptor gene in patients with familial hypercholesterolemia in the United Kingdom.
A sample of 200 patients with a clinical diagnosis of heterozygous (189) or homozygous (11) familial hypercholesterolemia (FH) attending lipid clinics in the London area have been screened for the presence of major gene defects in the low density lipoprotein (LDL) receptor gene by Southern blotting of genomic DNA with specific probes. This study is part of a project to determine the frequency of known mutations in the LDL receptor gene in this population. A new polymorphism for the enzyme Bgl II was identified by hybridization with a probe specific for the promoter plus exon 1 of the LDL receptor gene. The observed frequency of the rare allele, characterized by a Bgl II fragment of 13 kb compared with 10 kb for the common allele, was 0.08 in this group of FH patients. Several individuals who were heterozygous for the rare allele were also heterozygous for a mutation elsewhere in the LDL receptor gene that is known to cause FH. Eight different mutations, seven deletions and one duplication, were detected in a total of nine patients, accounting for 4.5% of the mutant alleles in this group. Three of the mutations are apparently identical to deletions that have been described previously in FH patients of British or European origin, while the remaining five have not been described. Two of these were in patients of Polish and Asian Indian origin, while the other three were in patients of apparently British ancestry.
Alleles↗
Catabolism of lipoprotein(a) in familial hypercholesterolaemic subjects.
The in vivo turnover of autologous lipoprotein(a) (Lp(a)) was studied in four heterozygous familial hypercholesterolaemic (FH) subjects and four subjects who were hyperlipidaemic but not FH. Each of the FH subjects exhibited a much lower fractional catabolic rate (FCR) for LDL than each of the non-FH subjects. Lp(a) was purified by sequential density gradient centrifugations and was radio-iodinated. The labelled Lp(a) ran as a single band on electrophoresis in gradient polyacrylamide gels. Less than 5% of the label was in lipid, with about 40% of the remainder on apolipoprotein B (apo B) and 60% on apo(a). Labelled and unlabelled Lp(a) competed equally poorly with LDL for binding to LDL receptors on cultured fibroblasts. The FCR of Lp(a), calculated from the decay of the specific radioactivity of the Lp(a) isolated from the daily blood samples, was the same in FH subjects as in non-FH subjects. There was no consistent relationship between Lp(a) FCR and the plasma Lp(a) concentration or between FCR and the Lp(a) phenotype, at least within this sample of subjects. There was a strong association between Lp(a) concentration and production rate, with values for non-FH and FH subjects falling on the same line. The rate of decline of radioactivity in whole plasma was consistently slower than the fall in specific radioactivity of the isolated Lp(a). This difference was more marked in FH subjects than in non-FH subjects and resulted from the accumulation of radioactivity derived from the injected Lp(a) at a lower density than Lp(a), in the fractions containing LDL. The amount of radioactivity in this fraction increased for the first few days after injection and then fell, the fall being more rapid in non-FH than in FH subjects. These results provide no evidence for the involvement of LDL receptors in the catabolism of Lp(a) itself but suggest that they could be responsible for some of the clearance of the lipid and apo B components after removal of apo(a) in the circulation.
Adult↗
Sex hormones, lipoproteins, and cardiovascular risk.
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Androgens↗
Identification of the 664 proline to leucine mutation in the low density lipoprotein receptor in four unrelated patients with familial hypercholesterolaemia in the UK.
Mutations in the gene for the low density lipoprotein (LDL) receptor cause Familial Hypercholesterolaemia (FH). One such mutation, a cytosine to thymine change in the codon for amino acid 664, causes proline (CCG) to be replaced by leucine (CTG) at this position, and creates a Pst I site in exon 14 of the gene. This mutation, previously identified in an FH homozygote of Asian Indian origin, results in a receptor with a reduced binding affinity for LDL and in delayed processing of the precursor form of the protein in cultured cells. A total of 224 unrelated heterozygous and 4 homozygous FH patients from London was screened for this mutation using direct amplification of genomic DNA by the polymerase chain reaction (PCR) and restriction digestion of the PCR product. Four patients were identified who were heterozgous for this mutation and the C to T base change was confirmed by sequencing. Affected relatives of these patients were also found to have the mutation. The effect of the mutation on LDL-receptor function in lymphoblastoid cell lines obtained from two of these patients was similar to that observed in heterozygous relatives of the original proband (MM). Eight polymorphisms of the LDL receptor gene were used to determine the haplotype of the defective allele carried by the patients and the individual (MM) in whom the mutation was first discovered. Two different haplotypes were found, suggesting that the mutation, which occurs at a CpG 'hotspot', has arisen independently at least twice. The presence of the same single base change in the LDL-receptor gene in several unrelated patients has not previously been reported in a population which is not geographically or culturally isolated.
Adolescent↗
Relationship between apolipoprotein(a) phenotype, lipoprotein(a) concentration in plasma, and low density lipoprotein receptor function in a large kindred with familial hypercholesterolemia due to the pro664----leu mutation in the LDL receptor gene.
In a large kindred of 66 individuals, 22 were identified as heterozygous and 3 as homozygous for a mutation (pro664----leu) in the LDL-receptor gene that gives rise to familial hypercholesterolaemia (FH). All the heterozygotes had a raised level of plasma total cholesterol and low density lipoprotein cholesterol, but were remarkably free from premature coronary disease. Determination of apolipoprotein(a) (apo(a)) phenotype and lipoprotein(a) (Lp(a)) concentration in plasma revealed that in many instances, involving individuals with various apo(a) phenotypes, there was no difference in plasma Lp(a) concentration between an FH heterozygote and an unaffected sibling with the same apo(a) phenotype. No significant difference in Lp(a) concentration was observed between groups of FH and non-FH of the same apo(a) phenotype, although in each case the mean value for the FH group was greater than that for the non-FH group. There was also evidence for an inherited trait that markedly increased Lp(a) concentration, which did not segregate with apo(a) phenotype or the defective LDL-receptor allele. The data provide no evidence for a strong multiplicative interaction between the gene loci for apo(a) and the LDL receptor.
Adolescent↗
Relation of serum lipoprotein(a) concentration and apolipoprotein(a) phenotype to coronary heart disease in patients with familial hypercholesterolemia.
Familial hypercholesterolemia carries a marked increase in the risk of coronary heart disease (CHD), but there is considerable variation between individuals in susceptibility to CHD. To investigate the possible role of lipoprotein(a) as a risk factor for CHD, we studied the association between serum lipoprotein(a) levels, genetic types of apolipoprotein(a) (which influence lipoprotein(a) levels), and CHD in 115 patients with heterozygous familial hypercholesterolemia. The median lipoprotein(a) level in the 54 patients with CHD was 57 mg per deciliter, which is significantly higher than the corresponding value of 18 mg per deciliter in the 61 patients without CHD. According to discriminant-function analysis, the lipoprotein(a) level was the best discriminator between the two groups (as compared with all other lipid and lipoprotein levels, age, sex, and smoking status). Phenotyping for apolipoprotein(a) was performed in 109 patients. The frequencies of the apolipoprotein(a) phenotypes and alleles differed significantly between the patients with and those without CHD. The allele LpS2, which is associated with high lipoprotein(a) levels, was found more frequently among the patients with CHD (0.33 vs. 0.12). In contrast, the LpS4 allele, which is associated with low lipoprotein(a) levels, was more frequent among those without CHD (0.27 vs. 0.15). We conclude that an elevated level of lipoprotein(a) is a strong risk factor for CHD in patients with familial hypercholesterolemia, and the increase in risk is independent of age, sex, smoking status, and serum levels of total cholesterol, triglyceride, or high-density lipoprotein cholesterol. The higher level of lipoprotein(a) observed in the patients with CHD is the result of genetic influence.
Adult↗
Variation in the size of human apolipoprotein(a) is due to a hypervariable region in the gene.
We have investigated whether the size heterogeneity of the human apolipoprotein(a) [apo(a)] is due to differences in the number of plasminogen kringle 4-like repeat units present in the different alleles. Using the Southern blot hybridization technique and a DNA probe for the kringle 4 domain of plasminogen, we have observed that in 31 different individuals a 5.8-kb PvuII restriction fragment band varies widely in intensity relative to other bands. A strong correlation (r = 0.76, P less than 0.001) was found between apo(a) protein size and the variation in intensity of the detected restriction fragment band. We confirmed this correlation in a large family where the parents are heterozygous for the apo(a) protein size isoforms. The specificity of the 5.8-kb band was established by using an apo(a)-specific oligonucleotide. These correlations strongly suggest that the observed size heterogeneity in apo(a) protein is due to different numbers of copies of the kringle 4 sequence in the apo(a) glycoprotein gene.
Alleles↗
Familial defective apolipoprotein B-100: detection in the United Kingdom and Scandinavia, and clinical characteristics of ten cases.
Familial defective apolipoprotein B-100 (FDB) is a recently identified, dominantly inherited genetic disorder, which leads to increased serum concentration of low density lipoprotein (LDL) cholesterol with reduced affinity for the LDL receptor. This disorder is associated with a G to A mutation in exon 26 of the apolipoprotein B (apo B) gene which creates a substitution of glutamine for arginine in the codon for amino acid 3500. We have searched for this mutation in 374 unrelated individuals with hyperlipidaemia from the United Kingdom, and in 371 unrelated individuals with a primary clinical diagnosis of atherosclerosis from the United Kingdom and Scandinavia. Ten individuals, 9 from the U.K. and 1 from Denmark, were identified. The frequency of the mutation was 3% in individuals classified clinically as having familial hypercholesterolaemia (FH) and 3% in individuals with type IIa hyperlipidaemia without FH, and was not found in patients with types IIb and III hyperlipidaemia. The mutation was rare in individuals with a primary clinical diagnosis of atherosclerosis. Plasma lipid levels and clinical characteristics of the ten patients identified in the present study are similar to those reported for heterozygous FH. Thus, in our study, FDB is associated with moderate to severe hypercholesterolaemia, and appears to be a serious disorder causing premature cardiovascular disease. Individuals with this mutation can be identified unambiguously using routine molecular screening techniques.
Adult↗
Rising cholesterol levels in children with familial hypercholesterolaemia.
Reference ranges (5th to 95th percentile) for fasting total serum cholesterol concentration were calculated for 571 unrelated children aged 4-19 years, without known predisposition to hypercholesterolaemia. Values were 3.31-5.81 mmol.l-1 for boys and 3.20-5.66 mmol.l-1 for girls, without significant differences between sexes at any age, compared to our laboratory reference ranges for men (3.46-6.87 mmol.l-1) and women (3.00-6.38 mmol.l-1). A further 85 children, each with a first degree relative with Familial Hypercholesterolaemia (FH), were studied. Initially, 39 had high cholesterol concentrations suggestive of FH. Repeated serial measurements were carried out in 18 of the 46 apparently unaffected children. Seven of these showed marked increases in serum cholesterol over 1-7 years, reaching concentrations above the 95th centiles of the appropriate reference ranges. The annual rate of increase was significantly higher than in the 11 who remained normocholesterolaemic. In 3 of these 7 children, diagnosis of FH was confirmed retrospectively, using recombinant DNA technology to show that each had inherited the defective allele of the LDL-receptor gene from an affected parent. Thus, serial cholesterol measurements may be needed to confirm or exclude FH in potential heterozygotes, while DNA studies can be used for definitive diagnosis in some families.
Adolescent↗
Endocrine control of plasma lipoprotein metabolism: effects of gonadal steroids.
Gonadal steroids are powerful modulators of plasma lipoprotein metabolism. In general, steroids with oestrogenic activity increase plasma levels of HDL, especially HDL2, and reduce levels of LDL. Steroids with androgenic activity have opposite effects, consistent with the sex difference in HDL and LDL levels. Triglyceride levels are lowered by exogenous administration of androgens and are raised by oral oestrogens, contrary to the observed sex difference in this lipid. The impact of administered gonadal steroids is modified by factors such as dosage and chemical structure, with synthetic steroids having a more pronounced effect than natural hormones. The effects of these steroids may depend on the pre-treatment lipoprotein pattern and endocrine status, and are modified by the route of administration, with oral hormones often having greater metabolic effects than those given parenterally. The net effects of oestrogen and progestagen combined preparations on lipoprotein metabolism depends on the balance between oestrogenic and androgenic activity. In contrast, endogenous changes in sex hormone levels, such as those accompanying puberty, the menstrual cycle and the menopause, have relatively little effect on plasma lipoproteins. Data concerning puberty and castration in males indicate that testosterone is a key factor in the sex difference in HDL levels. There is evidence that loss of ovarian function induces significant increases in LDL level, but endogenous changes in oestrogen levels have little effect on HDL metabolism in women. Changes in triglyceride levels are due mainly to alteration in VLDL secretion and catabolism. LDL levels are controlled by the activity of B100, E receptors and, to a lesser extent, changes in LCAT activity. Gonadal steroids affect HDL levels by altering apoAI synthesis and by controlling the activity of hepatic lipase. Lp(a) levels are increased during early pregnancy but may be decreased by anabolic steroids. The mechanisms behind such actions are unknown. Gonadal hormones influence all areas of plasma lipoprotein metabolism and therefore may affect cardiovascular risk by favourably affecting the plasma lipoprotein profile. In postmenopausal women, use of oestrogens has led to a 60% reduction in cardiovascular disease (Bush et al, 1987). Androgens and progestagens with androgenic properties induce changes in plasma lipoproteins which may increase risk. Further study of the mechanisms involved in these changes is obligatory given the widespread use of these hormones.
Androgens↗
Defects in the low density lipoprotein receptor gene affect lipoprotein (a) levels: multiplicative interaction of two gene loci associated with premature atherosclerosis.
The lipoprotein (a) [Lp(a)] contains two nonidentical protein species, apolipoprotein (apo) B-100 and a specific high molecular weight glycoprotein, apo(a). Lp(a) represents a continuous quantitative genetic trait, the genetics of which are only poorly understood. Genetic variation at the apo(a) locus affects plasma Lp(a) levels and explains at least 40% of the variability of this trait. Lp(a) levels were found to be elevated 3-fold in the plasma from patients with the heterozygous form of familial hypercholesterolemia who have one mutant low density lipoprotein receptor gene. This elevation was not due to a higher frequency of those apo(a) types that are associated with high Lp(a) levels in familial hypercholesterolemia patients. Rather Lp(a) levels were elevated for each of the apo(a) phenotypes examined. The effects of the apo(a) and low density lipoprotein receptor genes on Lp(a) levels are not additive but multiplicative. This is a situation not commonly considered in quantitative human genetics. We conclude that Lp(a) levels in plasma may be determined by variation at more than one gene locus.
Arteriosclerosis↗
The use of recombinant DNA techniques for the diagnosis of familial hypercholesterolaemia.
In the UK, about 5% of patients with familial hypercholesterolaemia have a detectable deletion or rearrangement of part of the LDL-receptor gene. This results in the detection of shorter or abnormal sized fragments of the LDL-receptor gene in a Southern blot hybridization. This can be used to follow the inheritance of the defective gene, and for diagnosis in the families of these individuals. In the families of the rest of the patients, diagnosis may be possible using linked restriction fragment length polymorphisms (RFLPs) detected with the LDL-receptor probe. There are now ten common RFLPs of the LDL-receptor gene, with variable sites in the 3' half of the gene. Over 80% of patients are heterozygous for at least one of these RFLPs, and therefore potentially informative for DNA diagnosis. For a foetus at risk of homozygous familial hypercholesterolaemia, antenatal diagnosis may also be possible using these methods. However, family studies require samples to be available from affected or unaffected relatives of the patient, and this limits the applicability of the tests. For some mutations, the base pair change causing the defect in the LDL-receptor itself creates or destroys a site for a restriction enzyme. Such 'mutation-specific' RFLPs could be used for population screening, but so far have only been reported for the familial hypercholesterolaemia mutation that is common in Lebanon. In the future it may be possible to develop mutation-specific oligonucleotide probes for the diagnosis of familial hypercholesterolaemia. These would be appropriate for population screening or screening patients with hyperlipidaemia. This information may be useful if different mutations require different therapeutic strategies.
DNA, Recombinant↗
The treatment of a hyperandrogenic and virilizing state in an elderly female with a synthetic LHRH agonist.
A case of hyperandrogenism and virilization is described in an elderly female. She had elevated testosterone levels, but normal DHEAS and 24-h urinary 17-oxosteroid excretion, suggesting an ovarian tumor. Stimulation and suppression tests, and radioisotopic and radiological scans proved unhelpful in the diagnosis although hyperthecosis of the ovary was later suggested by ultrasound. Testosterone and gonadotropin levels fell during therapy with cyproterone acetate and subsequently ethinyl estradiol. Because of side effects encountered on these drugs, she was treated with a synthetic, slow-release preparation of an LHRH agonist, D-TRP-6-LHRH (Decapeptyl), with symptomatic and biochemical improvement. Long term LHRH agonists might be a valuable treatment for hyperandrogenic states in elderly patients.
Aged↗
Four DNA polymorphisms in the LDL receptor gene: their genetic relationship and use in the study of variation at the LDL receptor locus.
We have studied four different restriction fragment length polymorphisms (RFLPs) for the LDL receptor gene, detected using the restriction enzymes StuI, PvuII, ApaLI, and NcoI, in normal subjects and in patients with familial hypercholesterolaemia (FH) from London. Significant linkage disequilibrium was detected between all four RFLPs. Used together they give a polymorphism information content (PIC) of greater than 0.7 which makes them useful for studying the inheritance of the LDL receptor gene in more than 70% of families with FH. The NcoI and ApaLI RFLPs were found to be the most useful, giving a combined PIC value of 0.6. The allele frequencies of all four polymorphisms were compared in the normal and FH groups and the frequency of the rarer N2 allele of the NcoI RFLP was found to be significantly higher in the FH group. This suggests that a mutation has occurred on the rare NcoI N2 allele and that it may be making a significant contribution to the defects causing FH in this patient group. We have also used these RFLPs to look for evidence that variation at the LDL receptor gene locus contributes to the determination of cholesterol levels in the normal population. People with different RFLP genotypes do not have significantly different levels of serum total or LDL cholesterol. At present we have no evidence that variation at this locus may be determining cholesterol levels in the non-FH population.
Alleles↗
The effects of reverse sequential anti-androgen therapy (cyproterone acetate and ethinyl estradiol) on hematological parameters.
Hematological parameters were studied in female patients receiving reverse-sequential anti-androgen therapy for hirsutism and acne. A significant fall in hemoglobin, total red cell count and packed cell volume occurred after 3-month treatment in 30 patients during the 10-day cyproterone acetate and ethinyl estradiol phase; this change was sustained in 14 patients studied to 12 months. A fall in hemoglobin and packed cell volume alone occurred after 3 months in 31 patients in the ethinyl estradiol phase. Reverse-sequential therapy may influence hemopoiesis by its anti-androgenic action on erythropoiesis, although we found no relationship between changes in hematological parameters and total testosterone levels.
Acne Vulgaris↗