Mary Seed

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.

Reductions in all-cause, cancer, and coronary mortality in statin-treated patients with heterozygous familial hypercholesterolaemia: a prospective registry study.

Aims To examine the changes in coronary, all-cause, and cancer mortality in patients with heterozygous familial hypercholesterolaemia (FH) before and after lipid-lowering therapy with statins. Methods and results A total of 3382 patients (1650 men) aged <80 years were recruited from 21 lipid clinics in the United Kingdom and followed prospectively between 1980 and 2006 for 46 580 person-years. There were 370 deaths, including 190 from coronary heart disease (CHD) and 90 from cancer. The standardized mortality ratio (compared with the population in England and Wales) was calculated before and from 1 January 1992. In patients aged 20–79 years, CHD mortality fell significantly by 37% (95% CI = 7–56) from 3.4- to 2.1-fold excess. Primary prevention resulted in a 48% reduction in CHD mortality from 2.0-fold excess to none, with a smaller reduction of nearly 25% in patients with established disease. Coronary mortality was reduced more in women than in men. In patients without known CHD at registration, all-cause mortality from 1992 was 33% (21–43), lower than in the general population, mainly due to a 37% (21–50) lower risk of fatal cancer. Conclusion The results emphasize the importance of early identification of FH and treatment with statins.

COMPARISON OF EFFECTS OF DIFFERENT COMBINED ORAL-CONTRACEPTIVE FORMULATIONS ON CARBOHYDRATE AND LIPID METABOLISM

Oral glucose-tolerance tests were performed and fasting serum cholesterol and triglyceride levels measured in 1628 Caucasian women taking combined oestrogen/progestagen oral contraceptives (o.c.) and 577 women not taking O.C. The former were divided into six groups according to the composition of the O.C Glucose tolerance deteriorated in all O.C. groups containing oestrane progestagens (nortestosterone-derived) or the gonane, norgestrel, but was unaltered by O.C. containing a pregnane progestagen (derived from progesterone). The greatest deterioration was with O.C. containing 75 microgram or more oestrogen, and this was associated with impairment of the early insulin response to glucose. In O.C. containing a pregnane progestagen insulin secretion was unaffected. In the remaining O.C. groups insulin secretion was increased; this was most pronounced with the O.C. containing a gonane progestagen. Serum-cholesterol was elevated only with O.C. containing 75 microgram or more oestrogen and an oestrane progestagen and tended to be lower in O.C. containing a gonane progestagen. O.C.-induced hypertriglyceridaemia was oestrogen-dose-related, and this effect was potentiated by the pregnane progestagen. The gonane progestagen antagonised oestrogen-induced hypertriglyceridaemia.

EFFECT OF PYRIDOXINE HYDROCHLORIDE (VITAMIN B6) UPON DEPRESSION ASSOCIATED WITH ORAL CONTRACEPTION

Abstract The known association between combined œstrogen-progestagen oral contraceptive (o.c.) administration and abnormalities of tryptophan and vitamin-B 6 metabolism has been investigated in a group of 22 depressed women whose symptoms were judged to be due to the effects of o.c. 11 of these women showed biochemical evidence of an absolute deficiency of vitamin B 6 . In a double-blind crossover trial this group of women responded clinically to the administration of pyridoxine hydrochloride. The remaining 11 women showed no such response. Placebo administration was without effect. Possible mechanisms for depression due to o.c. use and its treatment with pyridoxine hydrochloride are discussed.

A Common Variant in the Gene for Lipoprotein Lipase (Asp9→Asn) Functional Implications and Prevalence in Normal and Hyperlipidemic Subjects

Abstract Subjects with combined hyperlipidemia (CHL) were screened for mutations in the lipoprotein lipase (LPL) gene by single-strand conformational polymorphism, and a previously reported G→A DNA sequence change in exon 2, causing substitution of Asp by Asn at position 9, was identified in 2 individuals. Because this substitution destroys a recognition site for Taq I, pooling of DNA samples, amplification, and digest with Taq I allowed the rapid screening of 1563 healthy individuals and patients of Dutch, Swedish, English, and Scottish origin. In the general populations of all four countries, healthy carriers of the mutation were detected at a frequency of 1.6% to 4.4% (mean, 3.0%; 95% confidence interval, 2.0% to 4.0%). The frequency of carriers was roughly twice as high (range, 4.0% to 9.8%) in selected patients with CHL or type IV hyperlipoproteinemia or in subjects with angiographically assessed atherosclerosis; the frequency was consistently higher in each patient group compared with its matched control group. In 773 healthy men from two general practices in the United Kingdom, 25 carriers and 2 homozygotes for the mutation were identified. In these 27, plasma triglyceride but not plasma cholesterol levels were significantly higher than in noncarriers (2.25 versus 1.82 mmol/L, P <.02), and this difference was maintained in three subsequent annual measurements. Postheparin LPL activity data were available for some carriers and for 7 of 9 individuals from the patient groups, and 6 of 6 individuals from the control groups had LPL activity that was lower than the respective group mean. In vitro mutagenesis and transient expression in COS cells showed that compared with the LPL-Asp9 construct, LPL-Asn9 activity and mass were reduced by 20% to 30% in the culture media. Overall however, LPL-Asn9 had only slightly reduced specific activity (by 18%). Thus, although the precise mechanism of the effect is unclear, the data strongly suggest that the LPL-Asn9 variant is associated with and may play a direct role in predisposing carriers to develop hypertriglyceridemia.

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.

Linkage and Association Between Distinct Variants of the APOA1/C3/A4/A5 Gene Cluster and Familial Combined Hyperlipidemia

Objective—Combined hyperlipidemia is a common disorder, characterized by a highly atherogenic lipoprotein profile and a substantially increased risk of coronary heart disease. The purpose of this study was to establish whether variations of apolipoprotein A5 (APOA5), a newly discovered gene of lipid metabolism located 30 kbp downstream of the APOA1/C3/A4 gene cluster, contributes to the transmission of familial combined hyperlipidemia (FCHL). Methods and Results—We performed linkage and association tests on 128 families. Two independent alleles, APOA5c.56G and APOC3c.386G, of the APOA1/C3/A4/A5 gene cluster were overtransmitted in FCHL (P =0.004 and 0.007, respectively). This was paired with reduced transmission of the common APOA1/C3/A4/A5 haplotype (frequency 0.4461) to affected subjects (P =0.012). The APOA5c.56G genotype accounted for 7.3% to 13.8% of the variance in plasma triglyceride levels in probands (P <0.004). The APOC3c.386G genotypes accounted for 4.4% to 5.1% of the variance in triglyceride levels in FCHL spouses (P <0.007), suggesting that this allele marks a FCHL quantitative trait as well as representing a susceptibility locus for the condition. Conclusions—A combined linkage and association analysis establishes that variation at the APOA1/C3/A4/A5 gene cluster contributes to FCHL transmission in a substantial proportion of northern European families.

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.

A common DNA polymorphism of the low-density lipoprotein (LDL) receptor gene and its use in diagnosis.

A cloned gene probe coding for the low-density lipoprotein (LDL) receptor was used to detect a restriction fragment length polymorphism with the enzyme Pvu II. The frequency of the rare allele is approximately 0.2 both in normal controls and individuals with familial hypercholesterolaemia (FH). About 30% of individuals are heterozygous for the polymorphism, and are potentially informative for family studies and for early diagnosis of FH. This polymorphism was used to follow the inheritance of the LDL receptor gene in two families with FH. In these families, the polymorphism co-segregates with the disease unambiguously, and therefore can be used for early diagnosis.

The effect of nicotinic acid and acipimox on lipoprotein(a) concentration and turnover.

This study examines the effect of nicotinic acid (1 g t.d.s.) on serum Lp(a) concentration in a group of patients with type II hyperlipidaemia selected on the basis of a plasma Lp(a) concentration greater than 30 mg/dl. Reductions in total cholesterol, triglyceride, LDL-cholesterol and Lp(a) were 16.3%, 25.5%, 23.7% and 36.4%, respectively, with an increase in HDL cholesterol of 37.3%. The reduction in Lp(a) concentration did not correlate with any other lipoprotein changes. In order to establish the mechanism of the fall in Lp(a) concentration, in vivo turnover of autologous Lp(a) was studied in three subjects before and whilst taking nicotinic acid. The fractional catabolic rate in Lp(a) was unaltered in the subjects on therapy, indicating that nicotinic acid did not increase catabolism of Lp(a) but decreased the synthetic rate. Since nicotinic acid was poorly tolerated we examined the effect of acipimox, an analogue of nicotinic acid on lipoproteins using a placebo controlled double-blind crossover design in a group of hyperlipidaemic patients again selected with plasma Lp(a) concentration greater than 30 mg/dl. Acipimox was better tolerated than nicotinic acid but the percentage changes in lipoprotein concentrations were smaller.