Kåre Berg

Lipoprotein(a) and atherosclerosis.

Lipoprotein(a) [Lp(a)], a lipoprotein variant, was relegated for almost 25 years to the study of a few specialists. During the past 3 to 4 years, however, there has been a tremendous upsurge of interest in Lp(a), primarily because of multidisciplinary efforts in structural and molecular biology. Findings emerging from these efforts include the following: Lp(a) represents a cholesteryl-ester, low-density-lipoprotein (LDL)-like particle with apolipoprotein (apo) B-100 linked to apo(a); apo(a) is a glycoprotein coded by a single gene locus on the long arm of chromosome 6, which has several alleles, accounting for its remarkable size polymorphism (300 to 800 kD); apo(a) size polymorphism relates to plasma levels and density distribution of Lp(a); apo(a) is strikingly similar to plasminogen; and in vitro, Lp(a), in appropriate levels, competes for some physiologic functions of plasminogen in the coagulation and fibrinolytic cascade and may thus be thrombogenic. The LDL-like properties of Lp(a) may also confer atherogenic potential, but the mechanisms underlying this atherogenicity remain to be defined. In epidemiologic studies, high plasma Lp(a) levels have been associated with an increased incidence of atherosclerotic cardiovascular disease, especially in patients less than 60 years of age. Moreover, Lp(a) has been found as an intact particle in the arterial intima, particularly in association with atherosclerotic plaque. This finding suggests that Lp(a) can transverse the endothelium, possibly by a non-receptor-mediated process, and, at the intimal level, acquire thrombogenic and atherogenic potentials. Current information justifies the need to determine plasma Lp(a) levels in patients with a history of atherosclerotic cardiovascular disease. Unfortunately, the available techniques need to be standardized. Apolipoprotein(a) exists in isoforms of different sizes, and the importance of determining apo(a) phenotypes in clinical practice remains to be established.

Lp(a) lipoprotein and pre-β1-lipoprotein in patients with coronary heart disease

Certain properties of the atypical serum lipoprotein, referred to as pre‐β1‐lipoprotein, suggested that it might be identical to the lipoprotein carrying the Lp(a) antigen: Lp(a) lipoprotein. Both lipoprotein phenomena are under genetic control and occur in a certain proportion of healthy people. Pre‐β1‐lipoprotein occurs more frequently in patients with coronary heart disease (CHD) than in the healthy population.

Predicting zygosity in Norwegian twin pairs born 1915–1960

Present addresses of 12,752 like‐sexed twin pairs born in the period 1915–1960 were identified. A questionnaire, concerning the similarity of pair members, was sent to all individuals. Responses were obtained from 83.7% of the subjects. The zygosity of 207 pairs was established by examination of genetic markers. By using discriminant analysis on the responses from this subgroup, functions were obtained for prediction of zygosity from questionnaire data. It was estimated that 2.4% of the pairs would be misclassified if the questionnaire responses from both pair members were used, and 3.9% if only the response from one of the twins was used. Accordingly, zygosity could be predicted with satisfactory reliability also for twin pairs where only one of the twins had responded. The predicted percentage of monozygotic (MZ) pairs among pairs where one or both twins had responded, was 39.4 (4,402/11,175). The percentage of MZ pairs was significantly lower (34.5) in death‐discordant pairs than in pairs in which both twins were alive (39.6). The zygosity questionnaire data are sufficient to adequately score twin pairs for zygosity in the great majority of cases.

SERUM-HIGH-DENSITY-LIPOPROTEIN AND ATHEROSCLEROTIC HEART-DISEASE

Serum-high-density-lipoprotein (H.D.L.) concentrations were determined in 49 men who had had a myocardial infarction and in 102 healthy, middle-aged men, all from Northern Sweden. A quantitative immunological assay based on a monospecific antiserum to the main polypeptide (apoprotein A-I) of H.D.L. was used. The mean H.D.L. concentration was significantly lower in the men with coronary heart-disease than in the controls. The results accord with the hypothesis that high levels of H.D.L. to some extent protect against ischaemic heart-disease.

DNA polymorphism at the locus for human cholesteryl ester transfer protein (CETP) is associated with high density lipoprotein cholesterol and apolipoprotein levels

Cholesteryl ester transfer protein (CETP) is a protein involved in “reverse cholesterol transport” and it could play an important role in facilitating the removal of cholesteryl esters from peripheral tissues for transport to the liver or for transfer of cholesterol between plasma lipoprotein particles. Both functions may be relevant to susceptibility or resistance to atherosclerotic disease. We have studied 149 and 146 unrelated persons, respectively, for the A and B polymorphism at the CETP locus detectable with the restriction enzyme Taql. The B system is by far the more polymorphic. A search for association with risk or “anti‐risk” factor levels was conducted with the following quantitative parameters: total cholesterol, HDL cholesterol, triglycerides, apolipoprotein AI (apoA‐I), apolipoprotein B (apoB) and Lp(a) lipoprotein levels. Highly significant differences in apoA‐I concentration were found between the two categories of homozygotes in the B polymorphism. The association observed remained significant after multiplying the p value by the number of quantitative parameters used for the association tests. There was a dosage effect on the apoA‐I level of genes in the B polymorphism. We conclude that the associations observed are likely to reflect true biological phenomena. The effect of CETP genes appeared to be limited to non‐smokers.

Oestrogen receptor (ESR) polymorphisms and breast cancer susceptibility

The allele frequencies of three restriction fragment length polymorphisms at the oestrogen receptor (ESR) locus were compared between breast cancer patients and controls. Leucocyte or tumour DMA from 238 and 122 patients, respectively, and leucocyte DNA from 672 controls was analysed. Alleles having the XbaI restriction site detected by the M72 probe (covering exon 2 and flanking introns) were significantly more frequent in patients than in controls (P = 0.033). Within the breast cancer population, the presence of the XbaI restriction site was associated with late onset of the disease but this association was only of borderline significance. The allele frequencies of the BstUI polymorphism in exon 1 and the PvuII polymorphism in intron 1 did not differ between cases and controls. However, alleles with the PvuII restriction site were more frequent in patients with progesterone receptor negative primary tumours than in patients with progesterone receptor positive primary tumours (P = 0.027). There was no significant association between any of the ESR polymorphisms and the oestrogen receptor status of the primary tumours. The results indicate that the ESR gene or a gene closely linked to it is involved in the development of at least a subset of breast carcinomas.

The role of the children of twins design in elucidating causal relations between parent characteristics and child outcomes.

BACKGROUND Determination of causal connections between parental measures and child outcomes using typical samples is limited by the inability to account for all confounds, both environmental and genetic. This paper discusses the strength of the Children of Twins (COT) design to highlight the role of specific environments. METHODS A new analytical model is presented which helps differentiate and quantify the environmental and genetic processes underlying associations between family-level risk factors and child adjustment. In order to illustrate the COT design, the relation between smoking during pregnancy and child birth weight (BW) is examined in a sample of female twins and their children from Norway and the United States. RESULTS The results illustrate that smoking during pregnancy is influenced by genetic factors. However, the Children of Twins model supports the claim that smoking during pregnancy has a direct environmental influence on BW and that genetic and shared environmental confounds cannot account for the association. CONCLUSIONS An assessment of the strengths and limitations of the Children of Twins design and a comparison with other research strategies suggest that the design plays a unique role in the study of developmental psychology and psychopathology. Finally, the authors describe how methodological advances and future applications of the design will provide additional insight into the causal processes underlying childrens adjustment to environmental stimuli.

DNA polymorphism at the apolipoprotein B locus is associated with lipoprotein level

A strong association has been uncovered between DNA variation at the apolipoprotein B (apoB) locus (detectable with the restriction endonuclease Xbal) and apoB level. The findings are suggestive of associations also between this DNA polymorphism and total cholesterol as well as fasting triglyceride levels, confirming recent results reported by British workers. The data suggest that lipid/apolipoprotein associations with the Xbal polymorphism are primarily caused by an effect on apoB level.

Genetic and environmental contributions to the covariance between occupational status, educational attainment, and IQ: a study of twins.

Scores of occupational status, educational attainment, and IQ were obtained for 507 monozygotic and 575 dizygotic male twin pairs born 1931–1935 and 1944–1960. A multivariate genetic analysis with statistics from different cohorts showed heterogeneity between cohorts, and analyses were performed in four separate cohorts. The only set of results which departed clearly from the rest was found for the group born 1931–1935, where the ratio of environmental to genetic effects exceeded those of the other groups. Typical heritability values in the three youngest groups (weighted means) were .43, .51, and .66 for occupation, education, and IQ, respectively. The values in the oldest group were .16, .10, and .37, but this sample is small and the estimates are unstable. Genetic variance influencing educational attainment also contributed approximately onefourth of the genetic variance for occupational status and nearly half the genetic variance for IQ. The values for the between-families variances (reflecting family environment and assortative mating) varied from 2 to 35% in the three youngest groups but were higher for education (62%) and IQ (45%) in the oldest groups. All the between-families variance was common to all three variables. For educational attainment and IQ, the bulk of this between-families variance is probably genetic variance due to assortative mating. The common-factor environmental within-family variances were generally small, and the specific estimates seemed to contain mainly measurement error.

Lp(a) lipoprotein level predicts survival and major coronary events in the Scandinavian Simvastatin Survival Study

The Scandinavian Simvastatin Survival Study (4S) was a double‐blind. randomized placebo‐controlled multi‐centre clinical trial of long‐term Simvastatin therapy in patients with coronary heart disease who had total cholesterol levels between 5.5 and 8.0 mmol/1, comprising 4444 patients, equally distributed to a Simvastatin and a placebo group. Patients achieved a significant 30% relative reduction in overall mortality with Simvastatin therapy through a 42% relative reduction in coronary heart disease mortality. Lp(a) lipoprotein levels in Scandinavian coronary heart disease patients were strikingly higher than in healthy controls. Numbers of deaths in the Simvastatin group differed significantly between quartiles of Lp(a) lipoprotein levels, the reduction in deaths being most pronounced in the second (next to lowest) quartile. Subjects with major coronary events had significantly higher Lp(a) lipoprotein levels than subjects without such events, in all groups. The relationship between Lp(a) lipoprotein level and total mortality as well as between Lp(a) lipoprotein level and major coronary events was significantly different from zero, in logistic regression analyses. The findings show that Lp(a) lipoprotein predicts major coronary events as well as death in secondary prevention with Simvastatin. This prospective study provides independent confirmation that a high Lp(a) lipoprotein level is a significant coronary heart disease risk factor.