Tel-Aviv-Heidelberg Three Generation Offspring Study: Genetic and environmental sources of variation and covariation among plasma lipids, lipoproteins, and apoliproteins.

Multivariate genetic analysis, implemented in the statistical package for pedigree analysis, FISHER, was carried out on a large sample of Israeli pedigrees to evaluate heritability and genetic correlations among an array of plasma lipids: total cholesterol (TCHL), triglycerides (TRIG), HDL-C and HDL2-C, HDL3-C, LDL-C and HDL-C%, apolipoproteins A and B (APO-A1 and APO-B), lipoprotein LP(a) and fibrinogen (FIBR). Multiple regression analysis showed that although sex, age, smoking and other study environmental factors, have a significant contribution to the variation of each plasma lipid, they exert little effect on covariation in lipids. Genes, however, are important factors of the variation and covariation in lipids. Thus, variance component analysis showed that the genetic component of the study variables, adjusted on age, sex and environmental factors, ranged between 31% for logarithm-transformed TRIG and 77% for plasma concentrations of LP(a). Coefficients of multiple genetic determination of the genetic variation of each variable attributable to all of the other variables, ranged from low values (<30%) for TRIG, LP(a) and FIBR, to moderate (64%) for HDL2-C. The genetic variation of each of the remaining variables was completely explained by variation in other lipids. The results of a factor analyses of phenotypic, genetic and environmental correlation matrices were similar and clearly identified several clusters of variables. The first included APO-A1, HDL-C, HDL2-C and HDL3-C, and the second-APO-B, LDL-C and THCL. Further analysis showed that it was probable the genetic component of variation of HDL3-C plasma concentration that fully depended on APO-A1, while those of LDL-C and TCHL fully depended on APO-B. The degree of correlation between TRIG, LP(a), FIBR and other variables, if any, was considerably lower. Am. J. Hum. Biol. 9:357-370, 1997. © 1997 Wiley-Liss, Inc.

Tel Aviv-Heidelberg three-generation offspring study: genetic determinants of plasma fibrinogen level.

Elevated plasma fibrinogen concentrations (fibrinogen) are an important independent risk factor of atherosclerotic disease. Using the kinetic method, we measured fibrinogen in 808 individuals, of which 757 were members of 204 pedigrees. Correlation analysis and two-way analysis of variance (ANOVA) showed a significant association of fibrinogen with age, body mass index (BMI), sex, smoking habits, sport activity, and other lifestyle factors. However, multivariate regression analysis of fibrinogen established an independent significant contribution of only the first three factors. Fibrinogen levels adjusted respectively were subjected to complex segregation analysis. Our aim was to identify the contribution of major gene effects and residual (within the genotype) family correlations on fibrinogen variation. Results of this study suggest codominant alleles at a major locus accounting for 39% of variation. There was also evidence of a significant residual parent/offspring correlation.

[Geriatrics, a social medicine challenge]. / Geriatrie, eine sozialmedizinische Herausforderung.

The number of old people in our society is strongly increasing. In 1960 1.4 percent of the German population were older than 80 years, in 1993 this percentage was 3.8. 4000 persons older than 100 years are living in Germany today. A great number of these old people are ill and in need of help, often being multimorbid. It has to be the task of geriatrics to increase the number of symptom-free years and to relieve arising diseases.--Cardiovascular and cancer diseases--the leading diseases in our society--are for the most part caused and maintained by external factors. But genetic defects are also increasingly getting involved. About 5000 genetic defects in man have been described so far and results of the latest research suggest that every human being has four to eight pathologically changed genes. Which effects these genes have in the course of life is still the question. Environmental influences play an important role, also in genetically caused diseases.--The care insurance, recently established in Germany, involves considerable dangers. Most of the sick people who are in need of care are being nursed in families and households. These possibilities should be made use of also in the future. The number of people demanding care benefits will continuously rise in the coming years and the extent of necessary financial support is threatening to increase excessively. Bureaucratic selection procedures should be avoided. An important role will come up to the doctors in this field. It must be avoided letting the cultural evolution get out of control. This is also true for the field of geriatrics and gerontology.

Tel Aviv-Heidelberg three-generation offspring study: genetic determinants of apolipoprotein A1 and apolipoprotein B.

The contribution of major gene and multifactorial effects on variation of plasma apolipoproteins A1 and B has been tested in a large sample of population-based Israeli pedigrees. Our most parsimonious and best fitting model for both apolipoproteins is consistent with Mendelian transmissibility, with significant contribution of major genes (with 2 alleles recessive and dominant within each locus) and polygenes, but neglects effects of common sib environment as well as related intergeneration differences in polygenic effects. Total genetic effects explain 71 and 58% of phenotypic variance of APO-A1 and APO-B levels. The major genes account for about 44 and 32% of the variance in APO-A1 and APO-B, respectively, and the frequency of the recessive alleles determining the high level of apolipoproteins under the study in the Israeli population is in the vicinity of 40% at each locus.

Risk factor patterns for coronary heart disease in China, Japan and Germany.

The risk factor patterns for coronary heart disease in China, Japan and Germany were studied. 6,025 Germans, 7,580 Japanese and 2,047 Chinese aged 30-59 were investigated following the protocol of the Göttingen Risk, Incidence, and Prevalence Study carried out in West Germany in 1982. It is concluded that in China, the risk factor intervention focuses mainly on smoking and hypertension; smoking also remains the most important risk factor in Japan; while in Germany the major targets are obesity and hyperlipidemia. However, about 38% of the participants from West Germany showed 3 or more risk factors accumulated per person. Thus the multifactorial risk factor reduction might be necessary in Germany.

A new role for nicotine: selective inhibition of thromboxane formation by direct interaction with thromboxane synthase in human promyelocytic leukaemia cells differentiating into macrophages.

Thromboxane, one of the major oxygenated arachidonic acid metabolites of human macrophages, is the most potent vasoconstricting and proaggregatory molecule known. In addition, thromboxane has been shown to be related to host defence mechanisms. We studied the effects of nicotine and its major metabolites on thromboxane formation using cultured macrophage-like cells (HL-60), microsomal assays and purified thromboxane synthase. In intact cells, nicotine, cotinine and methylnicotine at submicromolar concentrations inhibited the rate of conversion of both arachidonic acid and the unstable endoperoxide prostaglandin H2 into thromboxane but not into other eicosanoids. This indicates that nicotine selectively inhibits thromboxane synthase at concentrations that are readily observed in the circulation of smokers. Microsomal assays revealed that nicotine decreased the maximal velocity of thromboxane synthase without affecting the apparent affinity of the enzyme for its substrate. In contrast, no effect of nicotine on kinetic parameters of prostaglandin H synthase or prostacyclin synthase could be observed. Difference spectra, using purified thromboxane synthase, revealed that nicotine directly interacts with the enzyme, presumably by binding the nitrogen of the nicotine ring structure to the iron of the cytochrome P-450 component of thromboxane synthase.

[Molecular mechanisms in atherogenesis]. / Molekulare Mechanismen der Atherogenese.

Disturbances of the lipid metabolism play a key role in atherogenesis, cholesterol, however, is not stored passively in the arterial wall, but on the basis of complex, partly still unknown humoral and cellular processes. The proliferative lesion of the arteriosclerotic vascular wall is characterized by injured endothelial cells, differentiating macrophages, immunocompetent T-lymphocytes and proliferating smooth muscle cells. Molecular biological investigations on cells of arteriosclerotic plaques among others clarified growth factors, cytokines, factors of angiogenesis and growth inhibitors in form and significance. Risk factors damage the endothelium and thus cause the production of these mediators. The adhesion proteins and the proto-oncogene c-sis play a further role. The latter might produce a connection between arteriosclerosis and cancer research.

Differences in the risk factor patterns for coronary heart disease in China, Japan, and Germany.

In Asia coronary heart disease mortality is almost 10 fold less frequent than in European countries. These findings attract interest to search for different risk factor patterns. From 1982 to 1985 epidemiologic surveys were carried out in China (n = 2047), Japan (n = 7580) and Germany (n = 6052). Healthy, male subjects, aged 30 to 59 years were enrolled. The prevalence rate of hypertension for the Germans was 20% versus 18% for the Japanese, and 11% for the Chinese. About 69% of Chinese, 55% of Japanese, and 37% of Germans were smokers. About 66% of the Germans were overweight (BMI greater than 25), 17% of the Japanese, and 11% of the Chinese. The highest risk group with cholesterol levels of greater than 300 mg/dl included no Chinese subject, 0.1% of the Japanese, but 5% of the Germans. The lipoprotein profiles among the Japanese and the Chinese collectives typically showed antiatherosclerotic characteristics, whereas most Germans exhibited profiles which support development of atherosclerosis. About 36% of the participants from Germany showed 3 or more risk factors accumulated per person (Japan and China 5%). Multifactorial risk factor reduction for Germany is recommended.

Incidence and mortality rates of myocardial infarction in Chinese workers aged 40-59 in relation to coronary risk factors. Results of a Chinese prospective study (Wuhan Study) in comparison to the Göttingen Risk Incidence and Prevalence Study (GRIPS).

Some 2045 male Chinese industrial workers aged 40-59 years living in the city of Wuhan in the People's Republic of China were examined for coronary risk factors in the year 1983. The investigation included a patient history, clinical examination, and ECG and laboratory tests, with special attention to serum lipids. After 5 years, a follow-up investigation of the study group was carried out. The results were compared to the similarly designed German GRIPS project. In comparison to the German population, significantly lower levels for total-, LDL-, and VLDL-cholesterol, apolipoprotein B, triglycerides, uric acid, body mass index, and diastolic blood pressure were found in China. The percentage of smokers, however, was remarkably higher in China than in the Federal Republic of Germany. During the 5 year observation period in the Chinese sample, four subjects suffered from sudden death and four from nonfatal myocardial infarction; in the German study group three times as many fatal myocardial infarction and cases of sudden death and 7.5 times as many nonfatal myocardial infarctions were recorded. Nonfatal coronary heart disease and peripheral vascular disease were also observed less often in China. The incidence of cerebrovascular diseases was 1.5 times higher in China than in Germany. Whereas in Germany, total-, and LDL-cholesterol values were the major distinguishing parameters between infarction and reference groups, in China these values have thus far had no significant influence on the level of risk. Instead in the Chinese incidence group, significantly higher levels for blood pressure, body mass index, uric acid, and the ratio LDL/HDL-cholesterol were found.

Socioeconomic differences in cardiovascular risk factors in China.

Socioeconomic conditions are important in explaining variation in cardiovascular morbidity in advanced societies. To analyse whether cardiovascular risk factors vary according to socioeconomic status in a developing country, and more specifically, in an urban area of China, we compared data from structured interviews and cardiovascular screenings in a group of 1169 male workers (45-65 years). These men participated in the five-year follow-up of a prospective investigation started in 1982/83 in several plants in Wuhan. Unhealthy behaviours such as heavy cigarette smoking and alcohol consumption were significantly more prevalent among men with low educational attainment and with jobs characterized by heavy physical workload, noise and heat. Men paid according to a new, highly demanding salary system exhibited significant increases in total cholesterol and systolic blood pressure from first to second screening. In conclusion, our findings show significant socioeconomic variation in cardiovascular risk factors among middle-aged male workers in China.

[The European cholesterol concensus conferences. Do coronary heart diseases still play a major role in our society?]. / Die Europäischen Cholesterin-Konsensus-Konferenzen.

Despite of certain successes from preventive measures, myocardial infarction and coronary heart disease are still responsible for a great part of deaths and premature disabilities in western industrialized nations. The rates are even increasing in Eastern Europe. In the Far East, however, incidence of myocardial infarction is low due to nutrition habits low in fat and low serum cholesterol levels. In 1986 and 1988 European Consensus Conferences have agreed on recommendations for the prevention of coronary heart disease. The population strategy seeks to improve the health-oriented behaviour of the whole population. The goal of the individual or high risk strategy is the identification and treatment of persons who are at particular risk. Among the influenceable risk factors hyperlipidemia, hypertension and cigarette smoking are of decisive importance. It is a goal to reduce cholesterol levels to 200 mg/dl by means of lipid lowering diet and, if necessary, drug treatment.

Platelet-derived growth factor--a growth factor with an expanding role in health and disease.

Platelet-derived growth factor (PDGF) is the principal mitogen for connective tissue-derived cells such as fibroblasts, smooth muscle cells, and glial cells. It is synthesized by a variety of cell types and the synthesis of PDGF and its receptors is tightly controlled. Accumulating evidence obtained in vitro and in vivo suggests that PDGF plays important roles in the pathogenesis of clinically important diseases such as atherogenesis and cancer. Moreover, PDGF is an important research tool to study the signal transmission pathway of growth factors and other hormones.

LDL-metabolism of the arterial wall--new implications for atherogenesis.

Increasing evidence arising from experimental work and epidemiological studies through the last few years shows an important role of LDL antioxidants in the pathogenesis of the early atherosclerotic lesions characterized by macrophagocytic foam cells. Also the maturation of the atherosclerotic lesion evolving from the fatty streak could be driven by pathological peroxidation of the LDL in the arterial wall. The search for new drugs against atherosclerosis should therefore include compounds that increase stability of LDL and reduce formation of cholesteryl ester formation in the foam cells via the scavenger receptor pathway. The aim of such a strategy is to keep LDL in the protective LDL-receptor-mediated pathway of the liver, and to reduce LDL trapping by the arterial wall.

Plasma cholesterol, lipid lowering, and risk for cancer. An update of the results from epidemiologic studies and intervention trials.

Plasma cholesterol has been shown to be correlated to the incidence of cardiovascular events. This observation and experimental data on the pathogenesis of atherosclerosis have led to a number of recommendations for the treatment of elevated plasma lipids by national and international consensus panels and organizations. However, the issue whether lowering cholesterol might increase the risk for other diseases including cancer is still controversial. In this article, an attempt is made to review the currently available data on the relation between plasma cholesterol and cancer. Special emphasis is given to the results of intervention trials aimed at lowering cholesterol by diet and/or drugs, because they apply best to the human situation and are particularly relevant for the clinician. Data from animal experiments are only briefly discussed.