Helmut G. Schrott

Hyperlipidemia in Coronary Heart Disease II. GENETIC ANALYSIS OF LIPID LEVELS IN 176 FAMILIES AND DELINEATION OF A NEW INHERITED DISORDER, COMBINED HYPERLIPIDEMIA

To assess the genetics of hyperlipidemia in coronary heart disease, family studies were carried out in 2520 relatives and spouses of 176 survivors of myocardial infarction, including 149 hyperlipidemic and 27 normolipidemic individuals. The distribution of fasting plasma cholesterol and triglyceride values in relatives, together with segregation analyses, suggested the presence of five distinct lipid disorders. Three of these-familial hypercholesterolemia, familial hypertriglyceridemia, and familial combined hyperlipidemia-appeared to represent dominant expression of three different autosomal genes, occurring in about 20% of survivors below 60 yr of age and 7% of all older survivors. Two other disorders-polygenic hypercholesterolemia and sporadic hypertriglyceridemia-each affected about 6% of survivors in both age groups. The most common genetic form of hyperlipidemia identified in this study has hitherto been poorly defined and has been designated as familial combined hyperlipidemia. Affected family members characteristically had elevated levels of both cholesterol and triglyceride. However, increased cholesterol or increased triglyceride levels alone were also frequently observed. The combined disorder was shown to be genetically distinct from familial hypercholesterolemia and familial hypertriglyceridemia for the following reasons: (a) the distribution pattern of cholesterol and triglyceride levels in relatives of probands was unique; (b) children of individuals with combined hyperlipidemia did not express hypercholesterolemia in contrast to the finding of hypercholesterolemic children from families with familial hypercholesterolemia; and (c) analysis of informative matings suggested that the different lipid phenotypes owed their origin to variable expression of a single autosomal dominant gene and not to segregation of two separate genes, such as one elevating the level of cholesterol and the other elevating the level of triglyceride. Heterozygosity for one of the three lipid-elevating genes identified in this study may have a frequency in the general population of about 1%, constituting a major problem in early diagnosis and preventive therapy.

Hyperlipidemia in Coronary Heart Disease I. LIPID LEVELS IN 500 SURVIVORS OF MYOCARDIAL INFARCTION

Plasma cholesterol and triglyceride levels were measured after an overnight fast in 500 consecutively studied 3-mo survivors of myocardial infarction. Virtually all patients under 60 yr of age (95% ascertainment) and a randomly chosen group of older survivors admitted to 13 Seattle hospitals during an 11 mo period were included. A comparison of their lipid values with those of 950 controls demonstrated that 31% had hyperlipidemia. These lipid abnormalities were most commonly found in males under 40 yr of age (60% frequency) and in females under 50 yr of age (60% frequency). Elevation in triglyceride levels with (7.8%) or without (15.6%) an associated elevation in cholesterol levels was three times more common in survivors than a high cholesterol level alone (7.6%). These results raise the possibility that hypertriglyceridemia may be as an important a risk factor for coronary atherosclerosis as hypercholesterolemia. The identification of hyperlipidemic survivors of myocardial infarction provided a unique source of probands for family studies designed to disclose the genetic origin of hyperlipidemia in coronary heart disease.

Myocardial infarction in the familial forms of hypertriglyceridemia

Among 74 hypertriglyceridemic patients who were referred for study because of hypertriglyceridemia, family investigations detected 19 with familial hypertriglyceridemia and 24 with familial combined hyperlipidemia. The frequency of myocardial infarction among adult living hyperlipidemic relatives of patients with familial combined hyperlipidemia was 17.5% (10/57). Five of these relatives had their infarct between the ages of 40 and 50 yr of age, and five before the age of 40 yr. The frequency of myocardial infarction in living hyperlipedemic relatives with familial hypertriglyceridemia was 4.7% (2/43) and was similar to the frequency of myocardial infarction among normolipidemic relatives (4.5%) or among spouse controls (5.2%). Mortality data due to myocardial infarction among relatives of index patients failed to contribute meaningful information.

Hyperlipidemia in Coronary Heart Disease III. EVALUATION OF LIPOPROTEIN PHENOTYPES OF 156 GENETICALLY DEFINED SURVIVORS OF MYOCARDIAL INFARCTION

Although analysis of lipoprotein phenotypes is widely used to diagnose and classify the familial hyperlipidemias, an evaluation of this system as a method for genetic classification has hitherto not been published. The present study of 156 genetically defined survivors of myocardial infarction was therefore designed to examine the relationship between lipoprotein phenotypes and genetic lipid disorders. The lipoprotein phenotypes of each survivor was determined primarily by measurement of his plasma triglyceride and low density lipoprotein (LDL)-cholesterol concentrations; his genetic disorder was identified by analysis of whole plasma cholesterol and triglyceride levels in relatives. The mean levels of LDL-cholesterol discriminated statistically among the three monogenic lipid disorders; it was highest in survivors with familial hypercholesterolemia (261+/-61 mg/100 ml [mean +/-SD]); intermediate in those with familial combined hyperlipidemia (197+/-50); and lowest in those with familial hypertriglyceridemia (155+/-36) (P < 0.005 among the three groups). However, on an individual basis no lipoprotein pattern proved to be specific for any particular genetic lipid disorder; conversely, no genetic disorder was specified by a single lipoprotein pattern. This lack of correlation occurred for the following reasons: (a) individual LDL-cholesterol levels frequently overlapped between disorders; (b) in many instances a small quantitative change in the level of either LDL-cholesterol or whole plasma triglyceride caused qualitative differences in lipoprotein phenotypes, especially in individuals with familial combined hyperlipidemia, who showed variable expression (types IIa, IIb, IV, or V); (c) lipoprotein phenotypes failed to distinguish among monogenic, polygenic, and sporadic forms of hyperlipidemia; (d) clofibrate treatment of some survivors with genetic forms of hyperlipidemia caused their levels of triglyceride and LDL-cholesterol to fall below the 95th percentile, thus resulting in a normal phenotype; and (e) beta-migrating very low density lipoproteins (beta-VLDL), previously considered a specific marker for the type III hyperlipidemic disorder, was identified in several survivors with different lipoprotein characteristics and familial lipid distributions. These studies indicate that lipoprotein phenotypes are not qualitative markers in the genetic sense but instead are quantitative parameters which may vary among different individuals with the same genetic lipid disorder. It would therefore seem likely that a genetic classification of the individual hyperlipidemic patient with coronary heart disease made from a quantitative analysis of lipid levels in his relatives may provide a more meaningful approach than determination of lipoprotein phenotypes.

Familial hypercholesterolemia in a large indred. Evidence for a monogenic mechanism.

Abstract The traditional view that familial hypercholesterolemia (type II hyperlipoproteinemia) is inherited as an autosomal-dominant trait has been recently questioned. Instead, it has been sugges...

Prenatal prediction in myotonic dystrophy: Guidelines for genetic counseling

Prenatal prediction of myotonic dystrophy (Dm) is feasible because Dm is closely linked to the secretor (Se) locus and the Se status of the. fetus can be determined by examination of the amniotic fluid. A pregiiant woman with Dm and her husband presented a favorable mating for prenatal diagnosis. A Se‐negative fetus would have been at high risk for Dm (92%, allowing for recombination). The fetus was found to he Se‐positive and pregnancy was not terminated. Overall, 37.5% of matings are potentially favorable for prenatal prediction by linkage. The affected parent must be heterozygous at the secretor locus; the spouse must he either se/se or potentially Se/se. Otherwise, prenatal diagnosis is impossible. Guidelines have been prepared for intrauterine prediction of myotonic dystrophy in matings of various Se genotypes.

Hyperlipidemia in Survivors of Myocardial Infarction: Relationship between Genetic Classification and Lipoprotein Phenotype

From the Departments of Medicine (Division of Metabolism and Gerontology, Veterans Administration Hospital, and Division of Medical Genetics, University Hospital) and Genetics, University of Washington, Seattle, Washington 98195.

Prenatal prediction of autosomal dominant diseases by linkage studies: myotonic dystrophy

Remarkable progress in adapting specific chromosomal and biochemical tests to amniotic fluid samples has allowed intrauterine diagnosis for an increasing number of inherited conditions. However, the lack of any specific tests for autosomal dominant diseases, especially those affecting the nervous system and muscle, has precluded such prenatal evaluation in genetic counseling. Genetic linkage offers a potentially useful alternative approach to such diseases. The gene for a particular disorder must be closely linked to a genetic marker which can be analyzed in amniotic fluid or cells obtained in the second trimester of pregnancy. We have recently applied linkage studies to the prediction of myotonic dystrophy (Dm) during pregnancy. Dm is known to be closely linked to the secretor locus (Se) , which determines the secretion of ABH blood-group substances into saliva and other body fluids, including the amniotic fluid of the fetus. Only certain families will be suitable for this analysis: the affected parent must have thesecretor-positive phenotype and be heterozygous (Se/se) at the secretor locus; the coupling of the Dm allele to the Se or se allele must be determined; and the spouse must be either secretor-negative or heterozygous secretor-positive. Secretor genotypes can be inferred from secretor phenotypes of close relatives, including the fetus at risk. Unfortunately, these criteria will be satisfied in only 5-10 percent of couples at risk to transmit myotonic dystrophy. In suitable couples, however, linkage analysis can be quite helpful.