Triglyceride Levels in Sons of Patients with Coronary Artery Disease

In this issue, the report by Uiterwaal and colleagues [1] indicates that healthy young sons of fathers with established coronary artery disease have a greater postprandial triglyceride response than do sons of fathers without this disease. This finding appears to be the result of a carefully conducted study, and although the difference in responses between the two groups is not great, it is statistically significant. Two alternative explanations could account for the difference in response in the two types of offspring: The difference could be either acquired or genetic. Both possibilities must be considered.

An acquired difference might be one of two kinds. First, sons may have acquired habits from their fathers before their fathers developed coronary artery disease. For example, they might have acquired their fathers' eating and exercise habits or attitudes toward work and stress. Although no definite evidence was obtained about these acquired habits, they could be subtle and difficult to detect without more extensive testing. If present, they could have affected the postprandial triglyceride response.

A second possibility is that sons were psychologically affected by their fathers' heart attacks and consequently these sons modified their behavior in an attempt to decrease their own risk. This is a strong possibility. We know that having a myocardial infarction is a strong motivating factor for changes in lifestyle (for example, stopping smoking and changing the diet) in affected patients, and some of this motivation probably “rubs off” on their offspring. An example of this effect is the lower fat intake in sons of fathers with coronary artery disease when compared with sons in the control group. A low-fat diet could induce an increased postprandial response by slightly increasing fasting triglyceride concentrations. This was not detected in the study by Uiterwaal and colleagues, but larger studies have shown that lower-fat diets increase triglyceride levels. Such an effect, therefore, cannot be excluded.

The alternative mechanism contributing to a difference in postprandial triglyceride response is a genetic difference, either monogenic or polygenic. If parents were heterozygous for a monogenic disorder of triglyceride metabolism, only half the sons should have inherited the defect; thus, only half would have shown an excessive response. Of course, the response in affected sons would have been bimodal. This possibility is not mentioned in Uiterwaal and colleagues' study, but it should have been examined. All affected parents certainly were not heterozygous for a monogenic defect in triglyceride metabolism. Thus, if a monogenic defect exists that affects triglyceride metabolism, it must have been much more marked in a few sons to make the average response statistically significant. It should have been relatively easy to identify such sons, but this was not done in Uiterwaal and colleagues' study.

The second alternative is that an increased postprandial response is polygenic. For example, fathers with coronary artery disease had higher levels of total cholesterol and low-density lipoprotein (LDL) cholesterol than did control fathers, and, on the average, they had “polygenic hypercholesterolemia.” It is interesting to note that this polygenic phenotype was “diluted” out in the sons or had not yet become manifest; sons of fathers with coronary artery disease did not have higher total cholesterol and LDL levels than did control sons. Perhaps it is possible that fathers with coronary artery disease had “polygenic postprandial hypertriglyceridemia,” and enough “abnormal” genes, albeit diluted by one half, were transmitted to allow this trait to be observed in their sons. Fathers with coronary artery disease certainly had higher fasting triglyceride levels than did control fathers, and therefore they very possibly could have had “polygenic hypertriglyceridemia.” Consequently, some of the hypertriglyceridemic genes may have been transmitted to their sons.

If so, what are some of these abnormal genes? They could have been a host of different genes affecting triglyceride and lipoprotein metabolism, such as those controlling hepatic lipid regulation; lipoprotein lipase; apolipoproteins B, Es, Cs, and As; and LDL receptors, to mention only a few. Increasing evidence suggests that inheritance of a constellation of genes having particular patterns of genetic variation can lead to mild to moderate dyslipidemia, which in turn predisposes to premature coronary artery disease. Because fathers with coronary artery disease definitely had a polygenic form of dyslipidemia, some of the abnormal genes undoubtedly were transmitted to their sons. Thus, findings in this study are compatible with the concept that genetic factors contribute to the mild to moderate dyslipidemia found in patients with premature coronary artery disease. It must be remembered, however, that a confounding effect of acquired characteristics cannot be excluded, which may have contributed to the postprandial responses noted in Uiterwaal and colleagues' study.

Does an increased postprandial response mean that increased levels of triglycerides are a risk factor for coronary artery disease? The evidence relating triglycerides to risk for coronary artery disease is complex, and there is not universal agreement on the meaning of this evidence. In my view, available data indicate that increased levels of triglycerides have an atherogenic effect, but this effect may be mediated through other mechanisms (for example, the presence of very-low-density lipoprotein remnants, small LDL particles, decreased levels of high-density lipoprotein cholesterol, and a thrombogenic tendency) [2]. This study sheds little light on the mechanisms involved. Nonetheless, the results are consistent with the possibility that triglyceride-rich lipoproteins have atherogenic potential. This assumes that the entire effect is not explained by modified behavior in sons after their fathers developed clinical evidence of coronary artery disease.

• Copyright ©2004 by the American College of Physicians