Background information on presentation by Ronald M. Krauss, M.D., Lawrence Berkeley National Laboratory, Berkeley, Ca., at AAAS symposium on "Gene-Diet Interactions in Coronary Heart Disease"
Saturated fat and cholesterol are two of the strongest dietary determinants of blood cholesterol levels, particularly the low-density lipoprotein (LDL) or "bad cholesterol" fraction. The LDL response to reduced saturated fat and cholesterol intake, however, can vary widely among individuals. Recent evidence indicates that genetic factors can contribute to these differences in dietary response.
The most well defined genetic trait affecting LDL response to diet is the apoE4 variant of apoprotein E, a protein that has a number of important functions in both the cardiovascular and nervous systems. ApoE4 is due to a single DNA change in the gene for apoprotein E and has a prevalence of approximately one in seven in the population. Compared with individuals who have the normal form of apoprotein E, designated apoE3, those with apoE4 have a tendency for higher blood cholesterol levels, increased heart disease risk, and as discussed elsewhere, increased risk of Alzheimer's disease. Most studies have found that LDL reductions on low-fat, low-cholesterol diets are greater in subjects with apoE4 than in those with apoE3.
Other less common lipoprotein gene variants also have been shown to influence the LDL response to diet. One, designated apoAIV-2, appears to prevent the rise in LDL induced by increased intake of dietary cholesterol.
A much more common genetically influenced condition that can influence the blood cholesterol response to a low fat diet is that responsible for the "small, dense" subtype of LDL, also called LDL subclass pattern B. This trait, which can be detected by specialized analytic tests, is found in about one in three adult men and one in 5 to 6 postmenopausal women. It is not so common in younger men and premenopausal women.
In addition to the presence of unusually small and compact LDL particles, pattern B is characterized by a cluster of other metabolic disturbances, including lower blood levels of the "protective" HDL cholesterol fraction, increased levels of triglyceride and apoprotein B (the major LDL protein), and predisposition to the most common form of diabetes mellitus. Each of these features confers increased risk of coronary heart disease, resulting in an overall three-fold higher risk compared with individuals with larger LDL (pattern A).
While blood levels of LDL are not elevated in pattern B individuals, it appears that small LDL may be particularly harmful because it has a greater likelihood of being retained in the artery wall than large LDL, and is more susceptible to oxidation, an event that appears to be of critical importance in the development of atherosclerosis and coronary heart disease. There is evidence that pattern B can result from alterations in one of several different genes, but as yet the specific mutations responsible for this trait have not been identified. Non-genetic factors, such as age, body weight, and diet, are also major determinants of the presence and severity of the pattern B trait.
In initial studies of dietary effects in a group of 18 men with pattern B, we were surprised to find that the reduction in LDL cholesterol levels induced by a low-fat, high carbohydrate diet was twice as great as in the 87 subjects with pattern A. More surprising, in approximately in one-third of the pattern A men, the low-fat diets resulted in a shift to the pattern B profile, without a reduction in LDL levels, and an increase, rather than a decrease, in the ratio of total cholesterol to HDl cholesterol, a powerful index of heart disease risk.
Studies in families have suggested that this response may be due to an underlying genetic predisposition to the pattern B trait that only becomes evident when dietary fat intake is reduced to a sufficiently low level, and is replaced by carbohydrates. These findings raise the possibility that in individuals with this response, low-fat diets may be of little benefit with regard to coronary disease risk, and may even have adverse consequences, although this remains to be demonstrated.
Recently, in a second study involving 133 men, we showed stepwise improvements in LDL levels in pattern B, but not pattern A, as dietary fat was reduced from 40% to 30% to 20% of total calories (the average fat intake in the U.S. is currently 34% of calories). In these subjects, we also compared the effects of replacing saturated fat with either carbohydrates or monounsaturated fats (olive and canola oil, common components of the "Mediterranean" diet). In addition to the lowering of LDL cholesterol seen with both diets in pattern B men, the high monounsaturated fat diet also reduced levels of triglyceride and apoprotein B, but only in the pattern B individuals.
Taken together, these findings indicate that efforts to reduce the incidence of heart disease by modifying fat intake may be much more effective in high risk pattern B individuals than in pattern A subjects who have a normal blood cholesterol profile.
Because of the relatively low prevalence of pattern B in women, particularly before menopause, we have not as yet studied dietary responsiveness in pattern B women. Instead, we tested the potential influence of genetic predisposition to pattern B by comparing the LDL response to a low-fat (20%) diet in 72 young women (nearly all pattern A) categorized according to their parents' LDL patterns. As predicted, the LDL reduction was much greater in daughters with two pattern B parents than in those with two pattern A parents, and intermediate in daughters with one pattern A and one pattern B parent. Similar parental influences were obtained in a study of 50 children of both sexes. This result strongly suggests that genetic factors underlying the predisposition to pattern B also influence the LDL response to reduced fat intake.
Dietary fat-induced changes in LDL particle size and density phenotypes are linked to candidate genetic loci. LDL particle size and density are influenced by genetic and non-genetic factors, including dietary fat and carbohydrate. Four genes previously shown to be linked to LDL particle size distribution were tested for linkage to variations in LDL particle phenotypes in 206 healthy males (siblings from 94 families) after consumption of both high-fat (40%) and low-fat (20%) diets for 4 weeks each. Dietary carbohydrate was substituted for fat; other components were constant. Linkage to the loci for LDL receptor (LDLR), apoAI-CIII-AIV, cholesteryl ester transfer protein (CETP), and manganese superoxide dismutase (MnSOD) was tested with genetic markers flanking these candidate genes using nonparametric sibpair statistical linkage analysis.
The results confirmed significant (p<0.01-0.05) linkage of LDL particle phenotypes to the LDLR and apoAI-CIII-AIV loci on both diets, and to the CETP locus on the low-fat diet. Mean LDL size decreased and density increased with change from the high-fat to the low-fat diet. Diet-induced changes in LDL particle phenotypes were linked to both LDLR (p<0.01) and CETP (p<0.05). In addition, change in apoB (a measure of lipoprotein particle number) was linked to the MnSOD locus (p<0.03).
These data indicate that genetic factors contributing to LDL particle phenotypes may also influence changes in these phenotypes induced by variation in dietary fat and carbohydrate intake.
Summary: Further information regarding this and other gene-diet interactions can help health practitioners and the general public better understand differences in dietary responsiveness observed among individuals, and recognize that individual responses cannot be reliably predicted from "average" dietary effects observed in large population studies. More important, we can expect that, as new tools become available for genetic analysis, these can be used to recommend appropriate, and more individualized, dietary practices for heart disease prevention.
1. Dreon, D.M., H.A. Fernstrom, B. Miller, and R.M. Krauss. Apolipoprotein E isoform phenotype and LDL subclass response to a reduced-fat diet. Arterioscler. Thromb. Vasc. Biol. 15:105-111, 1995.
2. Krauss, R.M., and D.M. Dreon. Low density lipoprotein subclasses and response to a low-fat diet in healthy men. Am. J. Clin. Nutr. 62(2) (Suppl.) 478S-487S, 1995.
3. Dreon, D.M., R.M. Krauss. Low density lipoprotein subclass patterns are associated with differing lipoprotein responses to low-fat and high-monosaturated fat diets. Circulation 92(Suppl.) I-155, 1995.
4. Dreon, D.M., R.M. Krauss. Differential benefit of reduced fat intake on lipoprotein profiles in subjects with small versus large low density lipoproteins is greater with 20% than 30% fat. Circulation 92(Suppl.) I-349, 1995.
5. Dreon, D.M., H.A. Fernstrom, P.T. Williams, R.M. Krauss. LDL subclass patterns and lipoprotein response to a low-fat, high-carbohydrate diet in women. Arterioscler. Thromb. Vasc. Biol. 17: 707-714, 1997.
6. Dreon, D.M., H.A. Fernstrom, P.T. Williams, and R.M. Krauss. Prevalance of small, dense LDL phenotype in children on a very-low-fat diet is related to parental LDL subclass phenotypes. Circulation 94(Suppl.): I-96, 1996.
7. Krauss, R.M. Understanding the basis for variation in response to cholesterol-lowering diets. (Editorial) American Journal of Clinical Nutrition 65: 885-6, 1997.
Note to reporters: This is one of four fact sheets about the symposium presentation.
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