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Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:3326-3331

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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:3326-3331.)
© 1997 American Heart Association, Inc.

Articles

Interaction of Diet and Genes in Atherogenesis Report of an NHLBI Working Group

Alan Tall; Carrie Welch; Deborah Applebaum-Bowden; Momtaz Wassef; ; and the Working Group

From the Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, New York (A.T., C.W.); the National Heart, Lung, and Blood Institute, National Institute of Health, Bethesda, Maryland (D.A.B., M.W.). The participants of the working group are: Alan Tall, MD (Chair), Department of Medicine, College of Physicians & Surgeons of Columbia University, New York, NY 10032; John M. Dietschy, MD, University of Texas Health Science Center, Southwestern Medical School, Dallas, TX 75235; Scott M. Grundy, MD, PhD, Center for Human Nutrition, University of Texas Health Center, Dallas, TX 75235; Aldons J. Lusis, PhD Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90024; P. Ruth McPherson, MD, PhD, University of Ottawa Heart Institute, Ottawa, Ontario, Canada K1Y 4E9; Timothy F. Osborne, PhD, Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA 92717; Lawrence L. Rudel, PhD Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, NC 27517; Ernst J. Schaefer, MD, Lipid Metabolism Laboratory, Tufts University, Boston, MA 02111; NHLBI Staff: Momtaz Wassef, PhD, Deborah Applebaum-Bowden, PhD, Atherosclerosis Research Group, Abby Ershow, Sc.D., Cardiovascular Homeostasis and Bionutrition Research Group, Division of Heart and Vascular Diseases, Rockledge II, MSC 7956, Bethesda, MD 20892.


*    Abstract
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 *Abstract
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Abstract Recent advances in genetics and information emerging from the Human Genome Project make it feasible to examine the importance of dietary-genetic interactions in the development of atherosclerosis. In the opinion of the Working Group, three approaches are necessary to examine this concern. The first approach utilizes animal models to map and identify candidate genes involved in dietary responsiveness and atherogenesis. The second approach involves the evaluation of these genes in specific physiological processes involved in dietary responsiveness and atherogenesis. Finally, the third approach is to extend the studies performed in animal models to human populations using linkage or association studies.


Key Words: atherogenesis • diet • genes


*    Introduction
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Atherosclerosis is a multifactorial disease in which complex interactions between environmental and genetic factors appear to play important roles in the pathogenesis. While certain dietary factors have been implicated in development of the disease, epidemiological and genetic studies indicate that there are wide differences in interindividual responses to such factors. Environmental variation and genetic heterogeneity have hampered human studies to identify possible genetic determinants of dietary responsiveness. The recent advancement of rat and mouse models as tools for genetic studies offers the potential for in-depth investigation of complex diet/gene interactions in the presence of one or more risk factors for atherosclerosis. In addition, progress in the Human Genome Project promises to facilitate the identification of mutant genes underlying complex quantitative responses to environmental stimuli. The identification of genes determining dietary responsiveness in rodents will likely lead to a greater understanding of responsiveness in humans.

The NHLBI recently held a Working Group meeting to examine dietary and genetic interactions affecting atherogenesis, and to determine areas in which further research is warranted. In this report, we provide a short overview of the field and discuss priority areas for future research as recommended by the Working Group.


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Background
Epidemiological, clinical, and biochemical studies have shown that dietary saturated fat and cholesterol raise total plasma cholesterol and LDL-C levels and induce atherosclerosis, whereas dietary polyunsaturated fatty acids do the reverse. Nevertheless, there is considerable evidence in both humans and monkeys that some individuals are more sensitive to a high fat, high cholesterol diet than others.1–8 This variability in plasma lipid response to diet has profound implications for an individual's susceptibility to atherosclerosis and its complications, and for predicting whether an individual will respond favorably to dietary treatment of hyperlipidemia. While it is highly likely that there is a major genetic component of dietary responsiveness, the genes involved and their common variants are largely unknown.

Human studies of dietary responsiveness of plasma lipoproteins have focused mainly on a few candidate genes. The best studied of these is apo E. Substantial population data demonstrate that heterozygosity or homozygosity for the E4 allele is associated with higher mean plasma cholesterol levels and more CHD, whereas heterozygosity for the E2 allele results in lower mean plasma cholesterol levels and apparently delayed CHD.9–11 The relationship of apo E isoforms to cholesterol levels is much more evident in populations consuming high fat, high cholesterol diets. Accordingly, a number of human clinical and population studies have determined the effect of apo E genotype on sensitivity to dietary cholesterol and fat. The results of these studies indicate that the E4 allele is associated with increased levels of LDL-C in response to dietary cholesterol relative to other apo E alleles12–14; one study suggested that the hyperresponsiveness was due to increased cholesterol absorption.15 However, inconsistent results have been reported from a number of other studies,16–19 suggesting that the apo E isoform is a minor determinant of dietary sensitivity in some populations.

Evidence for the involvement of two other candidate genes, the apo A-IV and apo B genes, in the genetic variability of dietary responsiveness has also been reported. Carriers of the apo A-IV-2 allele exhibited impaired cholesterol lowering in response to a low fat, low cholesterol diet20 and attenuated hypercholesterolemia in response to a high cholesterol diet relative to carriers of the apo A-IV-1 allele.21 Apo B polymorphisms were observed to affect plasma lipoprotein responses to low saturated fat feeding in males. Thus, homozygous male carriers of the apo B signal peptide 27 allele exhibited greater responses than homozygous carriers of the apo B signal peptide 24 allele or heterozygotes.22 Further studies of these genetic variants will be necessary to elucidate the mechanisms through which the genes regulate responsiveness to diet.

Additional studies have focused on interindividual differences in metabolic responses to dietary saturated fat and cholesterol. The role of cholesterol absorption efficiency in determining diet-induced plasma lipoprotein levels remains unclear; in one study, hyperresponders exhibited increased efficiency while in another study they did not.23,24 Impaired regulation of cholesterol biosynthesis1,3,25 and increased production of apo B26 were also observed in populations of hyperresponders relative to hyporesponders. Finally, direct effects of dietary saturated fatty acids on LDL receptor activity and dietary cholesterol on LDL receptor mRNA levels were reported in animal models.27–29 Consistent with these reports, a recent human study found that subjects most sensitive to the hypercholesterolemic effects of dietary saturated fat exhibited low LDL apo B fractional catabolic rates, suggestive of marked down regulation of hepatic LDL receptors.5 The wide range of metabolic responses to dietary fat and cholesterol documented by these studies is likely due to differences in diet/dietary regimen as well as genetic heterogeneity between populations (or animal models) studied. Clearly, metabolic responses to dietary fat and cholesterol are complex; further elucidation of the differences between hyperresponders and hyporesponders may be facilitated by preliminary studies in animal models.

Another important area in the study of the interaction of genes and nutrition in atherogenesis is individual susceptibility to weight gain in response to overfeeding. Both obesity and diabetes are significant risk factors for atherosclerosis. Recent studies in animal models indicate that diet may influence the expression of a number of genes involved in the expression of these traits, but the genes involved have yet to be identified.30,31 In humans, concordance of weight gain in response to overfeeding was observed among identical twins but not among unrelated volunteers, suggesting a genetic contribution to the population variance in diet-induced weight gain.32 Advances in animal models may shed light on the genetic determinants of human weight gain and the relationship between obesity, diabetes, and atherosclerosis.

New Opportunities for Understanding Gene-Diet Interactions
Recent advances in genetics make it feasible to map and identify genes regulating complex traits such as dietary responsiveness of plasma lipoproteins. Firstly, the development of highly polymorphic, easy to type, microsatellite markers distributed throughout the genome of humans,33 mice,34 and rats35,36 has vastly altered the way in which genetic studies are approached.37,38 In particular, genome wide searches using animal models reduces the environmental and genetic complexity of a trait, increasing the probability of success in gene mapping. Secondly, increasingly dense expression maps facilitate candidate gene identification,39,40 and the ability to perform targeted mutagenesis of these genes allows direct testing in animal models.41,42 Thirdly, extended knowledge of homology relationships between human and other genomes (especially mouse)43 allows the testing of human homologs of candidate genes identified in animal models to determine the relevance of these genes in human physiology and disease. For example, genetic markers can be identified in homologous regions of the human genome and tested for linkage in family studies or sib-pair analyses. Finally, targeted mutagenesis can also be used to create new animal models based on mutations identified in human studies. The ability to induce specific mutations provides novel opportunities for examining the effect of a mutation in different defined genetic backgrounds and exploring the physiological consequences of different combinations of mutant genes.

What is the significance of understanding genetic-dietary interactions at the molecular level? There are at least three important points. The first is that knowledge of genetic factors will help pinpoint important processes and pathways involved in atherosclerosis. Knowledge of such pathways is likely to contribute to better management of plasma lipoprotein levels and the development of new therapies. The second is that such studies promise to provide new, more specific diagnostic tests for identification of individuals at risk for the disease. Thirdly, studies of genetic-dietary interactions may reveal new information about basic homeostatic mechanisms in mammals.

Recommended Priority Areas for Future Research
1. Use of Animal Models to Identify Genes Determining Dietary Responsiveness

As mentioned above, an increasingly important approach to the study of complex traits such as dietary responsiveness of plasma lipoprotein levels is to utilize animal models to map and identify important genes and then to test the homologous genes in human populations. Critical to the success of dietary studies, the use of animal models allows for strict dietary control. Semi-purified diets can be used and food intake monitored for comparison across studies. Another important point is that the use of animal models allows for selective breeding, decreasing the genetic complexity of a trait.

Mouse and rat models have been specifically developed for genetic studies (in contrast to nonhuman primates, hamsters, and rabbits).44–46 Both species are easy to breed and relatively inexpensive to maintain. Hundreds of different inbred strains have been produced and maintained over the years, and many of these strains exhibit variations in relevant traits including plasma lipoprotein levels, dietary responsiveness, obesity, and atherosclerosis.46–50 The mouse genetic and physical maps have been developed to a similar state as those of human: more than 15,000 genes and genetic markers have been mapped34,40 and yeast artificial chromosome clones are available covering most parts of the genome.51 While the rat has long been the model of choice for physiological and nutritional studies (because its larger size facilitated experimental intervention), the organism has lagged far behind the mouse as a genetic tool. However, the recent convergence of molecular genetics and other fields of biomedical research have increased efforts to develop the rat for genetic studies. Microsatellite markers are being developed rapidly; the current genetic map contains more than 1000 genes and markers covering most of the genome.35,36 Finally, well-established technology for gene manipulation makes these rodent models valuable genetic tools.

Rat and mouse models have been employed recently in genetic searches for susceptibility genes for atherosclerosis-related traits. Genetic crosses between strains differing in blood pressure, plasma lipoprotein profiles, obesity and gallstone formation have led to the identification of chromosomal regions likely to contain QTLs.30,31,52–60 In contrast to studies in humans, fine structure mapping and positional cloning of the genes underlying the QTLs are feasible because individual loci can be isolated on common genetic backgrounds as "congenic strains".58,61,62 Various dietary hyperresponsive and hyporesponsive strains have been identified in feeding studies.47,48,50 These strains can now be used as progenitors of genetic crosses to identify genes contributing to variations in dietary responsiveness using a whole genome approach.

Targeted mutagenesis in rodent models allows for the direct testing of candidate genes and isolated functional studies. Transgenic and knock-out mouse models of atherosclerosis have provided supportive evidence for early hypotheses about the roles of lipoproteins in the development of the disease. For example, targeted mutations of the apo E and LDL receptor genes, and overexpression of apo B resulted in mice with hypercholesterolemia and increased susceptibility to atherosclerotic lesion development (reviewed in45). In addition, mice with high HDL cholesterol levels due to overexpression of apo AI in both wild type and apo E deficient backgrounds were resistant to lesion formation relative to control strains. Importantly, studies of genetically engineered mouse models have suggested that qualitative differences in lipoprotein particles might be important in determining the relative atherogenicity of particles45 and have led to the identification of genes, which may be important in lipoprotein remodeling.63–66 Similarly, individual genetic components of dietary responsiveness can be studied using planned genetic modifications in rodents. The influence of these genes on physiological processes such as cholesterol absorption and biosynthesis, bile acid synthesis, and body energy metabolism can be directly assessed.

The utility of mouse models for studying the relationship between dietary responsiveness and atherogenesis is limited by the relative resistance of naturally occurring strains to lesion development. Naturally occurring "susceptible" strains develop lesions only after feeding a diet high in cholesterol and containing cholic acid.49 Studies of dietary responsiveness and atherosclerosis could be carried out using more moderate diets in genetically-modified, atherosclerosis-susceptible strains (such as apo E or LDL receptor knock-out mutants). Alternatively, functional studies could be carried out using other animal models. There is strong evidence in nonhuman primates for a genetic component of dietary responsiveness of plasma lipoprotein levels and atherogenesis.6–8 Relevant physiological processes could be examined in detail in nonhuman primate models where invasive studies to isolate individual components of the metabolic response under strict dietary control can be accomplished.

2. Evaluation of Specific Molecular Processes Underlying Dietary Responsiveness

A number of different physiological processes are likely to be responsible for dietary responsiveness. These include, but are not limited to, cholesterol absorption and biosynthesis, bile acid synthesis, sterol-mediated regulation of gene expression, and the control of body energy metabolism. Although progress has been made, an overall understanding of each of these physiological processes is greatly lacking. For instance, evidence from patients with the genetic disorder phytosterolemia, in which there is abnormal absorption of dietary plant sterols, and studies with highly potent drugs inhibiting cholesterol absorption, clearly indicate that there are specific molecules mediating intestinal cholesterol absorption67–69; however, the nature of these molecules is unknown.

Recently, novel candidate genes for the regulation of some of these processes have been identified and evaluated in rodent and yeast model systems. Normal cholesterol absorption and esterification in ACAT knock-out mice suggested the existence of additional ACAT-related genes.70 Consistent with this hypothesis, novel ACAT homologous sequences have been identified;71 the role of these genes in cholesterol absorption and dietary responsiveness is under investigation. Novel transcription factors, such as the sterol regulatory element binding proteins, have been postulated to mediate responses to high or low cholesterol diets and control fatty acid and energy metabolism.72–74 The LXR75 and uncoupling protein-276 genes are two additional examples of recently identified candidate genes for dietary responsiveness. Further studies of these genes and the identification of new genes will provide insight to the genetic components and physiological pathways determining inter-individual responsiveness to dietary changes.

3. Genetic Basis of Dietary Hyperresponsiveness and Hyporesponsiveness in Humans.

The most common form of hyperlipidemia present in patients with CHD is FCHL. This disorder appears to have a strong familial component that is elicited by nutritional factors such as excess total calories (leading to obesity), saturated fatty acids, and cholesterol. Although these eliciting factors are present in the general population, FCHL develops in only a subgroup of the population. To date, a single genetic defect has not been discovered to account for the high frequency of FCHL in the population. However, the genetic contribution is so strong that the condition appears to be monogenic in family studies. One explanation for this observation could be genetic heterogeneity (different major genes affecting VLDL-C and LDL-C metabolism in different families). Early investigations suggested that FCHL is the result of overproduction of apo B-containing lipoproteins in the liver. More recent studies in transgenic animals point to a catabolic defect of triglyceride-rich lipoproteins as the site of one likely genetic abnormality.77 For example, the heterozygous form of lipoprotein lipase deficiency has been reported to be accompanied by the FCHL phenotype in some individuals. This phenotype has also been noted in transgenic mice overexpressing apo CIII (an inhibitor of lipoprotein lipase) in a setting of reduced LDL receptor activity. FCHL exemplifies the need to identify new candidate genes and specific pathways involved in dietary responsiveness.

Candidate genes identified in animal studies can be tested in humans, under carefully controlled dietary conditions. Relatively little information is available regarding the heritability of dietary responsiveness in humans. Estimates of the number or nature of genes involved could be obtained from genome scans using animal models. Then, pilot studies can be designed using small numbers of twins or nuclear families to test hypotheses and experimental conditions (including composition and duration of diet). The use of diets having markedly different nutritional compositions in crossover study designs will facilitate the detection of differences between study groups. Experience indicates that, in addition to careful monitoring of diet, it will be important to perform repeated measurements of responses. Dietary studies using obese and diabetic (Type II diabetes) populations would be of considerable interest since these conditions are likely to be important factors modifying dietary responsiveness. These pilot studies will likely provide important information necessary for carrying out larger sib-pair linkage analyses or association studies to test candidate genes or map new genes underlying dietary responsiveness. The long-term goals of these studies would be to determine the dietary-genetic interactions affecting atherosclerosis.


*    Selected Abbreviations and Acronyms
 
NHLBI = National Heart, Lung, and Blood Institute
LDL-C = low-density lipoprotein-cholesterol
apo = apolipoprotein
CHD = coronary heart disease
QTL = quantitative trait loci
ACAT = acylCoA:cholesterol acyltransferase
FCHL = familial combined hyperlipidemia

Received February 11, 1997; accepted May 21, 1997.


*    References
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