Nutrient Gene Interactions in Chronic Disease

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A further refinement for recommended nutrient intakes is to include consideration of the relationship of one or more nutrients to the development of chronic disease. Many chronic diseases are the result of an interaction between the genetic heritage or genotype of the individual and the lifestyle choices that individual makes. Conditions such as heart disease, diabetes mellitus, and obesity are in this category. There are also a number of genetic conditions that can be managed by diet. One of the most common of these is lactose intolerance. Approximately 75-80% of the adult population in the world today is lactose intolerant. That is, they cannot consume quantities of milk and some milk products without experiencing gastrointestinal distress. Table 2 lists some genetic disorders that are amenable to dietary management. There are also some relatively rare genetic diseases that affect genes involved in key nutritionally relevant biological processes. For example, mutations in the gene encoding the low-density lipoprotein receptor can impair the ability of the liver to clear cholesterol from the circulation. If cholesterol in the circulation cannot be removed by the liver, it can accumulate in the blood and perhaps lead to cardiovascular disease.

Many of the major chronic diseases (i.e., heart disease, cancer, stroke, diabetes, and obesity) have identifiable genetic linkages that are nutritionally responsive. That is, if an individual carries one or more gene messages that predispose that individual to one of these diseases, nutrient intake can affect the time course and appearance of the disease. For example, more than 150 mutations have been identified that associate with the development of

Table 2 Genetic disorders amenable to dietary management


Nutrition strategy


Increase zinc intake



Avoid fructose-containing foods


Avoid lactose-containing foods


Limit iron intake


Lactase deficiency

Avoid lactose-containing foods (milk and

milk products)


Vitamin B12 injections

Obesity (some

Consume only enough energy to meet


energy need; increase energy output



Control phenylalanine intake such that

the need for this amino acid is met but

that no surplus is consumed

Sucrase deficiency

Avoid sucrose-containing foods

diabetes. The phenotypic expression (the development of diabetes) of some of these genotypes can be influenced by diet. Numerous mutations, especially in the genes for the lipid-carrying proteins, have been identified as being associated with heart disease. These too may be nutrient responsive, but the details of this responsiveness are not known. Still other mutations have been found that associate with the development of obesity or with one or more of the diseases generically referred to as cancer. Again, the details of nutrient-gene expression in these diseases are lacking.

Although many genetic signatures have been associated with specific diseases, not all people who have these genetic characteristics develop the associated disease. This suggests that not only must one have the genetic characteristic but also one must provide the environment for the disease to flourish. An example of this was reported in the early 1960s. Newly arrived Yemenite Jews and Yemenite Jews who had resided in Israel for at least 20 years were compared with respect to diet, lifestyle, and the prevalence of type 2 diabetes. The newly arrived immigrants had very little diabetes, whereas the established Yemenite Jews had as much diabetes in their population as in the Israeli Jewish populations from other areas of the world. The diets and lifestyles of these population groups were compared to a matched group of Arabs living in the same locations in Israel. The diets were not greatly different among the groups, but the disease was far more prevalent in the Jews than in the Arabs. Studies of the diet consumed by the Jews in Yemen versus that in Israel revealed that there were very few differences with one exception: In Yemen very little refined carbohydrate was consumed. Sugar was not readily available, and what was available was very expensive. Once the Yemenites settled in Israel and adopted the Israeli diet with its abundance of refined carbohydrates, type 2 diabetes began to appear. It was suggested that the change in diabetes prevalence in the Yemenite group was due to an interaction between their genetic heritage and their increased consumption of refined carbohydrate. This report was the first to suggest such an interaction.

As mentioned previously, more than 150 mutations associate with diabetes mellitus, but the presence of one or more of these mutations does not necessarily mean that the person will become a diabetic. Diabetologists have acknowledged that there are far more people with a diabetes genotype than with a diabetes phenotype. That many of the diabetes phenotypes take so many years to develop suggests that given the appropriate lifestyle choices, the phenotype may never develop; however, it may develop very rapidly if poor lifestyle choices are made. In support of this argument, one has only to examine the numbers of new cases of diabetes in times of abundant food supplies and in times of food restriction. During World War II when food was rationed (as was gasoline for automobiles), people ate less and were more active. During this period, the number of new cases of type 2 diabetes declined. The number of new cases of type 1 diabetes (autoimmune diabetes or insulin-dependent diabetes) remained fairly constant. Because food was rationed and activity was increased, fewer people had excess fat stores, and this was probably a contributing factor to the decrease in diabetes development. When food became abundant after the war, food intake again was unrestricted, and over time the prevalence of both diabetes and obesity increased.

Some forms of diabetes and obesity share a genotype that phenotypes as obesity/diabetes, called 'dia-besity.' As with the group of diseases called diabetes, obesity has a number of mutations that associate with it. The expression of these genotypes depends largely on whether sufficient food is available and consumed to make possible the phenotypic expression of the obesity genotype. Several of these mutations affect food intake regulation and thus energy balance. If the brain does not receive an appropriate appetite-suppressing signal, then excess energy is consumed, with the result of excess body fat stores. Excess fat stores, particularly in the adipocyte, interfere with the action of insulin in facilitating the entry of glucose into the fat cell. When this occurs, abnormal glucose metabolism (type 2 diabetes) develops. Individuals with excess fat stores can normalize their glucose metabolism if these stores are significantly reduced through food intake restriction and increased physical activity. However, not all instances of diabesity can be resolved in this way.

Technological developments have made it easier to routinely determine the presence of polymorphisms in genes associated with the development of diseases. Given the significance of cardiovascular disease and its association with lipoprotein metabolism, much effort has been focused on this area. Currently, dietary recommendations on fat intake are made for the whole population, but it appears reasonable to suppose that individual responses to a diet designed to lower plasma lipid concentrations will depend on genotype. Evidence for this comes from a G/A polymorphism in the promoter region of the gene encoding the ApoAl lipoprotein, a major constituent of the high-density lipoprotein (HDL). The A polymorphism is less common and some studies have found an association with the possession of this form of the gene and higher HDL concentrations.

HDL is thought to be protective against heart disease. However, the association between the A polymorphism and elevated HDL is quite inconsistent. This is explained by considering diet. Women with the A polymorphism who consumed >6% of energy as polyunsaturated fatty acids (PUFA) had higher HDL cholesterol concentrations than women consuming <6% dietary PUFA. In women lacking this polymorphism, no such effect of diet was seen. Thus, although women with the A polymorphism would clearly benefit from the standard recommendation for increasing dietary PUFA, those who lack it may not, at least with respect to HDL.

The extent to which individual polymorphisms determine disease risk is likely to be limited. These chronic diseases are complex and outcome is likely to depend on polymorphisms in a number of genes and their interactions with dietary as well as other lifestyle factors. However, as technology improves and more polymorphisms are identified, an aggregate picture of risk will develop that will allow much more refined and specific dietary recommendations to be made. Knowing that these conditions are influenced by lifestyle choices, the identification of susceptible individuals should enable the design of effective strategies to delay disease development. It may not be possible to eliminate the problem, but it may be possible to appreciably delay its onset.

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