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Gene, Diet, Disease

Apo E and Cholesterol Management

APOE4 allele carriers are prone to high cholesterol and Alzheimer's disease. Low-fat diets can help reduce the risk for these diseases. This allele is more common (20-30% occurrence) in Africans and Caucasians than in other ethnic groups.

Apo E (Apolipoprotein E) represents one of the most well understood gene-diet interaction models in modern human population. Genetic variations in Apo E predispose people to different health risks and lead to distinct dietary responses.  The most prominent health risks caused by Apo E variation are cholesterol metabolism dysfunction and Alzheimer's disease, which can be avoided by genotype-tailored “Apo E diet”.

There are three common variants of Apo E: E2, E3, and E4.  The corresponding genes that encode these variants are Apo ε2, ε3 and ε4 respectively. The combination of any two of them gives rise to six genotypes: E2/E2, E2/E3, E2/E4, E3/E3, E3/E4, and E4/E4.  Apo E3/E3 represents the most common and the normal genotype, account for 60% of human population. The other 40% people who carry at least one Apo E2 or E4 variants associate with different degree of abnormity in cholesterol metabolism. 

Studies in European, Asian, African and American population show that the distributions of E2, E3 and E4 in different human populations are different.  American Indians, Chinese, Japanese and Mexican Americans have the highest frequency (> 84%) of most common variants Apo E3; Africans and African Americans have the highest frequency of E4 (20.1% and 31% respectively); African Americans and Caucasians (except Finns) have the highest frequency of E2 (7.3%-13.1%). The gene frequency distribution seems to be gender independent (see Table 1 below).  This differential distribution frequency among ethnic groups may reflect dietary shift from plant based to meat rich food sources during human evolution.  Alternatively, selective pressure of infectious diseases may play a role in the evolution of Apo E genotypes.

Table 1. Apo E gene and genotype frequency in human population (adapted from Eichner et al, 2002. Am J Epidemiol 155:487–95).

Gene Frequency Genotype Frequency
Population E2 E3 E4 E2/E2 E2/E3 E2/E4 E3/E3 E3/E4 E4/E4
African Americans 13.1% 66.8% 20.1% 2.0% 18.0% 6.0% 43.0% 28.0% 3.0%
Africans (Nigerians) 2.8% 66.2% 31.0% 0.0% 3.0% 3.0% 46.0% 37.0% 11.0%
American Indians (men) 1.7% 85.0% 13.3% 0.0% 3.0% 0.5% 71.6% 23.9% 1.2%
American Indians (women) 1.6% 85.8% 12.6% 0.1% 2.6% 0.5% 73.2% 22.7% 1.0%
Caucasians (Finland) 3.9% 76.7% 19.4% 0.3% 5.4% 1.8% 58.7% 30.6% 3.2%
Caucasians (France) 8.1% 80.2% 11.7% 0.8% 13.1% 1.6% 64.3% 18.7% 1.6%
Caucasians (Germany) 8.2% 78.2% 13.6% 0.9% 11.7% 2.9% 62.2% 19.9% 2.2%
Caucasians (Italy) 7.3% 82.7% 10.0% 0.4% 12.0% 16.5% 68.4% 1.5% 1.2%
Caucasians Americans (men) 8.3% 78.5% 13.1% 0.9% 12.9% 1.9% 62.9% 18.3% 3.0%
Caucasians Americans (women) 7.7% 78.9% 13.3% 0.3% 13.3% 1.4% 62.6% 19.3% 3.0%
Chinese 7.4% 84.4% 8.2% 1.4% 12.1% 0.0% 70.9% 14.9% 0.7%
Japanese 3.7% 84.6% 11.7% 0.3% 6.1% 0.7% 71.9% 19.3% 1.7%
Mexican Americans 3.9% 85.9% 10.2% 0.2% 6.7% 0.7% 73.8% 17.3% 1.1%

In general, Apo E2 carriers are associated with low LDL cholesterol and low coronary heart disease incidents. But in the presence of other environmental or genetic factors, E2/E2 genotype people are also prone to a server disease called type III hyperlipoproteinaemia. In contrast, Apo E4 carriers are prone to high LDL cholesterol, coronary heart disease, atherosclerosis and Alzheimer's disease. An interesting phenomenon about these genotypes is that the risks associated with genotypes, as well as the dietary and other environmental effects, are gene dose-dependent. Genotypes E2/E2 and E4/E4 represent two extreme situations while E2/E4 behaves very similar to E3/E3. The risks associated with E2/E3 are between that of E2/E2 and E3/E3; the risks associated with E3/E4 are between that of E3/E3 and E4/E4.

“Apo E diet” refers to the diets that following certain rules applied to different Apo E genotypes. For example, if you are an Apo E2 carrier, you may need to limit sugar and total carbohydrates in your diet more; if you are an Apo E4 carrier, the potential benefits of a glass of red wine daily do not apply to you. Overall, the most beneficial diet regiments to stay healthy are genotype-dependent: Apo E2 carriers should take high fat low carbohydrate diet while Apo E4 carriers are better off with low-fat and low-cholesterol diet.

Table 2 shows the dietary and exercise guidelines for each Apo E genotype. Please keep in mind that these guidelines are over-simplified to show the differential gene-diet compatibility. A rigorous dietary regimen needs to incorporate many other parameters including BMI, cholesterol screening results and other genetic predispositions to match maximally the types of food intake. The total calorie, types of fat (saturated vs. unsaturated, omega-3 vs. omega-6) and carbohydrate (glycemic index and glycemic load) are all critical factors to consider. The goal of a dietary regimen (lowing cholesterol vs. losing weight) could change the recommendation dramatically.

Table 2. General dietary and exercise guidelines for all Apo E genotypes under normal physiological condition (2,400 kcal calorie intake per day).  People with medical conditions need seek professional help to develop diet and exercise compatible regimens.

Diet recommendations Genotype
E2/E2 E2/E3 E3/E3 E2/E4 E3/E4 E4/E4
Energy source Fat 35% 30% 25% 25% 20% 20%
Protein 15% 15% 20% 20% 25% 25%
Carbohydrate 50% 55% 55% 55% 55% 55%
Diet supplements Fiber Beneficial No effect
Omega-3 Beneficial Caution Harmful
Exercise Aerobic 55% 55% 50% 50% 75% 75%
Anaerobic 45% 45% 50% 50% 25% 25%
Alcohol, moderate amount Beneficial Harmful

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