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Gene, Diet, Disease

APOA5 and Triglycerides Management

Minor alleles in APOA5 gene make their carriers susceptible to high blood triglycerides. Low calorie and omega-3 rich diets can help prevent disease development.  About 30% of Asians and Hispanics carry APOA5 minor alleles.

APOA5 gene is involved in the regulation of blood triglycerides level.  Triglycerides are the storage and transportation mode of fatty acids.  And fatty acids are cell membrane components and the long term energy supply of human body. Some fatty acids are cell signaling molecules, some hormone precursors.  Genetic variations called SNPs (single nucleotide polymorphisms) in the APOA5 gene lead to high blood triglycerides and high risks for cardiovascular diseases.  The three most significant SNPs in this respect are SNP-1131T>C, SNP 56C>G and SNP c553G>T.  These SNPs are distributed in normal human population in high frequency and are associated with different degree of blood triglycerides increase and LDL cholesterol decrease. 

SNP -1131T>C is more often distributed in Asian, African and Hispanic population (frequency 20%-50%).  Carriers are less likely to become obese, less favorably to response to ω-6 fatty acids intake and statin medicine intervention.  SNP 56C>G is more often distributed in Caucasians, African Americans and Hispanics (frequency 12%-28%).  Carriers of this SNP often respond favorably toward low cholesterol diet and triglycerides-lowing medicine fenofibrate but less favorably to exercise.  SNP c553 G>T is only reported in Asians.  It is often associated with severe hypertriglyceridemia (too much blood triglycerides), with an average triglycerides level more than 10-fold higher than normal in people who have two copies of this variant.  The frequency of these SNPs in representative population is shown in Table 1.

Table 1. APOA5 SNP frequencies in several ethnic groups.

Population SNPs
−1131T>C 56C>G c553G>T
Chinese 30 - 40% 1.0% 4.5%
Japanese 50.0% 0.6% 10.5%
Korean 30.5% 9.6%
Hispanics 30.0% 28.0%
Indians 30.0% 3.2%
Africans 20.0%
Africa-American 14.0%
Caucasian 8.0% 12.0%

Since higher triglycerides and lower HDL concentration are correlated with higher risks for coronary artery disease and myocardial infarction development, people who carry these SNPs need to limit total fat intake and gradually adapt to a low fat high carbohydrate diet regimen that is compatible with the BMI dependent calorie restriction. Calorie restriction is very important here since excess calories, no matter if it is from fat, protein or carbohydrate, will eventually be converted to storage fat and lead to metabolic syndromes including but not limited to high cholesterol, high triglycerides and diabetes.  

In addition, there is a specific interaction between the APOA5 SNP -1131T>C and the quantity and quality of PUFA (polyunsaturated fatty acids) intake. For a general human population, PUFAs are considered good fat in comparison to SFA (saturated fatty acids) and MUFA (monounsaturated fatty acids) because the two major PUFAs, ω-6 PUFA and ω-3 PUFA are both essential fatty acids.  They must come from diet for the synthesis of many important hormone and signaling molecules in human body.  But for the SNP -1131T>C, when PUFA consumption was 6% or more of total energy intake, carriers have significantly higher concentrations of fasting triglycerides in the blood (Fig.1).  Moreover, this PUFA effect on APOA5 -1131T>C is specific for ω-6.  When the PUFA is ω-3, the SNP -1131T>C and PUFA interaction no longer exist.  And the interaction observed for SNP -1131T>C was not shared by SNP 56C>G (Lai et al, 2006).



Figure 1. Fasting triglycerides concentration affected by APOA5 SNP -1131T>C (gray bar indicates TT, the normal allele; black bar, TC and CC, the SNP -1131T>C carriers) and PUFA intake categories (PUFA <6% and PUFA >6%). Adapted from Lai et al, 2006. Circulation, 113:2062-2070

The unfavorable interaction between SNP -1131T>C and ω-6 PUFA suggest that it is necessary to pay attention to the ω-6/ω-3 ratio when designing diet regimens for carriers of this specific APOA5 variant.  Traditional diets in the hunter-gatherer era have the ω-6/ω-3 ratio about 1, whereas in today’s Western diets the ratio is typically 20/1 to 30/1. Therefore, modern Western diets are harmful for SNP -1131T>C carriers.  Nevertheless, it is feasible to design SNP -1131T>C diet as long as the fatty acids composition is well understood. Table 2 gives an example of ω-6/ω-3 ratio in common food sources.  It is noticeable that many nuts that are traditional protein and fat rich snacks contain no ω-3.  Therefore, these nuts and food derived from them should be avoided for SNP -1131T>C carriers.

Figure 2. The ω-6/ω-3 ratio in common food sources.

Another interesting phenomenon about APOA5 SNP -1131T>C is that carriers of this variant have a slightly decreased BMI as a function of increased total fat intake despite the concentrations of triglycerides levels were elevated. In a normal genetic background (TT in Fig. 3), the percentage of total fat in human diet is positively correlated with BMI, therefore a higher percentage of fat in your diet will lead to a higher BMI.  It seems that carries the -1131T>C variant gene (TC+CC in Fig. 3), this correlation is reversed, meaning that higher percentage of fat in the diet lead to lower BMI.  Does this mean that SNP -1131T>C could potentially lose more weight by eat more fat?  The answer is absolutely no.  Because in any percentage of fat intake, the predicted BMI of -1131T>C carriers are overweight (BMI > 25).  And most importantly, higher fat intake will lead to higher blood triglycerides level, which is more harmful to human health than a slightly lower, but nevertheless overweight BMI.


Figure 3. The correlation of BMI and percentage of total fat intake in normal (TT) or -1131T>C (TC + CC) carriers (adapted from Corella et al, 2007. J Mol Med 85:119-28).

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