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Nutrigenomics: APOA Polymorphisms & Body Composition

Obesity continues to remain a primary health concern as its trajectory has spun out of control in the last two decades with no end in sight. Health practitioners and advocates diligently put the pressure on patients to be aware of their body mass index and associated health risks, while weight loss diets and exercise plans continue to flood the market.

At the same time, the low-carb Paleolithic (high-protein, moderate fat) and Ketogenic (moderate protein, high-fat) diets are also gaining momentum among health advocates and laypersons, alike. As science reveals more health benefits of kicking the sugar and carbs in favor of the protein and fat, consumers are more inclined to embark on these diet plans in hopes of shedding excess fat while gaining muscle mass, increasing energy, lifting brain fog, reversing insulin resistance, and improving most markers of health.

For many individuals, these diet trends are certainly favorable, especially for achieving a healthier body composition. But this is not true for all.

A small percentage of the population will find that either a Paleo or Keto diet will curtail weight loss and negatively affect their body composition due to a unique polymorphism they may possess. Researchers have been scrambling to understand the metabolic workings behind obesity as a problem that extends beyond food and activity, and discovered a strong association between the APOA2 gene locus and energy intake.

The APOA2 gene encodes for apolipoprotein A-II (APOA2), the second most abundant protein of high-density lipoprotein (HDL) particles and a regulator of triglyceride and postprandial metabolism. Transgenic animal models have shown APOA2 to be a potential indicator of cardiovascular disease risk, although studies are still inconclusive. APOA2 plays roles in cholesterol efflux, HDL remodeling, and cholesteryl ester uptake. There are also associations between serum APOA2 concentration, alcohol intake and body mass index (BMI).

More recently, as the field of nutrigenomics expands, researchers have found a direct link between APOA2 polymorphisms and obesity, but with one unique caveat – the clinical outcome is only expressed in the presence of a high saturated fat diet. Homozygous minor allele (CC) carriers of the APOA2 m265 gene showed higher energy consumption, macronutrient intake and anthropometric traits (namely, a higher BMI) in the presence of high saturated fat intake. Since both the Paleolithic and Ketogenic diets are naturally high in healthy saturated fats such as coconut, palm, and animal fats, the expected outcomes of these diet plans would not be seen in individuals with the APOA2 polymorphism.

In a study of 1402 subjects with a BMI that characterized them as overweight (BMI≥25 kg m−2)

or obese (BMI≥30 kg m−2), non-minor APOA2 carriers (TC and TT) and homozygous minor carriers (CC) were compared using various anthropometric measurements. The following characteristics were noted in homozygous minor carriers (CC):

  • Higher total energy intake and carbohydrate intake
  • Higher (but non-significant) total fat intake and saturated fat intake
  • Greater waist circumference in the presence of high saturated fat intake, but not with total fat intake
  • Reduced waist circumference when HDL cholesterol was increased
  • Higher ghrelin levels in the presence of high saturated fat intake

The APOA2 polymorphism presents a case in which the interaction between APOA2, saturated fat, energy consumption, and hormonal regulation of food increases the risk for obesity.

When the USDA decided to attack the problems of obesity and cardiovascular disease with its dietary guidelines that were established on a foundation of carbohydrates while demonizing fats, the outcomes backfired. As our health continued to decline during the low-fat era, independent researchers began pointing the finger at insulin resistance and high sugar diets. Shortly after, the high-protein/high-fat trends began to pull brainwashed consumers out of their sugary stupor. Sure enough, studies showed that fat (including saturated fat) was not a sole predictor of cardiovascular disease and obesity, but rather, refined carbohydrates were the enemy.

Therefore, the newest generation of dietary guidelines, including the Paleolithic and Ketogenic diets, are certainly worthy of consideration and use when dealing with our modern epidemic of obesity and cardiovascular disease. But, in staying true to the functional medicine mantra of individuality in health and disease management, practitioners must be aware of the subset of patients who would not benefit from the high saturated intake of these newest diet trends, and may even consider the benefit of genetic testing in cases where these diets have failed to meet expectations.

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