Topic 5: Digestion Section And Macronutrient Intake | Nutrition Genome

A popular question you will get from your patients is if the genetic results will show them if they should follow a Paleo diet, Ketogenic diet, Mediterranean diet or Plant-Based diet.

If you look at diets around the world, the protein, fat and carbohydrate ratios range based on the environment. Traditional diets show that as you get closer to the equator, you see a shift in more plant foods. As you get farther from the equator, you see more animal and fat consumption. In the modern era of agriculture, traditional cultures have varying ratios of not only the fat intake but the type of fat. The Japanese have a low saturated fat intake but high omega-3 fatty acid intake, while the French have a high saturated fat intake and range of omega-3 intake based on location. Both countries boast some of the lowest rates of cardiovascular disease.

Without a clear cultural and seasonal diet, global agriculture supplies a manufactured diet full of foods from every climate that we can ship from all over the world. We have the choice now of a year-round high-fat diet or plant-based diet despite our environment or time of the year. This can cause confusion for people because there are simply too many choices.

What the Nutrition Genome Report highlights is how your patient responds to different types of fat, amounts of protein, types of carbohydrates and requirements for fiber. These are based on their metabolic responses including fasting glucose, insulin and HbA1C and other factors. These markers can help you determine if your patients are thriving on their diets or not along with sleep patterns, stress, exercise and medications that increase blood sugar like Statin drugs. As you know, having these markers out of range increases the risk of Type 2 diabetes, cardiovascular disease, cancer, Alzheimer’s, dementia and more.

These genes also help tell your patients a story of their predominant ancestral dietary pattern. While we are all a mix of different environments and ethnicities now, and we see bits and pieces that help us determine what is represented more. For people with a higher sensitivity to saturated fats, their genes may represent more of the Mediterranean and coastal climates, thriving on monounsaturated and polyunsaturated fats. Interesting enough, coconut oil – found in island cultures – is a saturated fat and does not appear to affect the saturated fat genes like animal fats. People who do well with saturated fats may likely have more cold, northern or mountainous heritage.

Here is how you can break down the digestion section, including MTHFR 1298 from the methylation section and SHBG from the hormone section to help determine your patient’s macronutrient intake.

Analyzing Protein Metabolism


ADIPOQ
: ADIPOQ encodes for adiponectin, a protein secreted by fat cells that affect insulin and glucose metabolism. Low levels of adiponectin play a role in obesity, insulin resistance and Type 2 diabetes. Studies have found that carriers of the ADIPOQ rs2241766 TG and GG genotype are more likely to be associated with lower adiponectin, higher insulin resistance, heart disease and subsequent colon cancer risk compared with those carrying the wild TT genotype. A 2017 meta-analysis of twelve case-control studies found that variants in ADIPOQ rs2241766 were correlated with colon cancer risk, especially in cases of insulin resistance with rs2241766 in Ashkenazi Jewish and Chinese populations, with red meat having a compounding effect. Coffee, blueberries, mulberries, cranberries, raw almonds, strawberries, chili peppers and ginger have all been found to increase adiponectin levels.

MTHFR 1298 and 677: Homozygous variants in both of these genes point towards a higher need for methylfolate in the diet to maintain healthy homocysteine levels. BH4 structurally resembles folate and has been described to be reduced in endothelial cells when increased levels of homocysteine are present. High protein diets produce higher amounts of ammonia, which drains BH4, and the body stores ammonia as glutamate, compounding issues with the GAD1 and BDNF gene. This can potentially lead to higher anxiety levels and digestive issues, especially those with glutamate and GABA imbalances. 

BH4 plays an important role in the formation of all the neurotransmitters (serotonin, melatonin, dopamine, epinephrine, norepinephrine etc.) and immunity. Mice studies have shown that raising BH4 normalizes serotonin levels and digestive function. In one human study, levels of BH4 in cerebrospinal fluid was 42% lower in children with Autism Spectrum Disorder (ASD).

FTO: Homozygous variants in the FTO gene have been shown to cause higher ghrelin levels (hunger hormone) in many populations, which can create a greater appetite and the potential for overeating.

While the focus for much of the research is on how these individuals may be more prone to more abdominal obesity from saturated fat intake, protein and fiber intake have a major impact on grehlin levels. Research has found that a breakfast centered around protein and fiber-rich carbohydrates (especially prebiotic fiber) was the most effective at suppressing ghrelin levels throughout the day.

TC7FL2: This gene is unique in its relation to Type 2 diabetes because people with heterozygous or homozygous variants in TCF7L2 may not exhibit risk signs like obesity. In fact, they may have a low body mass index (BMI) and low triglycerides. The increased risk is hypothesized to be due to the effect of TCF7L2 on the sensitivity of the pancreatic β-cells to incretins, not overall insulin sensitivity.

Sufficient protein in particular shows promise in the management of type 2 diabetes by stimulating incretin, insulin secretion, and slowing gastric emptying. 

If you have a patient who has homozygous variants in FTO and heterozygous or homozygous variants in TC7FL2, there is a higher likelihood that this individual requires a higher protein and fiber intake to stabilize blood sugar, insulin and ghrelin levels, and will likely react poorly to a meal void of protein. 

ACATThe ACAT gene converts protein and fat to ATP (energy) in the mitochondria, and plays an important role in cellular cholesterol levels. The heterozygous or homozygous ACAT-02 may cause issues with protein and fat metabolism if B-vitamin deficiency is induced. Variants in this gene are not common, and the consequences have been reported in clinical settings by practitioners, however, has not received much attention in the research world. 

Analyzing Fat Metabolism

The six major standout genes for fat metabolism are SLC22A5, APOA2, ACSL1, PPAR-alpha, FTO, and ADIPOQ.

SLC22A5: SLC22A5 provides instructions for making a protein called OCTN2 that is found in the heart, liver, muscles, kidneys, and other tissues. This protein is positioned within the cell membrane, where it transports L-carnitine into the mitochondria and facilitates the transport of intermediate toxic compounds out of the mitochondria preventing their accumulation.

Research has postulated that polymorphisms in SLC22A5 (OCTN2) may result in a shortage of carnitine, affecting fatty acid travel into the mitochondria. This can affect your patient’s lipid profile and glucose metabolism (carnitine increases the sensitivity of the cells to insulin). Lysine, magnesium and vitamin C are the major precursors of L-carnitine production, making magnesium-rich nuts and seeds good sources of fat.

South Asian and Oceanic societies which use coconut oil as their primary source of dietary fat tend to have a low cardiovascular risk. MCT oil (coconut oil) does not require acetylcarnitine transferase to cross the inner mitochondrial membrane, and therefore, is also an excellent fat for those with a shortage of carnitine. Another point to make is that medium-chain fats in coconut oil are far less likely to be stored in adipose tissue and do not give rise to ectopic fat (deposition of triglycerides within cells of non-adipose tissue) metabolites that promote insulin resistance and inflammation.

APOA2: This gene is only relevant if homozygous. One study showed that the homozygous GG genotype for APOA2 had a body mass index (BMI) that was 6.8% higher than the normal and heterozygous genotype when consuming over 22 grams of saturated fat. The main saturated fat source was dairy. APOA2 acts as a satiety signal with saturated fat and negatively affects the function of lipoprotein lipase, responsible for breaking down fat. Essentially this means that the more saturated fat people eat with this genotype, the more they eat of everything because the signal that they are full is not being sent. I had a client with this genotype that said she could eat a pound of cheese each day and still wanted more.

ACSL1: The GG homozygotes had higher fasting glucose and insulin concentrations compared with the minor A allele carriers from fat intake, with the result that the GG homozygotes were more insulin resistant.  When the subjects switched to either a low fat intake (less than 35% of total calories) or a higher intake of polyunsaturated fats, their biomarkers completely normalized. Monounsaturated fats did not affect this genotype. This means that this patient may do better focusing on chicken, duck, fish, nuts, seeds, olive oil and avocado for their main sources of fat and PUFA.

PPAR-alpha: Plays a vital role in fatty acid metabolism and ketosis and is considered one of the most crucial targets for ameliorating abnormalities with triglycerides, HDL, LDL, VLDL, and ApoB. Those with variants in this gene have been found to have a poor response to fasting due to low ketone bodies and the research has stated that this genotype may explain diverse reactions to the ketogenic diet. 

PPAR-α agonists activate the gene, promoting the uptake, utilization, and breakdown of fatty acids. The activation of PPAR-α has also been demonstrated to inhibit tumor growth and angiogenesis.

Animal models have shown that PPAR-alpha activation reduces body mass, and treats insulin resistance and non-alcoholic fatty liver. Research has found that polyunsaturated fats (fish, nuts, seeds), astaxanthin (high in wild salmon), pterostilbene (blueberries, mulberries, cranberries, raw almonds), genistein (fermented soy), tomatoes, cinnamon, zinc, Lion’s Mane mushroom, Gynostemma tea and L-carnitine all activate PPAR-alpha gene expression. Human studies have shown that increasing polyunsaturated fat and decreasing saturated fat in those with variants in PPAR-alpha improved triglycerides levels, LDL particle size, and weight.

FTO: Gives you more data regarding saturated fat metabolism, especially if your patient is prone to weight gain. The FTO gene is highly expressed in the brain regions controlling feeding and energy expenditure and is one of many genes associated with being a risk factor for obesity, especially abdominal weight. Polymorphisms in the FTO gene have been shown to cause higher ghrelin levels (hunger hormone) in many populations, which can create a greater appetite and the potential for overeating.

The FTO rs9939609 homozygous AA genotype has been found to preferentially select high calorie/high-fat food compared to the normal TT genotype. Multiple studies have shown that a high dietary saturated fat intake (higher than 15.5% energy) and a low dietary polyunsaturated fat intake further increased the risk of being overweight or abdominally obese for the AA genotype.

ADIPOQ: ADIPOQ encodes for adiponectin, a protein secreted by fat cells that affect insulin and glucose metabolism. Low levels of adiponectin play a role in obesity, insulin resistance and Type 2 diabetes. Studies have found that carriers of the ADIPOQ rs2241766 TG and GG genotype are more likely to be associated with lower adiponectin, higher insulin resistance, heart disease and subsequent colon cancer risk compared with those carrying the wild TT genotype. A 2017 meta-analysis of twelve case-control studies found that variants in ADIPOQ rs2241766 were correlated with colon cancer risk, especially in cases of insulin resistance with rs2241766 in Ashkenazi Jewish and Chinese populations, with red meat having a compounding effect. Coffee, blueberries, mulberries, cranberries, raw almonds, strawberries, chili peppers and ginger have all been found to increase adiponectin levels.

Analyzing Carbohydrate and Fiber Metabolism

TCF7L2: The TCF7L2 gene has become the strongest indicator of Type 2 diabetes and gestational diabetes risk for multiple ethnicities in studies. 

Incretins are hormones that are released from the gastrointestinal tract after a meal and regulate the amount of insulin secreted. The two most important incretin hormones are GLP-1 and GIP. Researchers believe that increasing incretin sensitivity may decrease the risk of type 2 diabetes. 

One study found that the consumption of meals based on the Paleolithic diet (no grains or dairy) focusing on fish, polyphenol-rich foods, fiber-rich vegetables and spices high in phytochemicals resulted in significant increases in incretin and increased perceived satiety (feeling full). All three test meals were normalized to contain 50 grams of carbohydrates.

SHBG: Sex Hormone Binding Globulin (SHBG) is synthesized in the liver, and in the blood, it transports and regulates the access of sex steroids to their target tissues. 

Hypothyroidism, Type 2 diabetes, fatty liver, and obesity are associated with SHBG levels that are too low, and therefore very low SHBG can be a biomarker for these disorders. Dietarily, high fructose intake has been associated with all of these disorders and disrupted SHBG levels. In women, a low-fat and high-fiber diet alone or combined with exercise reduces insulin, BMI levels and increases SHBG levels to bring balance back to these individuals. 

In both sexes, extremes of SHBG levels can lead to problems with hormones. Variants in SHBG have been found to been correlated with different base SHBG levels, which can be influenced by the diet. The most negative influence for both sexes appears to be fructose and refined carbohydrates. 

FUT2: The heterozygous and homozygous variants in FUT2 (rs602662, rs601338 and rs492602) increase the need for prebiotics, probiotics and B12.

One study found that higher levels of indolepropionic acid produced by good bacteria due to a diet higher in prebiotic fiber-rich food decreased the risk of Type 2 diabetes.

The Krebs Cycle with SNP’s

Below you can see a visual of the ACAT gene and SLC22A5 gene in action for protein and fat metabolism, and the subsequent production of CoQ10.

1 Week 3 1 Krebs Cycle Genes Practitioner

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