GENETIC REPORT

PATIENT OVERVIEW YOUR ANALYSIS

PATIENT NAME:Todd Erb DATE OF ANALYSIS:February 23, 2018 HOW TO READ THIS REPORT

The Nutrition Genome Report is a book on you using genetic testing, nutrigenomics, and epigenomics.

You will see letters next to your genes using the alleles (base pairs) A, C, G and T. Each gene is represented by two letters to determine a "genotype." You will read this in the table as Normal, Heterozygous or Homozygous. It is important to note that "Normal" is also known as the wild type, meaning the most common genotype in our current population. A "Normal" genotype does not necessarily indicate a better genotype. Most Normal variants will not come up in the tables unless they are relevant.

A heterozygous variant means you have 1 copy from your mother or father, while a homozygous variant means you have 2 copies, 1 from your mother and 1 from your father. Both a heterozygous and homozygous gene variant may affect enzyme function, increasing the sensitivity to deficiency or toxicity. The homozygous genotype is the most clinically relevant because it has the most impact on enzyme function. There are exceptions when multiple genes in a class are heterozygous and have a cumulative effect on enzyme function. It should be noted that there are many factors that can determine enzyme function, and therefore it is important to line up gene variants with symptoms, blood work, stress levels, exercise and family history. This is why it is recommended that you share your report with your health care practitioner. On the next page, you will see a summary of your strengths and weaknesses. This is generated from your entire genetic analysis based on your gene variants and will tell you where the most focus is required. Table of Contents

YOUR FINAL RESULTS ...... 1 DIGESTION ...... 5 METHYLATION CYCLE ...... 11 HORMONE HEALTH ...... 16 NEUROTRANSMITTERS & MENTAL HEALTH ...... 18 INFLAMMATION & ANTIOXIDANT PROTECTION ...... 23 DETOXIFICATION: DRUG AND TOXIN SENSITIVITY ...... 28 DNA PROTECTION, DAMAGE AND REPAIR ...... 32 CARDIOVASCULAR HEALTH AND ATHLETIC PERFORMANCE ...... 35 SOURCES ...... 41 STRENGTHENING YOUR GENOME WITH NUTRITION

When you hear the word DNA, what comes to mind? Your first thought may be ancestry. DNA is your blueprint for where you have come from and how you are designed. It may have been a while since you heard the word deoxyribonucleic acid (DNA), but we will show you that there is much more to DNA than your family line. Genes are segments of DNA that are organized by 23 pairs of chromosomes from your mother and father. DNA encodes for proteins, known as the "workhorses" of the cell responsible for all the functions necessary for life. Enzymes are proteins, and many enzymes require nutritional co-factors to make sure these horses are not moving too slow or too fast. People have approximately 20,000-25,000 genes in their genome. Everyone has the same set of genes, but each one can vary by a few letters (called alleles – think of them as the horizontal segments that connect ladder-like strands of DNA) between people. Changes in these genes are referred to as "SNPs" or single nucleotide polymorphisms and gene variants. Differences in these gene variants help determine your nutritional requirements and sensitivities based on enzyme function. SNPs have been inherited over many hundreds of thousands of generations due to the geography of your ancestors and epigenetic changes in your diet, environment, and lifestyle. SNP's instruct enzyme function and are directed by vitamins, minerals, amino acids, and compounds to do their job of keeping you healthy. Their function is affected by deficiency, toxicity, stress, drugs, and toxins. Optimizing enzyme function with the dietary co-factors may help lower inflammation, balance hormones, improve mental health, optimize digestion, increase athletic performance, and decrease the probability of disease. Epigenetics is at the heart of understanding how to strengthen your genome. The "epigenome" is a term that describes a wide variety of chemical compounds that can tell your genome how to function by attaching to it (even turning genes on and off), and the epigenome remains flexible throughout your life (unlike your DNA, which remains fixed). These flexible epigenetic signals come from your stress levels, diet, environment, exercise, relationships and a sense of purpose. All of these factors determine the probability of certain hereditary susceptibilities being expressed, however, if we know where to focus, we can lower these probabilities. Nutrigenomics is the study of how diet interacts with your genes and how individual genetic differences can affect the way you respond to vitamins, minerals, and compounds in the foods we eat. We believe that genes are not your destiny; they are your blueprint. Once you learn how to read the blueprint and make epigenetic improvements where there are weaknesses in the design, the foundation becomes healthier and more resilient; how we live can even influence the health of multiple future generations.

1 STRENGTHS WEAKNESSES

- Your MTHFR A1298C gene function is working well for - Higher need for riboflavin and methylfolate due to BH4 levels and neurotransmitter function variants in MTHFR C677T - Improved breakdown of synthetic folic acid - Potentially higher sensitivity to antacids, antibiotics, - Good B12 transportation due to normal TCN2 gene proton pump inhibitors, Metformin, anticonvulsants, oral function contraceptives and certain psychiatric medications due to - You have improved PEMT function for homozygous MTRR gene phosphatidycholine levels for a healthy liver, memory, - More dietary antioxidant protection needed for the homocysteine levels and REM sleep mitochondria due to variants in SOD2 - Good catalase gene function for oxidative stress - Potentially higher oxidative stress from statin drugs - Good glutathione antioxidant protection in the lungs for - Higher inflammation from psychological stress due to GSTM1, increasing the probability of longevity variants in NOS1 - Good glutathione antioxidant protection for breast or - You have an increased need for folate to improve DNA prostate health for GSTP1 repair for the ATM gene in relation to pancreatic and - You have good antioxidant support for healthy eyes breast (females) health - Good COQ2 gene function for a lower likelihood of statin - Higher need for strategies to increase oxygen capacity drug induced muscle pain for aerobic exercise due to variants in PPARGC1A gene - Improved DNA repair for sun damage for the MDM2 - More post-recover days and dietary muscle recovery gene foods needed for proper muscle repair from intense - Good DNA repair for colon health exercise due to variants in IL6 gene - Good muscle strength - Higher probability of tendon and ligament injuries due to - Improved stress response for heart health variant in COL1A1 - Good F5 gene function for a lower probability of deep - Low circulating vitamin D levels due to variant in vein thrombosis CYP2R1 gene - Improved levels of fibrinogen (reduced risk of blood - Lower prebiotic production and bifidobacteria levels in clots) levels for the ESR2 gene the gut that may decrease B12 absorption and GABA - Good Lp(a) function for the LPA gene production due to variants in the FUT2 genes - Good VOKRC1*2 function for vitamin K2 unless gut - Potentially higher fasting glucose levels from higher function is compromised saturated fat intake due to homozygous ACSL1 gene - Good TNFA gene function for a lower catabolic effect on - Higher probability of weight gain from excess saturated muscle and increased ability to continue physical fats (mainly dairy) due to variants in APOA2 gene performance from heavier training - Potentially elevated levels of histamine in the central - Excellent PON1 gene function for pesticide nervous system, skin and bronchial tissue due to a variant detoxification and healthier HDL and LDL protection in HNMT - Good histamine breakdown in the digestive tract for - Reduced conversion of beta-carotene to vitamin A APB1 - Slower breakdown of dopamine, adrenaline and - Lower probability of chronically elevated uric acid levels estrogen, increasing circulating levels in response to - You have an improved insulin response for grain-based stress due to variants in the COMT genes carbohydrates due to a normal genotype for the TCF7L2 - You have a reduced glutamate to GABA conversion due gene to numerous variants in the GAD1 genes - You have a good conversion of plant-based omega-3 - You may have lower levels of BDNF affecting glutamate ALA (walnuts, flax seeds, pumpkin seeds) to EPA and levels DHA - You have an improved density of dopamine receptors for healthy dopamine levels. - You do not have the APOE E4/E4 genotype, improving cholesterol transport and the maintenance of brain neurons - Good SHBG gene function for hormones

2 VITAMINS, MINERALS AND OTHER COMPOUNDS

Your genetic report showed a higher focus for the following foods based on an increased need for certain vitamins, minerals, and compounds. These do not take into account any food sensitivities beyond gluten and lactose. Foods high in histamine may also need to be considered.

VITAMINS, MINERALS AND FOODS TO EMPHASIZE OTHER COMPOUNDS Broccoli, romaine lettuce, beets, liver, turnips, collard greens, spinach, Folate hummus, pomegranates, sprouted lentils, parsley, potatoes, strawberries, oranges and unfiltered fermented drinks Saturated fat intake should be < 22 grams daily for weight loss. Eliminate Saturated Fat cheese, cream and ice cream. Eggs and red meat are fine in moderation. Coconut oil is a saturated fat exception. Celery, parsley, cranberries, red onions, red wine, apples, cherries, Flavonoids tomatoes, broccoli, kale and citrus Red wine, peanuts, pistachios, blueberries, bilberries, cranberries, cacao and Resveratrol muscadine grapes Selenium varies widely in the soil based on geography. All seafood, crimini Selenium mushrooms and unfiltered beer are sources of selenium. VO2 Max Ashwagandha or eleuthero root (check with doctor first) Emphasize fish, almonds, pistachios, avocados, olive oil, walnuts, sunflower Monounsaturated and seeds, hemp seeds, pumpkin seeds and flax seeds (females) for Polyunsaturated Fat monounsaturated and polyunsaturated fat intake B12 Pastured eggs, grass-fed meat, wild fish, and grass-fed dairy Betaine Spinach, beets and quinoa Gerolsteiner mineral water, spinach, kale, almonds, parsley, and grass-fed Calcium dairy Pastured eggs, liver, heart, beef chuck, chicken thighs, pistachios and Choline almonds Carrots, parsnips, celery, dill, parsley, hops, cruciferous vegetables CYP1A2 Foods (especially fermented like sauerkraut), unfiltered beer, red wine, blueberries, blackberries, red grapes, kiwi, watermelon and spinach Vitamin A Pastured eggs, liver, cod liver oil, eel and grass-fed butter Turkey, chicken, liver, wild salmon, maitake mushrooms and portobello Niacin mushrooms Zinc Beef, lamb, shellfish, liver and sprouted pumpkin seeds Eggs, coconut, walnuts, almonds, tiger nuts, sunflower seeds, pumpkin L-Arginine seeds, sesame seeds and seaweed Vitamin C All freshly picked citrus, berries, broccoli, peppers and supplementation

3 VITAMINS, MINERALS AND FOODS TO EMPHASIZE OTHER COMPOUNDS Celery, parsley, high-quality olive oil, cloves, peppermint, anise, rosemary, Polyphenols sage, blueberries, black elderberry, strawberries, apples, peppers, blackberries, cherries, wine, raw cacao, pistachios, and flax seeds Pistachios, leeks, asparagus, radicchio, bananas, garlic, kiwi, onions, Prebiotics artichokes, Tiger nuts, chicory root and yacon syrup Fermented drinks like Kombucha, fermented veggies like sauerkraut, yogurt Probiotics and kefir Spinach, Swiss chard, hemp seeds, Gerolsteiner mineral water, fish, Magnesium sprouted nuts and seeds and supplementation (Mg is very low in water and soil in the US)

FOODS, DRINKS, TOXINS AND ADDITIVES TO MINIMIZE OR AVOID

FOODS, DRINKS, TOXINS MINIMIZE OR AVOID AND ADDITIVES Saturated fat over 22 grams per day. Avoid all types of dairy cream and use Saturated Fats coconut oil in its place. Vegetable oils (soy, corn, canola, sunflower, safflower), grains, charbroiled/burnt meats, smoked foods, cigarette smoke, gasoline/exhaust exposure, plastic CYP1B1 Foods to water bottles, plastic wrap, styrofoam cups, grain-fed meat and non-organic Avoid dairy, non-organic corn and soy, tap water, personal care and laundry products that contain parabens, artificial flavors and artificial sweeteners. Lactose Dairy foods. FD&C Yellow No. 5, FD&C Red No. 2 and 3, Red 40, Yellow 5,Yellow 6 and Food Dyes Blue 1. Sodium Benzoate Citrus sodas and certain electrolyte tablets may contain it. CYP1A2 Foods to Fried meat, smoked meat and fish, non-organic grain-fed dairy, non-organic Avoid peanuts, oats, and Brazil nuts. High fructose corn syrup, hydrogenated oils, phosphoric acid, benzoic acid, calcium propionate, food dyes, pesticides, herbicides, heavy metal toxicity, DNA Damage fluoride, chemical cleaners, glyphosate (Roundup) on GMO crops, polycystic aromatic hydrocarbons highest in (vegetable oils and grains), binge drinking, smoking, and BPA Plastic. Nitric Oxide Refined sugar, high fructose corn syrup, and vegetable oils (especially fried Antagonists food).

RECOMMENDED BLOOD TESTS

4 These are recommended routine blood tests based on your genetic results. These recommendations do not mean that these markers will be out of range, but may be relevant.

RECOMMENDED BLOOD WORK DETAILS BLOOD TESTS Homocysteine Homocysteine should be between 7-9 Fasting Glucose and HbA1C Check both fasting glucose and HbA1C If poor B12 status is suspected, methylmalonic acid (MMA) levels may be B12 needed to accurately assess B12 status, absorption, and requirements Vitamin D should be between 35-50 ng/ml. Check both 25 and 1,25- Vitamin D dihydroxyvitamin D

DIGESTION

Lactose, Prebiotics, Probiotics, B12, Protein, Fat and Carbohydrate Metabolism, Vitamin A and Histamines

5 GENE GENE GENE RSID NORMAL HETEROZYGOUS HOMOZYGOUS FUNCTION LCT LCT variants decrease the ability to breakdown lactose in dairy. LCT-rs4988235 GG FUT2 gene controls prebiotic production, B12 absorption and how FUT2 much bifidobacteria you carry in your digestive tract. Bifidus also produces intestinal folate. FUT2-rs492602 GG FUT2-rs601338 AA FUT2-rs602662 AA L-Carnitine is responsible for shuttling fats into your cells, modulating your SLC22A5 lipid profile, glucose metabolism, oxidative stress, fat loss and inflammatory responses in the mitochondria. 17 genes tested. SLC22A5-rs2631359 TT SLC22A5-rs671473 AA SLC22A5-rs274571 GG SLC22A5-rs274570 TT SLC22A5-rs274567 TT SLC22A5-rs635619 AA SLC22A5-rs274558 GG SLC22A5-rs274557 CC SLC22A5-rs17689550 TT SLC22A5-rs274551 CC SLC22A5-rs274550 TT SLC22A5-rs274549 CC SLC22A5-rs1045020 TT Long-chain acyl CoA synthetase 1 (ACSL1) plays an important role in fatty acid ACSL1 metabolism and triglyceride synthesis. Disturbance of these pathways may result in dyslipidemia and insulin resistance, hallmarks of the metabolic syndrome. ACSL1-rs9997745 GG The APOA2 gene contains instructions for making a protein called apolipoprotein A-II, APOA2 which is found in HDL cholesterol particles. The homozygous genotype has been linked to saturated fat intake and weight gain. APOA2-rs5082 GG APB1 APB1 is encodes for the DAO enzyme to breakdown histamines. 5 genes tested. Normal Variants Found HNMT stands for histamine methyltransferase and requires a methyl group to breakdown HNMT histamine. HNMT-rs1050891 AG BCMO1 BCMO1 encodes the conversion rate from β-carotene to vitamin A. 2 genes (379V and R267S 267S) tested.

6 GENE GENE GENE RSID NORMAL HETEROZYGOUS HOMOZYGOUS FUNCTION BCMO1 R267S- TT rs12934922 BCMO1 A379V- CC rs7501331 The ABCG2 (Q141K) gene is located at the membrane of kidney proximal tubule cells, ABCG2 where it mediates renal urate secretion. Variants in this gene are linked to reduced uric (Q141K) acid excretion. Normal Variants Found TCF7L2 polymorphisms have been associated with low incretin hormones and impaired TCF7L2 insulin secretion. Normal Variants Found The FADS2 gene encodes the conversion of plant based omega-3 fatty acid alpha linolenic FADS2 acid (ALA) to EPA. Normal Variants Found

ANALYSIS DIGESTION

Lactose

Research: You may have a decreased ability to breakdown lactose. Most people are born with the ability to digest lactose, the major carbohydrate in milk. Approximately 75% of the world’s population loses this ability at some point, while others can digest lactose into adulthood. A homozygous variant is connected to lactose intolerance.

The ability to digest lactose is much more common in people of European ancestry than those with African or Asian ancestry. This is because dairy was introduced earlier in Europe, approximately 8,000-10,000 years ago.

If you have a heterozygous or homozygous gene that decreases the ability to breakdown lactose, choose fermented versions of dairy only like yogurt and kefir, and ghee for cooking.

Since this gene only looks at lactose, sensitivities to dairy can still exist. Many people who have issues with cow dairy can often use goat and sheep dairy without issues. Prebiotics, Probiotics, B12

Improves FUT2 Gene Function: Prebiotics, probiotics, gelatin and B12.

Decreases Gene Function: Antibiotics, proton pump inhibitors, glyphosate, sucralose and Metformin.

Research: If you have heterozygous or homozygous variants in this FUT2 (rs602662, rs601338 and rs492602) you have an increased need for prebiotics, probiotics and B12. Gut flora plays a major role in anxiety (GABA production), depression, type 2 diabetes, immunity and nerve health.

People with homozygous (GG) and heterozygotes (AG) polymorphisms in the FUT2 gene have 15% lower vitamin B12 levels because it is not efficiently absorbed in their intestines.

7 Bifidobacteria is highly sensitive to glyphosate (a potent herbicide used on GMO corn and soy), and therefore choosing organic is important. Antibiotics, glyphosate and sucralose (Splenda) severely disrupt gut flora and increase the risk of salmonella and C-diff.

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.

Bifidobacteria are generally considered to synthesize folate (B9), biotin, thiamine, nicotinic acid, pyridoxine (B6), riboflavin (B2), and B12. The highest extracellular folate levels were produced by four strains of B. adolescentis and two of B. pseudocatenulatum. PABA is found in certain foods and also help probiotics colonize.

Drugs that deplete B12 include proton pump inhibitors, antibiotics and Metformin, and therefore may cause more B12 deficiency symptoms for those with variants in FUT2. L-Carnitine

Improves L-Carnitine Gene Function: Magnesium, vitamin C, lysine and B-vitamins 1-5.

Decreases Gene Function: Deficiency of magnesium, vitamin C, lysine and B1-5. Dietary habits (medications, excess coffee, flour based foods, excess alcohol, sugar) and medications that deplete vitamin C, magnesium and B-vitamins 1-5 may cause further issues with fat metabolism.

Research: L-Carnitine is responsible for shuttling fats into your cells, modulating your lipid profile, glucose metabolism (carnitine increases the sensitivity of the cells to insulin), oxidative stress, fat loss and inflammatory responses.

Research has postulated that polymorphisms in SLC22A5 (OCTN2) may result in a shortage of carnitine, affecting fatty acid travel into the mitochondria. If you have numerous homozygous genes in SLC22A5, you may have trouble breaking down fats and could be a source of inflammation.

Vitamin C and lysine plays an essential role in the production of carnitine. MCT oil (coconut oil) does not require acetylcarnitine transferase to cross the inner mitochondrial membrane, and therefore, is a good fat for those with multiple homozygous variants in SLC22A5. Fat Metabolism-ACSL1

Improves ACSL1 Gene Function: Total fat intake under 35%, lower saturated fat intake and increased PUFA intake.

Decreases Gene Function: A saturated fat intake over 35%.

Research: If you have the GG homozygous gene, it may be beneficial for fat intake to be below 35% of your total calories or have a higher intake of polyunsaturated fat from fish, nuts and seeds if you struggle with weight and high glucose.

The GG homozygotes had higher fasting glucose and insulin concentrations compared with the minor A allele carriers, with the result that the GG homozygotes were more insulin resistant. Among individuals within the top 50th percentile of PUFA intake, the metabolic syndrome risk associated with GG homozygosity was eliminated.

Foods that are higher on the insulin index include dairy and red meat, and insulin inhibits fat breakdown. Fat should come primarily from nuts, seeds, olive oil, avocados, poultry and fish if there are issues with fasting glucose, insulin or weight. Saturated Fat-APOA2

Improves APOA2 Gene Function: Keeping saturated fat intake below 22 grams.

Decreases Gene Function: High saturated fat intake, especially from dairy.

8 Research This gene is only relevant if you have the homozygous GG genotype.

One study showed that the homozygous GG genotype for APOA2 have a BMI that is 6.8% higher than the normal and heterozygous genotype when consuming over 22 grams of saturated fat. The main sources going over the 22 gram mark are likely coming from cheese and all the different types of cream.

The most interesting finding about the APOA2 gene was the suggestion that APOA2 acts as a satiety signal with saturated fat and proposed to affect the function of lipoprotein lipase, the enzyme that breaks down fats. Lipoprotein lipase is only produced when muscles are actively flexed, like when you stand. But when you sit for long periods of time, the enzyme becomes inactive.

If you have the GG genotype of APOA2, you should keep your total saturated fat intake (eliminate cheese, cream and ice cream) below 22 grams if you struggle with your weight. Coconut oil is a saturated fat exception. Avocados, olive oil, nuts, seeds, fish and coconut oil as your main sources of fat along with fiber, while eliminating cheese, ice cream and minimizing dairy in general. Fiber intake is associated with enhanced satiety and reduced food intake, and the people with the GG genotype will benefit from increasing their fiber intake when consuming a meal with saturated fat.You should also take many standing and walking breaks throughout the day to activate this enzyme to burn fat. Histamines-HNMT

Improves HNMT Gene Function: Vitamin C, choline, folate and magnesium, chamomile, basil, stinging nettle, echinacea, fennel, ginger and wild oregano.

Decreases Gene Function: Poor gut flora, gluten sensitivity, too many fermented foods, food dyes, sodium benzoate, and deficiencies in vitamin C, choline, folate and magnesium.

Research: HNMT stands for histamine methyltransferase. HNMT is the primary enzyme responsible for histamine metabolism in the skin, bronchial epithelia and central nervous system. This gene requires adequate methyl donors from methionine and choline. If you do not have enough methyl groups available, you may more prone to high histamine levels and subsequent sensitivity to dietary histamines. Magnesium deficiency increases histamines and makes the DAO enzyme slower and copper increases the DAO enzyme. HNMT polymorphisms differ considerably between Chinese and American populations.

Signs of histamine intolerance are heartburn, indigestion, itching, headaches, migraines, anxiety, arrhythmia, hypertension, diarrhea, hives, fatigue, abnormal menstrual cycle and nasal congestion.

Histamines are highest in fermented foods, cured meats, vinegar based foods, dried fruit, peanuts, smoked foods, alcohol, canned foods, raw tomatoes, raw spinach and eggplant. Cooking reduces histamines.

Certain medications can also increase histamines in the body like NSAID's, which also deplete folate and vitamin C. Increasing folate, magnesium and choline along with vitamin C helps breakdown excess histamines.

In children with ADHD, the adverse effect of food dyes and sodium benzoate on ADHD symptoms was determined by histamine degradation in the rs1050891 HNMT polymorphism.

In women, estrogen promotes the release of histamine, and high estrogen/low progesterone levels can make seasonal allergies worse. Environmental estrogens (xenoestrogens) including BPA plastic and phthalates enhance allergic sensitization in animal models and may enhance development of disorders like asthma in humans. Beta Carotene to Vitamin A Conversion Rate- BCMO1

Improves BCMO1 Gene Function: Vitamin A in the form of retinol and zinc.

Decreases Gene Function: Relying on beta-carotene for vitamin A requirements.

Research: If you are heterozygous or homozygous for BCMO1 A379V and you have a heterozygous or homozygous

9 BCMO1 RS267S, this means that you have a reduced conversion rate of beta-carotene to vitamin A. Many nutrition labels will have beta-carotene listed as vitamin A, however this is not true vitamin A.

The normal conversion for beta-carotene (carrots, sweet potatoes) to retinol is 1:6 and 1:12 for other carotenoids. Female volunteers carrying the T variant of rs7501331 (379V) had a 32% lower ability to convert beta-carotene, and those carrying at least one T in both SNPs (379V and R267S) show a 69% lower ability to convert beta-carotene into retinol.

You want to make sure you consume animal based vitamin A (pastured egg yolks, wild salmon oil, cod liver oil, butter) along with zinc for digestive lining repair, oral health, eye health, iron mobilization, mitochondria health, skin health (sunburns deplete vitamin A in the skin, and acne responds to vitamin A), healthy lung function, and increased immunity.

10 METHYLATION CYCLE

B12, Calcium, Lithium, B6 & FOLATE: Heart Health, Reproductive Health, Brain Health, Pregnancy

CHOLINE: Liver & Brain Health, Gallbladder, Pregnancy

ZINC: Mental Health, Skin Health, Immune Health

MAGNESIUM & VITAMIN C: Heart Health, Adrenal Health, Mental Health

11 GENE GENE GENE RSID NORMAL HETEROZYGOUS HOMOZYGOUS FUNCTION The MTHFR C677T gene encodes the MTHFR gene to convert folate into the active form, MTHFR methylfolate. Variants in this gene slow down enzymatic function, increasing the need for C677T folate and B2. MTHFR C677T- AG rs1801133 MTHFR A1298C is involved in converting 5-methylfolate (5MTHF) to tetrahydrofolate MTHFR (THF). Unlike MTHFR C677T, the A1298C mutation does not lead to elevated A1298C homocysteine levels unless paired with a heterozygous MTHFR C677T. MTHFR A1298C- TT rs1801131 (Methylenetetrahydrofolate dehydrogenase 1) encodes a protein that possesses three MTHFD1 distinct enzymatic activities in the interconversion of 1-carbon derivatives of G1958A tetrahydrofolate. MTHFD1 G1958A- AA rs2236225 DHFR Dihydrofolate reductase (DHFR) catalyzes the reduction of dihydrofolate to tetrahydrofolate A20965G (THF) and affect synthetic folic acid metabolism. Normal Variants Found MTR MTR (methionine synthase) combines folate, methyl B12 and homocysteine into A2756G methionine. MTR A2756G- AG rs1805087 MTRR MTRR attaches a methyl group to B12 and variants here will slow the process. When both A66G MTR and MTRR exist, dysfunction can occur. MTRR A66G- GG rs1801394 TCN2 Transcobalamin II (TCN2, or holotranscobalamin when bound) transports B12 to peripheral C766G tissues. Variants in this gene may affect B12 transport. Normal Variants Found MAT1 helps produce sufficient SAMe. Variants may decrease SAMe production and MAT1 increase the need for magnesium to produce SAMe. Use extreme caution with SAMe supplementation. 8 genes tested. Normal Variants Found MAT1-rs2993763 AG MAT1-rs4934028 AA MAT1-rs756208 GG MAT1-rs7081756 TT Variants in PEMT may increase the need for choline and increase the sensitivity to PEMT anticholinergic drugs. 3 genes tested. PEMT-rs7946 TT

12 GENE GENE GENE RSID NORMAL HETEROZYGOUS HOMOZYGOUS FUNCTION NBPF3 NBPF3 has been associated with vitamin B6 levels. Normal Variants Found Betaine-homocysteine methyltransferase (BHMT) catalyzes the remethylation of BHMT homocysteine. BHMT-rs3797546 TT CBS The Cystathione Beta-Synthase (CBS) enzyme pulls homocysteine to hydrogen sulfide A360A (H2S) and glutathione, requiring B6 and SAMe as a modulator. CBS A360A- AG rs1801181 CBS C699T-rs234706 AG

METHYLATION ANALYSIS

Folate-MTHFR 677

Improves MTHFR C677T Gene Function: Riboflavin and methylfolate.

Decreases Gene Function: Proton pump inhibitors, birth control pills, NSAIDs, anticonvulsants, antivirals, antibiotics, acid blockers/antacids and hypothyroidism.

Research: The frequency of the C677T polymorphism of MTHFR in the Caucasian population is 12% homozygous and up to 50% heterozygous. The homozygous genotype has been found to be particularly common in northern China (20%), southern Italy (26%), and Mexico (32%). If you have a heterozygous MTHFR 677 (30% reduced function) or homozygous (50% reduced function) gene, your methylfolate requirement is higher. Reduced levels of methylfolate lead to decreased production of neurotransmitters, reduced conversion of homocysteine to methionine, and reduced s- adenosylmethionine (SAMe) concentrations. Multiple studies have considered riboflavin status and shown that the MTHFR 677 homozygous genotype is associated with high homocysteine when riboflavin (B2) status is low. Even with a homozygous MTHFR 677 or present or one heterozygous 677 and one 1298, not all people will develop high homocysteine levels.

Homocysteine is a non-protein amino acid that is created and recycled in the methylation cycle. Sluggish enzymes in the cycle can cause elevated levels in the blood, which can cause inflammation in the blood vessels. High homocysteine has been implicated in amyloid buildup, DNA damage and cancer, mitochondrial dysfunction, cardiovascular disease, age related macular degeneration, apoptosis of neurons and depression. Stabilizing MTHFR with B2 and targeting the slow enzymes with methylfolate helps bypass it and can help maintain normal levels of homocysteine.

It is important to consider riboflavin intake, PEMT, MTR/MTRR, BHMT and CBS activity to assess overall homocysteine metabolism. Too high or too low levels of B12, B6, folate or their co-factors may cause dysregulation of methyl donor activity. The amount of methylfolate used in studies to reduce homocysteine with MTHFR variants has been 400-800mcg, and should be used with B12, B2, niacin and B6.

13 Folate-MTHFD1 G1958A

Improves Gene Function: 5-formyl-tetrahydrofolate (folinic acid) and choline

Decreases Gene Function: Folate and choline deficiency, proton pump inhibitors, birth control pills, NSAIDs, anticonvulsants, antivirals, antibiotics, and acid blockers/antacids.

Research: A meta-analysis strongly suggests that the MTHFD1 G1958A polymorphism might be associated with maternal risk for neural tube defects in Caucasian populations. However, the evidence of this association should be interpreted with caution due to the selective nature of publication of genetic association studies. Another study found that the polymorphism decreases enzyme stability and increases risk of congenital heart defects.

5-formyl-tetrahydrofolate is the second most common type of folate after methylfolate in the certain foods. This is why dietary folate is optimal because it addresses both upstream and downstream folate gene polymorphisms in the methylation cycle.

Checking MTHFR 677, SLC19A1 and PEMT genes along with MTHFD1 helps you determine your requirements for folinic acid, methylfolate and choline to help stabilize enzymatic function. B12-MTRR

Improves MTRR Gene Function: B12, B6 and folate.

Decreases Gene Function: Antacids, antibiotics, proton pump inhibitors, Metformin, anticonvulsants, oral contraceptives, certain psychiatric medications, yeast overgrowth and poor FUT2 function.

Research: Methionine synthase reductase (MTRR) is a vital enzyme of homocysteine/methionine metabolic pathway and is required for the conversion of inactive form of methionine synthase (MTR) to its active form. MTRR helps recycle B12. If MTR is working 100%, MTRR variants may be less pronounced. Variants in both MTR and MTRR may lead to issues with B12.

Several epidemiological and case control studies have reported that the GG genotype may be a risk factor for several disease/disorders like neural tube defects, Down syndrome, coronary artery disease, male infertility and cancer through sustained hypomethylation if not addressed. An additional effect is a decreased availability of folate. Several studies show that DNA hypomethylation is the main causative factor of defective gene expression.

Caucasions with late life depression who were homozygous (GG) were more likely to still be depressed after a course of SSRI antidepressant treatment compared to individuals who are homozygous at the A allele or who were AG heterozygotes. This points toward the hypothesis that factors which elevate homocysteine concentrations have an adverse effect on depression treatment response.

Heterozygous or homozygous variants in MTRR may require more B6, folate and B12 if combined with MTHFR 677 and MTR variants. If you suffer from migraines, B6, folate and B12 may be effective in reducing migraines. Research has also found B6, folate and B12 to help prevent macular degeneration. Magnesium-MAT1

Improves MAT1 Gene Function: Magnesium and boron.

Decreases Gene Function: Sugar, chronic stress, high alcohol intake, coffee, tea, fluoridated water, phosphoric acid, non-fermented grains, intense exercise, high protein diets, high calcium supplementation, high arsenic levels, antacids, proton pump inhibitors, ACE inhibitors, birth control, hormone replacement therapy, Estradiol, Premarin, antibiotics, antivirals, immunosuppressants, methylphenidate, Tamoxifen and corticosteroids.

Research: Methionine adenosyltranferases (MATs) produces S-adenosylmethionine (SAMe) via an ATP-driven process. SAMe donates methyl groups to all the neurotransmitters and functions as an anti-depressant. Adequate supplies of SAMe are crucial for maintenance of neurotransmitters and DNA synthesis. High arsenic levels may deplete

14 SAMe.

There are 8 genes tested for MAT1. If you have a majority that are heterozygous or homozygous, you may require more magnesium to produce SAMe. ATP is highly dependent on magnesium, and therefore variants in MAT may increase the need for magnesium if deficiency in present to produce sufficient SAMe along with methionine. Approximately 6-8mg of magnesium per kilogram of body weight is recommended. Betaine-BHMT

Improves BHMT Gene Function: Betaine, zinc and choline.

Decreases Gene Function: Oral contraceptives, mercury, cadmium, acid blockers, ACE inhibitors, nighttime pain relievers, antihistamines, sleep aids, antidepressants, incontinence drugs and narcotic pain relievers and malabsorption issues.

Research: If MTRR/MTR is inhibited, the compensation pathway is BHMT, increasing the dietary need for betaine and choline (converts to betaine). If fatty liver is present and there are variants in PEMT and BHMT, increasing choline and betaine rich foods can assist. This pathway can also help lower homocysteine, mainly if folate intake is low.

15 HORMONE HEALTH

Testosterone, Estrogen, Progesterone and Thyroid

RELATED GENE GENE RSID NORMAL HETEROZYGOUS HOMOZYGOUS GENE Sex Hormone Binding Globulin (SHBG) is synthesized in the liver, and in the blood it transports SHBG and regulates the access of sex steroids to their target tissues. Variants here can cause high estrogen and low progesterone in females, and low testosterone in males. Normal Variants Found DI01 DI01 is connected to thyroid health and is responsible for the deiodination of T4 into T3. DI01-rs2235544 AC DI02 is connected to thyroid health and is responsible for the deiodination of T4 into T3. D2 is DI02 the only activating deiodinase in the brain. DI02-rs225014 CT

16 HORMONE ANALYSIS

Looks Good!

17 NEUROTRANSMITTERS & MENTAL HEALTH

Serotonin, Dopamine, Norepinephrine, Epinephrine, Glutamate, GABA, Acetylcholine and APOE

18 RELATED GENE GENE RSID NORMAL HETEROZYGOUS HOMOZYGOUS GENE MAO-A (Monoamine oxidase A) is a critical enzyme involved in breaking MAO-A down important neurotransmitters such as serotonin, estrogen, norepinephrine, and dopamine. Normal Variants Found ANKK1 ANKK1 modulates the density of dopamine receptors in the brain. Normal Variants Found COMT COMT is the gene for dopamine, adrenaline and estrogen metabolism. COMT-rs5993883 GG COMT H62H-rs4633 CT COMT V158M-rs4680 AG GAD1 converts glutamate to GABA. Variants in GAD1 may cause elevated glutamate levels GAD1 depending on diet, lifestyle and other genes. 11 genes tested. GAD1-rs10432420 AG GAD1-rs3791878 GT GAD1-rs3749034 AG GAD1-rs2241165 CT GAD1-rs2058725 CT GAD1-rs701492 CT GAD1-rs3791850 AG Choline is required for acetylcholine, a neurotransmitter of the vagus nerve that enervates PEMT numerous organs. 3 genes tested. PEMT-rs7946 TT Apolipoprotein E (APOE) is a lipid binding protein that transports triglycerides and cholesterol APOE in multiple tissues, including the brain. Only the double homozygous APOE E4/E4 genotype generates a paragraph. APOE-rs429358 TT APOE-rs7412 CC BDNF is a synaptic modulator of glutamate while GABA synapses are also regulated by BDNF BDNF. BDNF-rs6265 CT

19 MENTAL HEALTH ANALYSIS

COMT-Dopamine, Adrenaline and Estrogen

Improves COMT Gene Function: Vitamin C, magnesium and copper (copper should not be too low or too high).

Decreases Gene Function: Chronic stress, proton pump inhibitors, low magnesium levels, low vitamin C levels, low and high copper levels, constipation, high serotonin levels, xenoestrogens, high homocysteine levels, high SAH levels, IPA beers (due to high amounts of hops), estrogen based medications, high calcium supplementation, mercury toxicity (mercury amalgams and too much large fish) and dietary catechol’s including too much green tea, black tea, coffee and wine.

Research: COMT (catecholamine methyltransferase) shares a pathway with MAO-A and is the gene for dopamine, estrogen and adrenaline. This pathway requires magnesium, vitamin C and copper. If you have variants in COMT V158M and COMT H62H, you may be more sensitive to chronic stress, low magnesium levels, low vitamin C levels, low or high copper levels, plastic, high calcium supplementation, mercury toxicity (mercury amalgams and too much large fish) and dietary catechol’s including too much green tea, black tea, coffee and wine.

Studies have found that the A allele in V158M results in a 40% decrease in COMT enzyme activity. This can lead to anxiety, impulsiveness, obsessive behavior, irritability (especially under stress), ADHD and abnormal behavior.

The positive side of the AA genotype is that there is a higher IQ, high creativity, better memory, drive, reading comprehension and overall cognitive function. The downside of the AA genotype is that the body overreacts to stress.

Constipation can cause the COMT enzyme to move slower, creating high estrogen/anxiety levels. Magnesium, vitamin C and are need much higher to normalize function, while copper levels are also important. Higher magnesium and vitamin C supplementation may be essential for these variants, especially in cases of constipation, high stress, ADHD, anger, fear, and trouble sleeping. GAD1-Glutamate to GABA Conversion

Improves GAD1 Gene Function: Probiotics, B6, B2, taurine, magnesium, lithium, choline, vitamin C, zinc, vitamin D, progesterone (for women), CBD oil, lemon balm, ashwagandha, exercise, meditation and deep sleep.

Decreases Gene Function: Antibiotics, caffeine, high estrogen, excessive wheat, broth cooked longer than 24 hours, excessive sugar, low blood sugar, poor sleep, manganese deficiency, boron deficiency, chronic stress, proton pump inhibitors, diuretics, hormone replacement therapy, MAOI's, fibrates, MSG, low progesterone (women), sucralose and aspartame.

Research: If you have multiple heterozygous and homozygous variants in GAD1, you may need to increase the neurotransmitter GABA and lower the neurotransmitter glutamate. GABA and glutamate account for 80% of brain activity. Glutamate is excitatory while GABA is calming. In the right amounts, glutamate helps focus, cognitive function and productivity. Too much, however, can be excitatory and damaging.

If your mind is racing at night and it keeps you from sleeping or you have had too much coffee, you have experienced high glutamate and low GABA. The reason that sugar and caffeine addiction is so high for many people is due to the excitatory feeling of glutamate, and at healthy levels it can increase learning, cognition and memory (think coffee while working or studying). However, glutamate levels that are too high with low amounts of GABA and B6 overstimulate and are excitatory to cells, leading to digestive and neurodegenerative disorders. There is also a potentially higher chance of anxiety/panic attacks from antibiotics if FUT2 gene function is compromised.

There are numerous glutamate receptors in all organs and tissues. The entire GI tract, from the esophagus to the colon, has numerous glutamate receptors. The entire electrical conducting system of the heart is replete with glutamate receptors. The lungs, the ovaries, all the reproductive systems and sperm itself, adrenal glands, bones and even calcification are all controlled by glutamate receptors. They act and operate exactly like the glutamate receptors in the brain. This is why glutamate has been linked to so many neurodegenerative disorders including heart attacks, strokes,

20 ADHD, OCD, multiple sclerosis, Huntington's disease, ALS, Parkinson’s disease, Alzheimer’s disease, dementia, glaucoma, mood disorders, IBS, Tourette’s syndrome and seizures. One study found that the GAD1 gene is associated with ADHD susceptibility, contributing particularly to the hyperactive/impulsive symptom domain. Small studies have also found that elevated glutamate levels in the brain are connected to alcohol cravings.

Excess glutamate is supposed to convert to GABA with B6 and magnesium. Numerous GAD1 variants slow down the conversion of glutamate to GABA and increase the need for B6/magnesium to make it run normally. Lithium is thought to help regulate the neurotransmitter glutamate by keeping the amount of glutamate between brain cells at a stable, healthy level. Studies have found that exercise helps the brain direct excess glutamate to be used as an energy source and prevent toxic build-up.

Research has found that variants in the GAD1 genes rs3828275 and rs3791878 were associated with an increased risk for post-traumatic epilepsy occurring less than 1 week and between 1 week and 6 months post-head injury respectively.

Natural progesterone in women (B6 helps produce progesterone) has powerful effects on enhancing GABA activity in the brain. When progesterone is too low, it causes elevated glutamate levels. Abnormalities in GABA neurotransmitter system have been noted in subjects with mood and anxiety disorders, which is why anticonvulsants are also marketed for mood disorders.

GABA also requires adequate probiotics (bifidobacterium produces large amounts of GABA, so the FUT2 gene function should also be assessed) zinc, B2, B6, vitamin C, vitamin D and deep sleep to keep glutamate in check. Taurine (found in grass-fed animal protein, wild fish and eggs) appears to increase the levels of GAD1 to reduce glutamate and help bind to GABA receptors in brain cells.

One study found that neuronal excitability from glutamate appears to be attenuated when eating or supplementing with the mushroom Lion’s Mane. Research on Lion's Mane also shows that the hot water extract stimulates the Nerve Growth Factor (part of a family of similar proteins that serve to promote the health and normal function of the brain and nervous system) and accelerates the growth of the myelin sheath. This has exciting potential for those with neurodegenerative disorders from high glutamate levels.

The artificial sweetener aspartame is especially troubling for those with GABA and glutamate imbalances. The lowered levels of serotonin due to aspartame consumption might cause lowered activity of the GABA transporters. Glutamate-BDNF

Improves BDNF Gene Expression: Running, DHA, low glycemic diet, normal levels of glutamate, lithium, acetylcholine, sunlight and heat exposure, bifidobacterium longum, intermittent fasting, turmeric, and estradiol (women).

Decreases BDNF Gene Function: Chronic stress, high blood sugar and head injuries.

Research: BDNF (brain-derived neurotrophic factor) is the most important protein abundantly expressed in brain functions related to repair, spatial learning, episodiac memory, and adaptability.

BDNF is a synaptic modulator of glutamate while GABA synapses are also regulated by BDNF. Therefore, BDNF regulates glutamate release and regulates glutamate receptor function. Chronic stress leads to decreased BDNF expression in the hippocampus, leading to enhanced anxiety-related behaviors.

There is building evidence that shows impaired glutamate synapses where compromised BDNF function has been observed such as Alzheimer’s, Parkinson’s, Huntington's disease, depression, bipolar disorder, and anxiety with the BDNF polymorphism Val66Met. It should be noted that a 2015 meta-analysis did not find a correlation with BDNF val66met and Alzheimer’s disease.

BDNF is present in many regions of the central nervous system, including the hippocampus, cerebral cortex, cerebellum, hypothalamus, substantia nigra, amygdala and spinal cord. The CT and TT genotypes have lower secretion and blood levels of BDNF and research suggests that upregulating BDNF-activated pathways may be therapeutically relevant.

Evidence suggests that a decrease in hippocampal BDNF may account for the cognitive deficits and the impairment of

21 memory in depression and anxiety disorders. Another study with depressed patients with BDNF polymorphisms found that the individuals with heterozygous or homozygous genotypes were significantly associated with increased risk of suicidal behavior.

A 2012 and 2017 study found that episodic memory improves as maximal oxygen capacity increases. Aerobic activity induces structural change in hippocampal volume and vasculature, responsible for episodic memory. It is the hippocampus that displays dramatic volume changes in disease states such as Alzheimer’s disease and depression.

Mice studies have shown that the hormone irisin is generated by the muscles during endurance exercise and is responsible for producing BDNF. Further research has found that running produces a higher levels of neurogenesis compared to resistance training and high-intensity training.

Exercise has been shown to cause a rise in serum BDNF and is especially enhanced in the heat. Since permeability of the blood-brain barrier increases with exercise in the heat, the hypothesis was raised that this causes a higher cerebral output of BDNF.

Research also found that BDNF levels are equally decreased in bipolar disorder during the occurrence of manic and depressive episodes. An interesting connection here is that when glutamate plummets, depression occurs. When glutamate spikes, mania occurs. If BDNF is suppressed, glutamate modulation is compromised.

An example of low glutamate can be seen in female patients with depression that have been found to have abnormally high expression levels of many genes that regulate the glutamate system. Recent studies found that a low dose of the drug ketamine, which alters glutamate system activity, can rapidly eliminate depression in two-thirds of patients who do not respond to conventional antidepressants. Conventional antidepressants target the monoamine (MAO) systems, which secrete the neurotransmitters dopamine, serotonin or norepinephrine.

In a 2017 study of 458 soldiers, those with the BDNF Met/Met genotype (homozygous TT), 57.9 percent had a history of one or more prior concussions, compared with 35.6 percent of those with other BDNF genotypes. Those with the BDNF Met/Met genotype also reported greater aggression and hostility personality characteristics. When combined in a predictive model, prior military deployments, being male, and having the BDNF Met/Met genotype were independently associated with increased lifetime history of concussions in active-duty soldiers.

Low levels of BDNF have been shown in research to cause impaired glucose metabolism, highlighting the blood sugar connection of type 2 diabetes to dementia and depression in epidemiological studies. Other studies have found high BDNF levels in those who already have Type 2 diabetes, with researchers hypothesizing that BDNF tries to overcompensate to reduce insulin and glucose levels, as has been found when BDNF is injected into diabetic rats.

When reviewing your genetic analysis, it is important to also look at the genes PEMT, APOE, GAD1, SLC17A7, TCF7L2, FADS2, and TCN2 to see how BDNF is most affected, and where you need to focus most nutritionally.

22 INFLAMMATION & ANTIOXIDANT PROTECTION

SOD2, SOD3, Glutathione Genes, Catalase and Nitric Oxide

23 RELATED GENE GENE RSID NORMAL HETEROZYGOUS HOMOZYGOUS GENE Superoxide dismutase (SOD2) is manganese dependent and protects against superoxide SOD2 for the mitochondria of the cell. Variants here increase the need for intracellular antioxidant protection. 2 genes tested. SOD2-rs2758331 AC SOD2-rs4880 AG CAT makes an enzyme called catalase, which helps reduce oxidative stress. 18 genes CAT tested. Normal Variants Found CAT-rs2300181 CT CAT-rs7933285 CT CAT-rs2073058 AG CAT-rs10488736 CT Glutathione S-Transferase (GSTM1) is linked to the metabolism of mutagens, GSTM1 carcinogens, and other poisonous chemicals, and plays a crucial role in the detoxification process. GSTM1 is connected to lung health. Normal Variants Found Glutathione S-Transferase (GSTP1) is linked to the metabolism of mutagens, GSTP1 carcinogens, and other poisonous chemicals, and play a crucial role in the detoxification I105V process, thereby protecting cells from these compounds. GSTP1 is connected to prostate, lung and breast health. Normal Variants Found The GPX1 (Glutathione peroxidase 1) gene encodes a protein responsible for the GPX1 modulation and detoxification of hydroperoxides and hydrogen peroxide to protect the mitochondria and cytoplasm of cells against oxidative damage. GPX1-rs1050450 AG This gene encodes the mitochondrial form of a B6 dependent enzyme responsible for SHMT2 glycine synthesis. Normal Variants Found The CTH (Cystathionine Gamma-Lyase) gene encodes an enzyme in the trans-sulfuration CTH pathway that converts cystathionine derived from methionine into cysteine. Glutathione synthesis in the liver is dependent upon the availability of cysteine. CTH-rs1021737 GT NOS1 (nNOS) codes for brain neural transmission, memory, learning, psychological NOS1 stress, the peripheral nervous system and potentially the lymph nodes. 4 genes tested. NOS1-rs2293054 AG NOS1-rs545654 CT NOS2 (iNOS) codes for wound, tissue damage, infection and hypoxia (low oxygen). 3 NOS2 genes tested. NOS2-rs2248814 AG

24 RELATED GENE GENE RSID NORMAL HETEROZYGOUS HOMOZYGOUS GENE Variants in the HFE genes may lead to an iron overload due to increased iron absorption HFE-H63D and disrupted metabolism. Normal Variants Found CFH (complement factor H) polymorphism is associated with increased risk of age related CFH macular degeneration (AMD). Normal Variants Found ARMS2 polymorphism is associated with increased risk of age related macular ARMS2 degeneration (AMD). ARMS2-rs10490924 GT

ANTIOXIDANT ANALYSIS

Cell Protection-SOD2

Improves SOD2 Gene Function: Manganese, vitamin, A, C, E, omega-3 fatty acids, CoQ10, boron, lutein, lycopene, cordyceps, holy basil, reishi and cryotherapy.

Decreases Gene Function: Glyphosate, fluoridated water, chronic stress, poor sleep, shallow breathing, high iron levels and food dyes.

Research: SOD2 is superoxide dismutase, which protects against the inflammatory superoxide inside the cell for the mitochondria (power house of the cell). SOD2 is manganese dependent, and adequate intake is important. Manganese is crucial for heart health, blood sugar, male fertility, bone health and protecting the brain against glutamate toxicity.

Exercise also helps improve SOD2 activity. Studies show exercise intensity can reduce cardiac arrhythmias and myocardial infarction due to improved SOD2 function. Glutathione level and activity of antioxidant enzymes (catalase, superoxide dismutase, glutathione peroxidase and glutathione reductase) have been found to be increased in yoga practitioners. One year of Tai Chi training has been reported to promote superoxide dismutase activity and lessen lipid peroxidation.

One study found that young men exposed to cryotherapy for 3 minutes at -202°F (−130°C) everyday for 20 days doubled the activity of one the antioxidant enzyme glutathione reductase, and increased superoxide dismutase by 43%.

Chronic stress, poor sleep, shallow breathing and food dye consumption are examples of ways intracellular inflammation can occur. Food dyes have been found to inhibit mitochondrial respiration; the ability of the powerhouse of your cells to convert nutrients to energy and food dyes are often used ironically in sports drinks and multivitamins.

Variants in SOD2 increase the need for manganese to protect the mitochondria and lactobacillus in the gut. Colitis has been linked to impaired SOD2 genes.

Vitamin, A, C, E, omega-3 fatty acids, cordyceps and reishi help protect mitochondria against intracellular superoxide in red blood cells.

Fluoride decreases SOD2 activity in studies, and 75% of the water in the U.S. is fluoridated compared to 3% of western Europe. Reverse osmosis systems remove fluoride from water. Here is a link for more about fluoride and portable

25 systems to reduce fluoride. Glutathione-GPX1

Improves GPX1 Gene Function: Testosterone, estradiol, selenium, melatonin, vitamin C, vitamin E, black cumin seed oil, flavonoids, ginger, cumin, anise, fennel, caraway, cardamom and cryotherapy.

Decreases Gene Function: Statin drugs, iron deficiency or elevated iron, and lead.

Research: Superoxide dismutase (SOD) transforms the inflammatory superoxide to hydrogen peroxide (H2O2), and the next step is for glutathione peroxidase (GPX1) to transform it to water (H2O). When GPX1 function is modulated by polymorphisms and other factors affecting its function, a hydroxyl radical may be more likely to form which attacks DNA and causes strand breaks.

Statins inhibit the biosynthesis of selenium containing proteins, one of which is glutathione peroxidase serving to suppress peroxidative stress. An impairment of selenoprotein biosynthesis may be a factor in congestive heart failure, reminiscent of the dilated cardiomyopathies seen with selenium deficiency. A meta-analysis found that East Asian populations may be prone to cardiovascular issues with GPX1 polymorphisms.

One study found that elite kayakers that engaged in whole body cryotherapy (-248 to 284°F or -120 to 140°C) for 3 minutes a day for 10 days increased the activity of superoxide dismutase by 36% and glutathione peroxidase by 68%. Glutathione -CTH

Improves CTH Gene Function: Folate, B2, B6, B12 and cysteine.

Decreases Gene Function: High homocysteine and oxidative stress.

Research: Cysteine is an important amino acid for glutathione. Variants in CTH may increase the need for dietary cysteine. Homozygotes for this gene also had significantly higher mean plasma homocysteine concentration than subjects with other genotypes, and the effect sizes of CTH and MTHFR genotypes were similar.

Oxidative stress has been suggested as a mechanism of autism. A three-SNP joint effect was observed for genotype combinations of SNPs in glutaredoxin, glutaredoxin 3 (GLRX3), and cystathionine gamma lyase (CTH). These results suggest that variation in genes involved in counterbalancing oxidative stress may contribute to autism, though replication is necessary.

If you have the homozygous variant in CTH, you may require more cysteine-rich foods and need to focus on other genes in lowering homocysteine and boosting glutathione. Nitric Oxide -NOS1

Improves NOS1 Gene Function: Carotenoids, polyphenols and DHA.

Decreases Gene Function: Psychological stress and pesticides.

Research: Nitric oxide acts as a neurotransmitter, neuromodulator, vasodilator, anti-microbial, ant-tumorigenic, insulin secretions, peristalsis, inhibiting calcium entry into the cell, increasing potassium channels and decreasing intracellular calcium.

NOS1 has a role in the regulation of the serotonin pathway, the HPA axis and psychological stress. Chronic stress increases NOS1 expression in many parts of the brain, including the hippocampus (affecting emotion and memory). Recent studies have reported gene-specific and global changes in DNA methylation in response to psychological stress in humans. Chronic psychosocial stress has been associated with accelerated aging at the cellular level including shortened telomeres, low telomerase activity, decreased anti-oxidant capacity and increased oxidative stress.

26 Variants in NOS1 may benefit from balancing the HPA axis (primary stress response system) and polyphenol consumption. There is considerable evidence showing that cellular oxidative damage occurring in Parkinson's disease might result also from the actions of altered production of nitric oxide. Polyphenols modulate neuroinflammation by inhibiting the expression of inflammatory genes and the level of intracellular antioxidants.

NOS1 also plays a role in oxidative stress and cancer prevention. For oxidative stress, interactions were found between pesticides, SOD3 and the NOS1 SNPs rs12829185, rs1047735, and rs2682826. If you have numerous variants in these NOS1 genes along with SOD3 and PON1, you want to focus on eating organic to reduce pesticide exposure and focusing on red, orange and yellow vegetables. The foods correlated in research to improved NOS1 function include carrots, tomatoes, squash, corn, orange peppers, red peppers, yellow peppers, pumpkin, red beets, red onions, yellow beets and sweet potatoes to offset oxidative stress. One study found that carriers of the variant allele for NOS1 (rs2293054) that had the highest intake of these foods had a 50% reduced risk of non-Hodgkin's Lymphoma and up to 30-70% reduced risk of diffuse large B-cell lymphoma. Nitric Oxide -NOS2

Improves NOS2 Gene Function: Eggs, coconut, walnuts, almonds, sunflower seeds, pumpkin seeds, sesame seeds, seaweed, whey protein, cordyceps mushrooms.

Decreases Gene Function: Heavy metals, vegetable oils, high blood sugar, high acidity and poor breathing habits.

Research: Nitric oxide acts as a neurotransmitter, neuromodulator, vasodilator, anti-microbial, ant-tumorigenic, insulin secretions, peristalsis, inhibiting calcium entry into the cell, increasing potassium channels and decreasing intracellular calcium. You can trace many systemic inflammatory disorders to nitric oxide going haywire.

NOS2 codes for wound, tissue damage, infection and hypoxia (low oxygen). When you feel neck, shoulder and back spasms, this is nitric oxide uncoupling. The uncoupling leads to superoxide, the adversary leading to high levels of inflammation.

Nitric oxide uncoupling occurs due to chronic stress, poor diet and environmental stressors including heavy metals, vegetable oils, high blood sugar, high acidity and poor breathing habits.

Heterozygous or homozygous variants in NOS2 may benefit from cordyceps to prevent hypoxia and whey protein to normalize NOS levels, lower oxidative stress and increase wound healing. Whey protein was found to significantly decrease the levels of nitric oxide (NO) and ROS and significantly decrease the time required for wound healing.

27 DETOXIFICATION: DRUG AND TOXIN SENSITIVITY

28 GENE GENE GENE RSID NORMAL HETEROZYGOUS HOMOZYGOUS FUNCTION In the estrogen pathway along with CYP1B1, CYP1A2, CYP31A, SULT’s and COMT. CYP1A1 CYP1A1 is involved in the metabolism of benzopyrene, a suspected cause of lung cancer. Normal Variants Found CYP1A2 CYP1A2 metabolizes various environmental procarcinogens, such as heterocyclic C164A amines, nitrosamines, and aflatoxin B1. CYP1A2 C164A- AA rs762551 CYP2A6 is expressed in the liver, lung, trachea, nasal mucosa, and sex organs such CYP2A6*2 as breast. This enzyme metabolizes oral contraceptives, dexamethason, phenobarbital C164A and nicotine. Normal Variants Found CYP1B1 The CYP1B1 polymorphism is an ultra rapid metabolizer, and metabolizes pro- N453S carcinogens such as polycyclic aromatic hydrocarbons and 17 beta-estradiol. Normal Variants Found CYP1B1*6 L432V- GG rs1056836 CYP2C9*2 CYP2C9 *2 and *3 variants increase sensitivity to Warfarin, sulfonylurea, hypoglycemic C430T drugs NSAIDS due to reduced clearance. Normal Variants Found CYP2C9*3 A1075C- AC rs1057910 CYP2D6 CYP2D6 metabolizes many beta blockers, antidepressants, and opioids. T2850C CYP2D6 T2850C- AG rs16947 Research has identified CYP2E1 as the primary P450 isozyme CYP2E1*4 responsible for benzene metabolism at low concentrations and acrylamide to A4768G glycidamide. Normal Variants Found The CYP3A4 enzyme is involved in the metabolism of approximately 50% of drugs that CYP3A4*1B are used today, cholesterol homeostasis, and the oxidative deactivation of testosterone. Normal Variants Found CYP2C19*17 metabolizes phenytoin (Dilantin), amitriptyline, phenobarbital, CYP2C19*17 omeprazole (Prilosec), Clopidogrel and other drugs. Normal Variants Found The COQ2 gene encodes an enzyme that functions in the final steps in the COQ2 biosynthesis of CoQ10 and homozygous variants increase the risk of statin induced myopathy. Normal Variants Found

29 DETOX ANALYSIS

Liver Enzyme-CYP1A2

Improves CYP1A2 Gene Function: Unfiltered fermented drinks (Kombucha, beer, wine), hops, marinades, cruciferous vegetables, blueberries, blackberries, red grapes, kiwi, watermelon, parsley, and spinach.

Decreases Gene Function: Heterocyclic amines, nitrosamines, aflatoxin B1, polycyclic aromatic hydrocarbons, dioxins, and β-naphthoflavone. Omeprazole and primaquine are inducers. Caffeine and Tylenol combined with these compounds can make the effect worse.

Research: Approximately 200 polymorphisms exist in CYP1A2 gene region, with numerous studies focusing on rs762551. If you have a homozygous (AA) CYP1A2 you want to reduce heterocyclic amines, nitrosamines and alfatoxin B1.

The cytochromes P450 liver enzymes play an important role in the development of various cancers, since they are involved in the metabolic transformation of numerous endogenous and exogenous compounds including carcinogens. CYP1A2 is a key factor in the metabolic activity of carcinogenic aromatic and heterocyclic amines, and researchers have found that the inhibition activity of this enzyme may represent a logical strategy for preventing the development of human cancers induced by the aromatic and heterocyclic amines.

Heterocyclic amines (HCA’s) are created by high heat reacting with the proteins. The way to reduce HCA’s is to use marinades. Marinades reduce HCA's by up to 90 percent. For further protection, pair with cruciferous vegetables (especially fermented like sauerkraut) and an unfiltered beer or Kombucha due the protection of the yeast. Red wine, blueberries, blackberries, red grapes, kiwi, watermelon, parsley, and spinach all inhibit the mutagenic activity of certain HCAs in vitro.

High antioxidant fruits, lemon juice, herbs and spices help keep meat fresh and juicy, while protecting against HCAs and reducing AGE’s.

Grass-fed meat is higher in vitamin E, and in a study adding concentrations of vitamin E to the surface of ground beef reduced HCA production by 70%. Aim for medium to medium rare for red meat, flip often and avoid burning. The darker the color the higher the HCA concentrations.

Nitrosamines are used in pesticides, created by frying meat, and from a conversion in the gut by nitrites from cured meats. Vitamin C prevent nitrites from becoming nitrosamines. Limit cured meat consumption using nitrites and take vitamin C when needed.

Aflatoxin B1 is the most common in food and amongst the most potent genotoxic and carcinogenic. It can occur in grain- fed milk, nuts/grains stored in hot conditions or bins, vegetable oils, cocoa or coffee beans stored in warm conditions, and dried fruit. I don’t recommend Brazil nuts because they are prone to aflatoxin contamination. Choose nuts and seeds in sealed bags, preferably sprouted. You also want to minimize or avoid oats (unless tested free of ochratoxin). Low protein diets may increase the toxicity of alfatoxin and promote cancerous growth.

Hops in beer contain a flavonoid called xanthohumol, which strongly inhibits CYP1A2. Xanthohumol has anti- carcinogenic properties and has been found to scavenge reactive oxygen species, including hydroxyl- and peroxyl radicals, and to inhibit superoxide anion radical and harmful nitric oxide production.

CYP1A2 is the main liver enzyme involved in metabolizing the drug clozapine. Case studies have shown ultra-rapid

30 metabolizers (AA genotype) of clozapine that presented as resistant to treatment. Liver Enzyme-CYP1B1

Improves CYP1B1 Gene Function: Apigenin, quercetin, myricetin, ghee, chrysoeriol (rooibos tea and celery) vitamin C and resveratrol.

Decreases Gene Function: Heterocyclic amines, xenoestrogens, vegetable oils, grains, fried meat, excess of smoked foods, cigarette smoke exposure and exhaust.

Research: If you have a heterozygous or homozygous variant in CYP1B1, you want to reduce xenoestrogens, vegetable oils, grains, fried meat, smoked foods, cigarette smoke exposure and exhaust.

Due to the carcinogenic activation of polycyclic aromatic hydrocarbons and estrogens to genotoxic catechol estrogens - both which cause DNA mutations - this gene is important for breast, ovarian, colon, lung and prostate health. This is especially true for those with variants in GSTM1 and GSTP1. Minimizing polycystic aromatic hydrocarbons, xenoestrogens and high estrogen levels in the body is a priority for CYP1B1.

It has been demonstrated in studies that the metabolic hydroxylation of resveratrol by CYP1B1, results in its conversion to piceatannol, a tyrosine kinase inhibitor and a compound of known anticancer activity.

Inhibition of CYP1B1 activity was observed for the flavonols quercetin, apigenin and myricetin.

Chrysoeriol, present in rooibos tea and celery, acts selectively to inhibit CYP1B1 in vitro and may be especially relevant to patients with CYP1B1 overactivity.

31 DNA PROTECTION, DAMAGE AND REPAIR

ATM, TP53, MDM2 and MLH1 GENE GENE GENE RSID NORMAL HETEROZYGOUS HOMOZYGOUS FUNCTION ATM ATM coordinates DNA repair by activating enzymes that fix the broken strands. Normal Variants Found ATM-rs664677 CT ATM-rs1801673 AT ATM-rs664143 AG Variants in the MDM2 gene encode a protein that reduces cellular levels of the p53 tumor MDM2 suppressor protein. Normal Variants Found TP53 TP53 is a tumor suppressor gene responsible for DNA repair. TP53-rs1042522 CC MLH1 MLH1 codes for a DNA repair enzyme linked to colon health. Normal Variants Found

32 DNA REPAIR ANALYSIS

DNA Repair-ATM

Improves ATM Gene Function: Folate, higher nut, vegetable and fruit intake, exercise, and intermittent fasting (waiting 13-16 hours to eat from dinner to breakfast).

Decreases Gene Function: Smoking, obesity (especially abdominal fat), diabetes, binge drinking, chronic pancreatitis, heterocyclic amines, polycyclic aromatic hydrocarbons and isolated fructose.

Research: People who have a homozygous ATM gene will benefit from nutrients that have been found in studies to improve DNA repair in regards to pancreatic health and breast health. While early studies linked ATM gene variants to breast health, further research has shown conflicted results, with ATM homozygous variants being most relevant when coupled with other genes like BRCA-1 and BRCA-2 and familial breast cancer.

DNA repair is needed when cells are harmed by sunburns, chemicals, toxins and stress. Efficient repair of damaged DNA strands helps maintain the stability of the cell's genetic DNA. DNA repair enzymes are typically working poorly in families with a lot of cancer and require more support. Nutrition plays a major role in DNA repair enzymes.

Pancreatic Health

Studies have found that a high dietary intake of fresh fruit and vegetables reduced the risk of developing pancreatic cancer, and recent epidemiological studies have associated nut consumption with a protective effect against it.

One cohort study found a significantly decreased risk of pancreatic cancer by 55% for the highest levels of dietary folate compared with the lowest. Another cohort found that the highest blood folate levels showed a significantly decreased risk compared to the lowest. Folic acid supplements did not show a protective effect in these studies.

Breast and Ovarian Health

If breast cancer runs in your family and you have done BRCA testing, the following research will be helpful in your nutrition plan. BRCA-1 and BRCA-2 are tumor suppressor genes that are responsible for DNA repair and linked to breast and ovarian health. It is the reduced function with certain variants that causes impaired DNA repair. Most breast cancers that occur in women with BRCA1 mutations are estrogen receptor-negative (ER-) and typically lack expression of progesterone receptor (PR) and human epidermal growth factor receptor (HER) 2 overexpression (so-called 'triple- negative' breast cancers).

Research has found that women with the BRCA-1 and BRCA-2 mutations who consumed up to 27 different fruits and vegetables a week (variety important) saw their cancer risk diminish by fully 73 percent. Selenium and choline have both been found to improve BRCA-1 and BRCA-2 function and lower the risk of breast cancer. Iodine also plays a special role in breast health. Check your PEMT gene function to see your need for choline.

The compound luteolin found in celery, broccoli, thyme and parsley was found in animal studies to kill cancer cells, stop triple-negative cells spreading to the lungs and block spreading throughout the body.

Lignans are highest in flax seeds and research shows that women who have the highest level of lignans in their body have the lowest risk of breast cancer. In postmenopausal women, lignans can cause the body to produce less active forms of estrogen.

Animal studies have shown that both flaxseed oil and lignans can reduce breast tumor growth and spread, even for ER negative cancer cells. One study in mice concluded that flaxseed inhibited the growth of human estrogen-dependent breast cancer.

33 Another study found that enoki mushroom extract was shown to inhibit the growth of both estrogen-receptor positive (ER+) MCF-7 and estrogen-receptor negative human breast cancer cell lines. Furthermore, the extract inhibited breast cancer cell colony formation by 99%. DNA Repair-TP53

Improves TP53 Gene Function: Vitamin C, niacin, reishi, zinc and selenium.

Decreases Gene Function: Excessive sun exposure in females.

Research: TP53 is a tumor suppressor gene responsible for DNA repair. A heterozygous Tp53 may only be relevant when combined with variants in MDM2.

Researchers analyzed rs1042522 in 4,029 people from 67 populations located throughout eastern Asia, from 11° south of the equator (Indonesia) to 65° north (northern China). They found that the C version of this SNP is more common at higher latitudes, as was expected based on the work in European and African populations.

Researchers postulated that the C allele would have been an advantageous adaptation for fertility in colder climates to activate LIF, a gene important for embryo implantation in the womb.

Variants in Tp53 combined with the homozygous GG genotype of MDM2 may increase the need for niacin, zinc and selenium to improve DNA repair.

Research has found that zinc is involved in the structural stabilization and activation of Tp53 that appears to be an important component of the programmed cell death. Research has also found that selenium may be protective by preventing DNA damage from occurring as well as by increasing the activity of repair enzymes such as DNA glycosylases and DNA damage repair pathways that involve p53, BRCA1 and Gadd45.

One study found that niacin supplementation elevated skin NAD content, which is known to modulate the function of DNA strand scission surveillance proteins p53 and poly(ADP-ribose) polymerase, two proteins critical in cellular responses to UV-induced DNA damage. Dietary supplementation with 0.1%, 0.5%, or 1.0% niacin reduced the control incidence of skin cancer from 68% to 60%, 48%, and 28%, respectively, at 26.5 weeks after the first UV treatment.

34 CARDIOVASCULAR HEALTH AND ATHLETIC PERFORMANCE

Blood Pressure, Blood Clots, Caffeine, Stress, Muscle Strength, Lp(a) CRP, PON1, Aerobic Performance, Vitamin D, K2, Muscle Injury, and Muscle Recovery

35 GENE GENE GENE RSID NORMAL HETEROZYGOUS HOMOZYGOUS FUNCTION ADD1 Variants in ADD1 are associated with hypertension. Normal Variants Found GAMT GAMT encodes for the creatine enzyme to produce muscle strength. Normal Variants Found Variants in NOS3 (eNOS) are associated with hypertension and glaucoma. 3 genes NOS3 tested. NOS3-rs1800783 AT NOS3-rs1800779 AG NOS3-rs3918188 AC Beta-2 adrenergic receptor (ADRB2) is abundantly expressed in cardiac cells, and ADRB2 bronchial smooth muscle cells and is connected to stress levels and heart health. Normal Variants Found ADRB2-rs1042714 GG F5 Variants in F5 increase the risk of deep vein thrombosis, especially if using birth control. Normal Variants Found ESR2 codes for estrogen receptor beta (ER-β), one of two main types of estrogen ESR2 receptor activated by estrogen and is linked to fibrinogen levels in post-menopausal women. ESR2-rs4986938 CT Lp(a)is a sticky form of LDL that appears to affect plaque growth, LDL particle size and LPA increase the risk of plaque rupture and blood clotting. Normal Variants Found 9p21 is considered an important genetic marker for cardiovascular health. 6 genes 9p21 tested. 9p21-rs4977574 AG CYP1A2 Variants in CYP1A2 determine caffeine metabolism and effects on bone density and C164A cardiovascular health. CYP1A2 C164A- AA rs762551 FADS1 is involved in fatty acid metabolism, and variants in this gene are linked to FADS1 elevated triglyceride levels. Normal Variants Found Variants in VOKRC1*2 may increase the need for vitamin K2 and a sensitivity to dosing VKORC1*2 of the drug Warfarin. Normal Variants Found It has been demonstrated that variants in the PPARGC1A gene affect the exercise- PPARGC1A induced change in maximal oxygen uptake (VO2). PPARGC1A-rs8192678 TT

36 GENE GENE GENE RSID NORMAL HETEROZYGOUS HOMOZYGOUS FUNCTION IL6 is an interleukin that acts as both a pro-inflammatory cytokine and an IL6 anti-inflammatory myokine. IL6-rs1800795 CC COL1A1 produces alpha 1 chain of type I collagen, a major protein in tendons and COL1A1 ligaments. COL1A1-rs1800012 CC Tumor necrosis factor (TNF-α) is a pro-inflammatory cytokine with a potent catabolic TNFA effect on muscle. Normal Variants Found CYP2R1 CYP2R1 is connected to circulating vitamin D levels. CYP2R1-rs12794714 AG Vitamin D is technically a hormone. Vitamin D receptor (VDR) is found in most cells, not VDR Taq just those involved with bone and mineral homeostasis. VDR Taq-rs731236 AG VDR -rs1544410 CT PON1 (Paraoxonase) plays a large role in removing pesticides. It is also involved with PON1 supporting HDL function and LDL oxidation. Normal Variants Found

CARDIOVASCULAR AND ATHLETIC ANALYSIS

Omega-3 Fatty Acids-NOS3

Improves NOS3 Gene Function: Omega-3 fatty acids for elevated triglycerides and estrogen for post-menopausal women.

Decreases Gene Function: High blood sugar, high blood pressure, heavy metals, high carbon monoxide exposure, vegetable oils, chronic stress, shallow breathing and very low estrogen in women.

Research: NOS3 codes for endothelial nitric oxide synthase. The uncoupling of NOS has been linked to play an essential role in cardiovascular pathologies including dilated cardiomyopathy, ischemia reperfusion injury, endothelial dysfunction, atherosclerosis, hypertension and diabetes. The uncoupling leads to superoxide, a potentially dangerous adversary leading to high levels of inflammation. This is especially true if you have multiple variants in SOD2 and SOD3.

NOS3 may also play a role in the etiology of glaucoma; it is found in the human outflow pathway and the vasculature supplying retinal ganglion cells, which may affect the regulation of intraocular pressure and blood flow to the optic nerve. Estrogen may modulate intraocular pressure by upregulating NOS3, thereby enhancing the release of nitric oxide to

37 regulate blood flow to the optic nerve. Early menopause has been associated with an increased risk of primary open angle glaucoma (POAG), and the use of estrogen with progestin was associated with a reduced risk of POAG.

Menopause is accompanied by a dramatic rise in the prevalence of hypertension in women, suggesting a protective role of endogenous estradiol on blood pressure.

If you have a homozygous variant in NOS3, you may be more responsive to omega-3 supplementation to lower triglycerides which also lowers blood pressure. Stress-ADRB2

Improves ADRB2 Gene Function: Deep breathing techniques, magnesium and vitamin C.

Decreases Gene Function: Chronic stress and shallow breathing.

Research: ADRB2 activation regulates various biological functions, including heart rate, blood pressure or respiration, and it may modulate the vasodilatation in normal coronary arteries.

If you have heterozygous or homozygous variants in ADRB2 and cardiovascular disease runs in your family, you may be more prone to high blood pressure and arterial damage from stress. You may also be more sensitive to beta blockers, leading to high triglycerides.

Since ADRB2 is connected to catecholamine epinephrine, it is also important to look at your COMT function. Magnesium, vitamin C and adaptogens should be considered while making lifestyle changes and strategies if chronic stress is present.

Relaxation techniques that involve slow, deep breathing have been found to be an effective therapeutic intervention that counteracts the adverse clinical effects of stress in disorders including hypertension, anxiety, insomnia and aging. Caffeine-CYP1A2

If you have the normal genotype CC and and cardiovascular disease runs in your family, caffeine may be a compounding factor for risk in the CC genotype because caffeine is metabolized at a slower rate. People with the CC genotype have also been found to have elevated fasting blood sugar from caffeine consumption.

Individuals who are homozygous for the CYP1A2 AA allele are "rapid" caffeine metabolizers, whereas carriers of the variant CYP1A2 CC alleles are "slow" caffeine metabolizers.

For the AA genotype, caffeine decreased 40-km time in cyclists by an average of 3.8 minutes in the AA homozygotes as compared to 1.3 minutes in the C allele carriers.

Over 4 cups of coffee daily may lower bone density in males but not females. Intake of coffee was associated with an increased risk of nonfatal heart attacks only among individuals with slow caffeine metabolism (CC), suggesting that caffeine plays a role in this association.

If you are the CC genotype and you drink coffee, you should consider limiting coffee intake to 1 cup daily. VO2 Max-PPARGC1A

Improves PPARGC1A Gene Function: Cold water exposure, aerobic exercise, ashwagandha and eleuthero root.

Decreases Gene Function: Sedentary lifestyle.

Research: Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A) is a master regulator of mitochondrial biogenesis, mitochondrial respiration, skeletal muscle fiber transformation (from fast to slow twitch), glucose and fatty acid metabolism, and the anti-oxidation machinery. PPARGC1A is expressed in cell types with high oxidative function (heart, skeletal muscle slow- twitch fibers, liver, and pancreas) and in brown adipose tissue.

38 Several studies have shown that SNPs in PPARGC1A are associated to a significant lower level in aerobic power (i.e., VO2 max) in insulin resistant and untrained individuals as well as in athletes. Healthy untrained adults display a large individual variation in VO2 max that ranges from -20% to more than 50%.

Research indicates that the exercise-induced variation in VO2 max is 47% explained by genetics. If you have heterozygous or homozygous variants in PPARGC1A, you may have a naturally lower VO2 max for aerobic exercise and increased CRP (C-reactive protein) levels.

To increase VO2 max, consider cold exposure. Since mitochondria are what give us the ability to use oxygen in order to produce cellular energy, the more we have the more the aerobic potential.

Cold exposure activates the PPARGC1A gene and PGC1α protein, which makes more mitochondria in the muscle. One study found that 15 minute exposure to cold water (50°F or 10°C) following high intensity running, increases PGC1α in muscle tissue. Another study found that men that were immersed in cold water at 50°F (10°C) for 15 minutes 3 times a week for four weeks after running were able to increase mitochondrial biogenesis occurring in their muscle tissue.

Adaptogens are another way to increase your VO2 max. One study found that ashwagandha increased velocity, power, VO2 max, lower limb muscular strength and neuromuscular coordination. A second study used elite Indian cyclists for 8 weeks. One group received 500mg of the root extract 2x a day, while the other group received a placebo. There was significant improvement in the experimental group in all parameters, namely, VO2 max and time for exhaustion on treadmill.

A study using eleuthero root found that using 800mg for 8 weeks increased VO2 max of by 12%, endurance time improved 23%, the highest heart rate increased 4%, and metabolism was altered which spared glycogen storage. The study concluded that “this was the first well-conducted study that shows that 8-week ES supplementation enhances endurance capacity, elevates cardiovascular functions and alters the metabolism for sparing glycogen in recreationally trained males.” Muscle Recovery-IL6

Improves IL6 Gene Function: Vitamin C, curcumin, ginger, dandelion, broth and cryotherapy.

Decreases Gene Function: Depression, bacterial overgrowth and workout routines without enough recovery days.

Research: Exercise increases IL6 cytokines even when muscle damage hasn't occurred. It is produced in large amounts during heavy weight lifting and endurance races. The GG genotype is associated with lower levels of inflammation and the GC/CC genotypes may have slower recovery times after workouts, and require more post-workout anti-inflammatory support.

In one study, sixty healthy, trained women, aged 13-25 years, were enrolled in the six-week investigation and randomly categorized into three groups (cinnamon, ginger or placebo) and received 3 g of ginger, cinnamon or placebo powder each day, depending on the group they belonged to. The IL-6 level and Likert Scale of Muscle Soreness were evaluated at the beginning and the end of the study and compared among the groups.

Six weeks of 3 g of dietary ginger and cinnamon, on consecutive days, reduced the plasma levels of IL-6 caused by eccentric exercise in female martial athletes, and 3 g of ginger also effectively reduced muscle soreness, but this finding was not supported by 3 g of cinnamon consumption.

One study had professional tennis players engage in whole body cryotherapy (184°F or 120°C)twice a day (in the morning and evening while training in the afternoon) for five days had a 2.5-fold decrease in the potent pro-inflammatory cytokine TNF-alpha and a 23% decrease in the cytokine IL6.

If you suffer from osteoarthritis, vitamin C, broth or collagen powder and MSM supplementation may provide relief. The polymorphism of gene encoding IL-6 may predetermine the development of osteoarthritis. The effect of IL-6 on joint cartilage is not different from other cytokines and, in synergy with them, causes a decrease in the production of type II collagen and increases the production of enzymes.

39 Muscle Injury-COL1A1

Improves COL1A1 Gene Function: Vitamin C, glycine, proline, lysine, B6 (all precursors to collagen production) and cryotherapy.

Decreases Gene Function: Deficiencies in the amino acids and vitamins above, and excessive NSAID use.

Research: According to one study, the gene encoding for the alpha1 chain of type I collagen (COL1A1) has been shown to be associated with cruciate ligament ruptures and shoulder dislocations.

ACL ruptures are considered the most severe injury sustained in sports. The T variant produces more COL1A1. Two TT’s reduced risk of ACL rupture by ten times, while only 5% have two TT’s.

Cryotherapy has been shown to inhibit harmful collagenase (activity on collagen enzyme that breaks down collagen) and also decreased the production of inflammatory E2 series prostaglandins. For athletes, cryotherapy post-training could be a useful tool to help prevent injuries. Vitamin D-CYP2R1

Improves Gene Function: Vitamin D and vitamin D co-factors.

Decreases Gene Function: Lack of sun exposure, high fructose intake and vitamin D co-factor deficiencies.

Research: Studies confirm that CYP2R1 is the principal 25-hydroxylase in humans and demonstrates that CYP2R1 alleles have dosage-dependent effects on vitamin D homeostasis.

Oral administration of vitamin D led to significantly lower increases in serum 25-hydroxy-vitamin D in heterozygous subjects than in control subjects, whereas homozygous subjects showed negligible increases. One study found that moderate swimming was beneficial in improving vitamin D status.

Vitamin D can influence the expression of more than 1,000 genes and vitamin D deficiency has been linked to fatty liver, seizures, infertility, osteoporosis, cancer, autism (mother deficient), depression, heart attacks, Alzheimer's, dementia, high blood pressure, autoimmune disorders and more. The literature is mixed on optimal vitamin D levels, which most likely vary based on your heritage, skin color and current health issues.

Clinical vitamin D deficiency is below 25 ng/ml. There is little evidence to prove there is a benefit for levels above 50 ng/ml. The latest cancer research has found that women with 25(OH)D concentrations greater than 40 ng/ml had a 67% lower risk of cancer than women with concentrations less than 20 ng/ml.

Research has found that sunlight is the optimal way to optimize vitamin D levels along with exercise, vitamin D rich foods and vitamin D cofactors, however supplementation may be necessary.

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