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DETOXIFICATION
The human body is exposed to thousands of toxins every single day which need to be processed,
neutralized and eliminated. Substances such as nutrients, food additives, pesticides, medication, air
pollution, alcohol and hormones are transformed from being fat-soluble to water soluble, allowing them
to be more easily excreted from the body via urine and bile.
The detoxification process in the body is governed primarily by a family of enzymes known as the GST
family of enzymes.
GST enzymes are responsible for making harmful compounds in the body more water soluble and
therefore more easily excreted from the body through sweat and urine.
There are specific vegetables that help the GST enzymes to function. These are the cruciferous and
allium vegetables. Hence the reason why they help increase the activity of your detoxification system,
aiding the removal of harmful substances from your body.
Detoxification occurs predominantly (although not
solely) in the liver in two major phases:
Phase I Reactions
Phase II Conjugation
And then there is the less well-known third phase:
Phase III Antiporter Activity
Your Genetic Detox + Genetic Nutrition,
Plus Action Plan
2
DETOXIFICATION
Phase I Reactions
Phase I is made up of a family known as the CYP450 Family of enzymes. You can think of these enzymes
as the first line of defense. The method of protection is to use oxygen to modify toxic compounds,
however a significant side effect of Phase I detoxification is the production of free radicals as the toxins
are transformed from their original state, causing them to be more reactive, volatile and potentially
damaging to the body.
The act of modification within Phase I is known as Biotransformation. Biotransformation describes
substrates such as chemical compounds such as drugs and steroid hormones to be primed for
conjugation (conversion and elimination) via the oxidation (oxygen). This process supports the
conversion of environmental pro-carcinogens to reactive intermediates, but still having a carcinogenic
effect due to the volatility of Phase I. Another example is that CYP enzymes are involved in the oxidative
metabolism of innate oestrogens, which may otherwise play a critical role in the formation of breast and
prostrate cancer.
So once Phase I has achieved biotransformation, many of these modified toxins go on to the next phase
(Phase II) within the detoxification sequence to support clearance of volatile compounds from the body.
We can now see that increased Phase I enzyme activity is both good and bad. Because it increases the
metabolism of environmental toxins which is essentially a good thing. But can also significantly leads to
higher circulating free radicals.
Within detoxification this is the most significant detail, which can and does typically under-pin why so
many people struggle with detoxification.
The importance of understanding the background of the individual’s basic health blueprint toward
Oxidative Stress and further more Inflammation cannot be over-looked.
These TWO factors alongside the presence and functionality of Phase I and Phase II enzymes heavily
determines the success of any detox, as well as reaction state known as a Healing Crisis especially when
raised Phase I increases the potency of certain prescription medications.
For this reason ALL gene enzyme variants within the Phase I enzyme activity are reported as negative.
Inducers of Phase I activity:
Cigarette smoke, charred food, caffeine, alcohol, cruciferous vegetables, and St John’s Wort.
3
DETOXIFICATION
Phase II Conjugation
Foods which influence Phase II conjugation are those we typically consider when influencing the liver for
detoxification.
Kale, cruciferous vegetables, spring onions, celery, garlic etc typically upregulate the enzymes involved
within Phase II detoxification.
During Phase II, substrates made volatile via Phase I are then de-activated and made water-soluble. This
is a crucial process that prepares them for excretion which occurs courtesy of bile (stored within the
gall-bladder) deposited into small intestine. Or via the kidneys to urine.
Foods to support Phase II Conjugation
Cauliflower
Broccoli
Onion
Garlic
Purple sprouting
Green tea, and other teas
Olive oil
Apple (Granny Smith)
Mung beans
Sesame
4
DETOXIFICATION
Six Conjugation Pathways within Phase II Liver Detoxification:
There are 6 conjugation pathways within Phase II of liver, all of which must be functioning
adequately to achieve complete and successful detoxification from within the liver.
1. Glucoronidation (UGT)
Substrates are conjugated with glucuronic acid via UDP-glucuronosyltransferase
2. Sulphonation (SULT)
Substrates are conjugated via suphontransferase enzymes
3. Glutathione conjugation (GST)
Substrates are conjugated with glutathione via glutathione transferase enzymes.
4. Amino acid conjugation (GLYAT)
Substrates are conjugated with glycine via glycine N-acyltransferase in the
mitochondria of liver and kidney cells. This process affects mitochondrial ATP
production.
5. Acetylation (NAT)
Substrates are conjugated via the addition of an acetyl group by the N-terminal
acetyltransferase enzymes.
6. Methylation (MT)
Substrates are conjugated by the addition of a methyl group via methyltransferase
enzyme.
5
DETOXIFICATION
Phase III Transporter
Phase III involves the transportation of the now inert substances. This can be across cellular barriers
within the liver into bile for elimination. As well as the conjugated and now inert substances across
blood-brain barrier or removal of xenobiotics from the blood within the kidney and small intestine.
Phase III strongly influences the absorption, distribution and elimination of xenobiotics and
pharmaceutical drugs.
6
DETOXIFICATION
7
LIFESTYLE FACTORS INFLUENCING DETOXIFICATION
Lifestyle factors and habits that negatively influence toxicity burden:
o Eating a standard western diet.
o Eating without fasting between meals.
o Over-eating.
o Exposure to heavy metals like mercury and lead
o Petrochemicals, residues, pesticides, and fertilizers.
o Food allergies, environmental allergies.
o Mould and mycotoxins.
o Medications
o Internal Toxins; bacteria, fungus, viruses and yeast
o Hormonal and metabolic toxins that aren’t eliminated properly.
o Mental, emotional, and spiritual.
(isolation, loneliness, anger, jealousy and hostility)
8
DETOXIFICATION
Toxic exposure is both generated from within as well as through lifestyle
choices:
INTERNAL EXTERNAL Oxidative stress Smoking
Stress Alcohol
Dysbiosis from bacterial, fungal, viral infections
Diet: sugar, trans-fats, food chemicals, herbicides, pesticides
Hormones and other inflammatory chemicals Air pollution
Histamine Household detergents
Emotions Cosmetics
Radiation
Water with chlorine and fluorine
Mould, pollen and certain algae
Heavy metals (aluminum, lead, mercury)
Electrical smog
INTERNAL VS EXTERNAL OFF-SETTING
Whole food, lifestyle, and an informed elimination diet
alongside an increase in the correct nutrients to match
genetic requirements can significantly cut the internal
noise down, in the form of inflammation and oxidative
stress.
Eat: Cleansing foods, brassica family, beetroot
Increased phytonutrient intake
Support the body with: Quality nutrients, protein
powders and antioxidants
Consume: Organic foods
Avoid allergenic foods: Elimination diet
Reduce environmental exposure, including electrical
smog
9
DETOXIFICATION
Do Environmental Toxins have the same impact on everyone?
No, there is a spectrum of vulnerability which is reflected clearly within each individual genetic profile.
Phase I, Phase II, Phase III all play specific roles within the downstream and net clearance of toxins from
our tissues. There are also lots of other factors to consider throughout this process.
Not only is oxidative stress and our ability to deal with oxidation hugely important, but our ability deal
with inflammation from a genetic perspective is also hugely influential upon our ability to successfully
move volatile compounds around the body.
Therefore, there is a small group of people whose threshold can be so much lower than the rest of us,
when it comes to our capacity to detoxify. These people have been termed ‘the canaries in the coal-
mine’, since they react more acutely to the toxins we are all exposed to.
This remains an important consideration within any detox programme. However, if you are one of the
sub-section who finds it difficult to shift toxins due to a combination of genetic factors, then your
Genetic Detox will be even more vital in creating a precision programme to lessen this challenge.
Gene SNP / SNV = Potentially the Weakest Link
in the chain
10
DETOXIFICATION
DOSE IS NOT ALWAYS THE POISON!!
In terms of toxicology we used to think of DOSE being THE poison..
However, we now know that when low levels of toxins are presented in the body together the affects
can be far more harmful than one singular dose of a high-level poison.
External Exposure + Internal Exposure = TOTAL Toxic Burden (& cellular mayhem!!)
1+1 = Exponential Harm
PLUS, GENETICALLY SOME OF US ARE GIVEN A SMALLER BUCKET!!
How big and how full is your bucket?
o Clean diet
o Clean air
o Clean water
Vs
o Pesticides
o Alcohol
o Caffeine
o Sugar
o Allergenic food
What this means is that some of us have a Genetic predispositions to having a smaller bucket!, and
therefore do not have optimal functioning detoxification pathways, running the risk of filling up that
bucket more quickly.
11
DETOXIFICATION
Signs of Poor Detoxification:
Symptoms of poor detoxification results from Internal + External toxicity burden MINUS the rate at
which the liver can eliminate toxins. Primarily this is determined by the individual’s genetic
detoxification strengths and weaknesses. Second to this, detoxification pathways are influenced
greatly (induced or inhibited) by nutrition and lifestyle habits.
Poor detoxification can look like this:
• Gastro-Intestinal Tract:
Halitosis, bitter taste, bloating, fatty stools, constipation, diarrhea, intolerance to
fatty foods, swollen liver, gallbladder problems
• Immune System:
Food allergies, skin issues, asthma, recurrent infections
• Endocrine System:
Infertility, PMS, weight gain, depression, anxiety, mood swings
• Nervous system:
Recurrent headaches, dementia, poor memory and concentration, neuralgia
• Musculo-Skeletal System:
Muscle aches and weakness, arthritis
• Other:
Sensitivity to chemical and odours, chronic fatigue, lethargy, anaemia and
premature ageing
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DETOXIFICATION
GENETIC RESULTS: PHASE I
ADH1B Alcohol Dehydrogenase 1B, Beta Polypeptide
ADH1B Variant Result Description Rs1229984 Arg48His Conversion of ethanol to acetaldehyde
Rs2066702 Arg370Cys Conversion of ethanol to acetaldehyde
Variants on this gene affects metabolism of a wide variety of substrates such as ethanol, retinol,
alcohols, hydroxysteroids, lipid peroxidation products.
ADH1C Alcohol Dehydrogenase 1C, Gamma Polypeptide
ADH1C Variant Result Description i6060959 IIe350Val High enzyme activity and rate of conversion of
ethanol to acetaldehyde. Increased risk of acetaldehyde toxicity.
Rs1693482 Arg272GIn High enzymatic activity and rate of conversion of ethanol to acetaldehyde. Increased risk of acetaldehyde. Most common genotype in Caucasions
Variants on this gene affects metabolism of a wide variety of substrates such as ethanol, retinol,
alcohols, hydroxysteroids, lipid peroxidation products.
Low enzyme activity may increase vulnerability to ethanol intoxication, however high enzyme activity
may increase the risk of acetaldehyde toxicity. Acetaldehyde is significantly more toxic than alcohol and
is carcinogenic in humans.
ALDH2 Aldehyde Dehydrogenase 2 Family (mitochondrial)
ALDH2 Variant Result Description Rs671 Glu457 Detoxification of acetaldehyde
Variants on this gene affects alcohol metabolism. Low enzyme activity or absence of this active form
increases the chance of acute alcohol intoxication. With the increased exposure of acetaldehyde in
those with the inactive form to greater susceptibility to many types of cancer.
13
CYP1A1 Cytochrome P450, Family 1, Subfamily A, Polypeptide 1
CYP1A1 Variant Result Description Rs1048943 A4889G Normal enzyme activity. Lower risk of oxidative
Rs1799814 1295C>T Conversion of ethanol to acetaldehyde
Primarily the role of this enzyme is involved in oestrogen metabolism. However, variants on this enzyme
also affect how we metabolise drugs and the synthesis of cholesterol, steroids and other lipids. It is
unduced by chemicals released from burnt food and other substances; coal, tobacco, wood, chargrilled
meat.
Variant associated with up-regulation can lead to good oestrogen metabolism, but also result in high
amounts of circulating pro-carcinogens. Particularly when Phase II detoxification pathways are not
working adequately.
CYP1A2 Cytochrome P450, Family 1, Subfamily A, Polypeptide 2
CYP1A2 Variant Result Description Rs762551 -163A Normal (slow) metabolism of substrates such as
caffeine and paracetamol and other pharmaceutical drugs
Variants on this enzyme affect how we metabolise chemicals released from burnt food and other
substances; coal, tobacco, wood, chargrilled meat and caffeine and paracetamol. These are metabolized
into carcinogenic intermediates that need to then pass through our system.
The most common variants are associated with up-regulated enzyme activity and increased metabolism
of environmental toxins which may increase the risk of oxidative damage.
CYP1B1 Cytochrome P450, Family 1, Subfamily B, Polypeptide 1
CYP1B1 Variant Result Description Rs10012 R48G Some up-regulation of enzyme activity. Increased
risk of oxidative damage and some cancers, particularly if COMT activity is low and GSTM1 id null
Rs1056836 L432V Normal CYP1B1 enzyme activity. Lower risk of oxidative damage
Rs1800440 N453S Normal CYP1B1 enzyme activity. Lower risk of oxidative damage
14
Variants on this enzyme affect how we metabolise chemicals released from burnt food and other
substances; coal, tobacco, wood, chargrilled meat and caffeine and paracetamol. These are metabolized
into carcinogenic intermediates that need to then pass through our system.
CYP2A6 Cytochrome P450, Family 2, Subfamily A, Polypeptide 6
CYP2A6 Variant Result Description Rs1801272 479T>A Normal metabolism of nicotine, and of
anticoagulant and other pharmaceuticals
Variants on this enzyme affect how we metabolise warfarin and other pharmaceutical drugs, as well as
nicotine, aflatoxin and nitrosamines from cigarette smoke
Variants are associated with down-regulation, with slower metabolisers not able to efficiently
metabolise warfarin or nicotine. This can exert greater effect and therefore influence dosage.
CYP2C19 Cytochrome P450, Family 2, Subfamily C, Polypeptide 19
CYP2C19 Variant Result Description Rs12248560 -806C>T Normal metabolism of anticoagulants and other
pharmaceutical drugs
Rs4244285 681G>A Down-regulated CYP2C19 enzyme activity and slower metabolism of substrates
Rs4986893 Trp212Ter CYP2C19*1 genotype. Normal CYPC19 enzyme activity and metabolism of substrates
Variants on this enzyme affect how we metabolise a wide variety of pharmaceutical drugs including
anticonvulsants, proton pump inhibitors, antidepressants, sedatives and antimalarials. This can exert
greater effect and therefore influence dosage.
CYP2C9 Cytochrome P450, Family 2, Subfamily C, Polypeptide 9
CYP2C9 Variant Result Description Rs1057910 1359L Normal enzyme activity and metabolism of anti-
inflammatories and anticoagulant drugs
Rs1799853 R144C Normal enzyme activity and metabolism of ibuprofen and warfarin
Variants on this enzyme affect how we metabolise a wide variety of pharmaceutical drugs including
anticonvulsants, blood sugar lowering drugs, anti-inflammatories, and anticoagulants. Variants are
15
associated with a down-regulated enzyme activity and slower metabolism of certain drugs, most notably
ibuprofen and warfarin.
Warfarin may also be impacted by a the -1639G>A variant on the VKORC1 gene which controls the
activation of vitamin K. This can exert greater effect and therefore influence dosage.
CYP2D6 Cytochrome P450, Family 2, Subfamily D, Polypeptide 6
CYP2D6 Variant Result Description Rs1065852 T100C Normal enzyme activity and substrate
metabolism including many common clinical drugs
Rs1135840 S486T Increased (rapid) enzyme activity and substrate metabolism
Rs16947 R296C Increased (rapid) enzyme activity and substrate metabolism
Rs28371706 T1071 Normal (extensive) enzyme activity and substrate metabolism including many common clinic drugs
Rs35742686 2549delA Normal (extensive) enzyme activity and substrate metabolism
Rs3892097 1846G> Normal (extensive) enzyme activity and substrate metabolism
Rs5030655 1707delT Normal (extensive) enzyme activity and substrate metabolism
Variants on this enzyme affect how we metabolise as many as 25% of commonly prescribed drugs as
well as lipids, hormones and toxins. To include antidepressants, antispsychotic, analgesics and anti-
tussives, beta adrenergic, blocking agents, antiarrythmics and antiemetics.
Poor metabolisers do not clear codeine to morphine and thus experience no analgesic effect.
Rapid metabolisers (3+ functional alleles) experience morphine toxicity.
CYP2E1 Cytochrome P450, Family 2, Subfamily E, Polypeptide 1
CYP2E1 Variant Result Description Rs2031920 Rsal Normal enzyme activity and alcohol metabolism
Metabolises endogenous substrates that are carbon based, such as ethanol, acetone, and acetal. As
well as exogenous substrates including benzene, tetrachloride, ethylene glycol and nitrosamines.
This enzyme is involved in varied liver processes, such as gluconeogenesis, hepatic cirrhosis, diabetes
and cancer – accountable for up to 10% of ethanol oxidation in the liver.
16
CYP3A4 Cytochrome P450, Family 3, Subfamily A, Polypeptide 4
CYP3A4 Variant Result Description Rs2740574 -392G>A Normal enzyme activity and metabolism of
pharmaceutical drugs. Lower risk of oxidative damage
The CYP3A4 enzyme is involved in the metabolism of approximately half the drugs in use today. To
include acetaminophen, codeine, cyclosporine A, diazepam and erythromycin. It also metabolises some
steroids and converts oestradiol to oestriol.
Inhibited by grapefruit, antifungals, and antibiotics.
MAOA Monoamine Oxidase A
MAOA Variant Result Description Rs3027399 G82315C Wild genotype. High MAOA activity and rapid
metabolism of monoamine neurotransmitters
Rs6323 R297R Low MAOA activity and slow metabolism of monoamine neurotransmitters
Rs909525 C42795T Low MAOA activity and slow metabolism of monoamine neurotransmitters
MAOA enzymes deactivate certain neurotransmitter activity. Men only carry ‘one allele’ inherited from
their mother, and therefore will not inherit a ‘balancing’ allele.
MAOA enzyme is responsible largely for the breakdown of serotonin, melatonin, noradrenalin and
adrenalin. It also metabolises dopamine, tyramine and tryptamine equally with another gene that we
will be looking at next, MAOB
MAOA has been nicknamed one of the ‘warrior genes’, because variants have been associated with
anger and aggression due to slower neurotransmitter breakdown – which may in turn be amplified if
COMT variants are also present.
Conversely, a combination of wild allele has been labelled the ‘worrier’ genotype, associated with low
mood due to rapid breakdown of neurotransmitters.
MAOB Monoamine Oxidase B
MAOB Variant Result Description Rs1799836 A118723G Possible reduced MAOB enzyme leading to
breakdown of substrates.
17
MAOB enzymes deactivate certain neurotransmitter activity. Like MAOA, men only carry ‘one allele’
inherited from their mother, and therefore will not inherit a ‘balancing’ allele.
MAOB is the main enzyme responsible for the breakdown of phenethylamine, benzylamine, histamine
and some pharmaceuticals. It also metabolises dopamine, tyramine, and tryptamine equally with MAOA
PON1 Paraoxonase 1
PON1 Variant Result Description i6060365 L55M Associated with low PON1 enzyme activity
Rs6323 R297R Low MAOA activity and slow metabolism of monoamine neurotransmitters
Rs662 Q192R Reduced PON1 activity and reduced ability to detoxify inflammatory oxidants, as well as dietary carcinogens
Variants on this enzyme decrease activity and therefore increase risk of exposure to harmful chemicals,
oxides lipids and the development of atherosclerosis. Since Pon1 enzymes are responsible for the
detoxification of organophosphates (the base for insecticides herbicides, and nerve agents), oxidized
lipids and also aromatic esters. It is associated with HDLs and may protect against development of
atherosclerosis.
18
DETOXIFICATION
GENETIC RESULTS PHASE II
COMT Catechol-O-Methyltransferase
COMT Variant Result Description Rs4633 H62H Associated with low COMT activity
Rs4680 V158M Approximately 4X lower COMT activity leading to slow methylation and deactivation of substrates
The COMT gene is responsible for breaking down and inactivating dopamine, adrenalin and noradrenalin
by transferring a methyl group from SamE to itself rendering it more agreeable for excretion.
Because there is competition between SamE and SAH for the binding site on COMT, a build-up of SAH
with reduce COMT activity.
COMT is also involved in oestrogen metabolism.
Reduced COMT may lead to reduced function and excess methyl groups causing irritability, heightened
stress response, hyperactivity, abnormal behavior and heightened pain sensitivity. Individuals with
normal COMT activity and variants on VDR causing low activity may have low dopamine levels and
increased need for methyl donors and dopamine precursors.
All this may lead to imbalance between noradrenalin levels and dopamine levels, which have been
implicated in conditions such as ADD/ADHD and Parkinson’s disease.
GSTM1 Glutathione S-Transferase Mu 1
GSTM1 Variant Result Description Rs366631 -A1998G Associated with low PON1 enzyme activity
GSTM1 is a member of a class of enzymes which function in the detoxification of certain carcinogenic
compounds, therapeutic drugs, environmental toxins and products which can create oxidative stress in
the body. Over 50% of the population have a NULL genotype, with both copies absent.
GSTP1 Glutathione S-Transferase Pi 1
GSTP1 Variant Result Description Rs1138272 A1114V Normal GSTP1 enzyme activity. Normal
glutathione conjugation of substrates
19
Rs1695 I105V Associated with decreased glutathione conjugation activity
GSTP1 are a family of enzymes that play an important role in detoxification of xenobiotcs and therefore
play a role in susceptibility to cancer and other diseases.
GSTT1 Glutathione S-Transferase (GST) Theta 1
GSTT1 Variant Result Description Rs11550605 Thr104Pro
GSTT1 is a member of a family of proteins that that play an important role in detoxification of certain
drugs pesticides, herbicides, and carcinogens. GSTT1 is also often entirely absent 50-6-% om Asians,
15% om White populations, 15-20% in African and less than 10% in Hispanic populations. This gene is
associated with cancer.
NAT1 N-Acetyltransferase 1
NA1 Variant Result Description Rs4986782 R187Q
Variants on this gene affect metabolism of various prescription drugs, caffeine, other xenobiotics and
function in folate catabolism. Slow activity has been linked to various forms of cancer including lung,
bladder, breast and pancreas.
NAT2 N-Acetyltransferase 2
NA2 Variant Result Description Rs1799930 G590A Normal to slow acetylation of substrates
Rs1799931 G857A Rapid acetylation of NAT2 substrates
Rs1801279 G191A Rapid acetylation of NAT2 substrates
Rs1801280 T341C Rapid NAT2 enzyme activity and acetylation of substrates
NAT2 variants both activate and deactivate various pharmaceutical drugs and carcinogens, as well as
detoxifies caffeine.
Variants are associated with slow activity and increased incidence of cancer and drug toxicity. For
accurate assessment consider the four SNP panel in orchestra.
20
SULT1A1 Sulfotransferase Family, Cytosolic, 1A, Phenol-Preferring, Member 1
SULT1A1 Variant Result Description i6018900 Arg213His Associated with possible reduced sulfotransferase
activity
Rs1042157 C973T Associated with decreased sulphonation of compounds including steroid hormones, catecholamines and phenolic drugs
The Sulfotransferase family binds to and therefore helps eliminate many steroid hormones,
neurotransmitters, drugs, fat soluble vitamins as well as xenobotic compounds. Decreased activity of
this enzyme results in impaired sulphoconjugation.
SULT1E1 Sulfotransferase Family, 1E, Member 1
SULT1E1 Variant Result Description Rs11569705 Asp22Tyr Associated with normal SULT1E1 enzyme activity
and sulfonation of substrates
Rs34547148 Ala32Val Normal SULT1E1 sulphation of substrates
SULT1E1 is expressed in much of human tissue, to include the liver, the jejunum, the mammary
epithelium cells, endometrium and testis, This enzyme helps to control levels of oestrogen receptor
within these tissues and the activation / inactivation of oestrogen.
Impairment of this enzyme can lead to the growth of tumors in hormone sensitive cancers such as
breast or endometrial cancers.
SULT2A1 Sulfotransferase Family, Cytosolic, 2A, dehydroepiandrosterone (DHEA),
Member 1
SULT2A1 Variant Result Description Rs11569680 Lys227Glu Normal enzyme activity
Rs182420 C47868938T Associated with decreased enzyme activity
Sulfotransferases aid in the metabolism of drugs and endogenous compounds by converting toxic
compounds into more hydrophilic water-loving sulphates to then be easily excreted. This enzyme also
plays a role in catalyzing the sulphation of steroids, particularly DHEA, and bile acids in the liver and the
adrenal glands. It is thought this plays a significant role in the inherited adrenal androgen excess in
women with polycystic ovary syndrome.
21
TPMT Thiopurine S-Methyltransferase
TPMT Variant Result Description Rs1142345 Tyr240Cys Normal enzyme activity and metabolism of
thiopurine drugs
Rs1800460 Ala154Thr Normal enzyme activity and metabolism of thiopurine drugs
Rs1800462 Ala80Pro Normal enzyme activity and metabolism of thiopurine drugs
Variants on this enzyme can result in sensitivity and toxicity to thiopurine drugs.
UGT1A1 UDP Glucuronosyltransferase Family 1, Member A1
UGT1A1 Variant Result Description Rs4148323 G211A Associated with UGT1A1 enzyme activity
Rs4148324 T179333G Associated with UGT1A1 enzyme activity and glucoronidation substrates
UGT1A1 is an enzyme of the glucuronidation pathway, that transforms steroids, bilirubin, hormones,
and drugs into water-soluble excretable metabolites. The most common deficiency of UGT1A1 enzyme
is Gilbert’s syndrome, characterized by intermittent unconjugated hyperbilirubinemia.
Decreased enzyme activity also leads to inactivation of oestrogens and reduced detoxification of
environmental toxins, carcinogens and their relative metabolites.
UGT1A6 UDP Glucuronosyltransferase Family 1, Member A6
UGT1A6 Variant Result Description Rs17863783 Val209Val Normal enzyme activity
UGT1A6 is an enzyme of the glucuronidation pathway, that transforms steroids, bilirubin, hormones,
and drugs into water-soluble excretable metabolites.
22
DETOXIFICATION
GENETIC RESULTS: PHASE III
ABCB1 ATP-Binding Cassette, Subfamily B, Member 1
ABCB1 Variant Result Description Rs104542 3435T> Slower antiporter activity. May support
detoxification
Rs1128503 1236T>C Slower antiporter activity. May support detoxification
Also, known as the Multi Drug Resistance 1 (MDR1), this gene is member of a family of genes involved in
the clearance and decreased drug accumulation in multi-drug resistant cells. Mediating the resistance
to anticancer drugs.
This protein is also an integral part of the blood-brain barrier transportation system, shuttling a variety
of drugs from the brain back into the blood.
The wild genotype (CC) is associated with lower bioavailability and plasma levels of certain drugs due to
more effective detoxification.
23
24
METHYLATION
Methylation can be a complex topic for many. It is a process by which ‘methyl groups’ in the form of
active nutrients, are then added to molecules. This process occurs within almost EVERY biochemical
reaction in the body. So, as you can imagine, virtually all of our biological processes involve methylation
to complete task in hand. And that methylation not only occurs billions of time every second, but also
contributes to numerous bodily functions, including:
• Detoxification
• DNA integrity
• Energy production
• Inflammation control
• Immune function
• Gene expression vs suppression
• Neurotransmitter balance
• Telomere protection (ageing)
Environmental factors such as diet, chemical or drug exposure and STRESS are all known to play a role in supporting or hampering methylation activity.
The Role of Genes in Methylation:
The purpose of understanding a genetic variant in the context of methylation provides guidance on how
to support the weakness. This can be ‘bottleneck-ing’ or ‘bypass-ing’ the genetic variant, thus
influencing health.
This report provides genotype variations organized within by the following methylation sub-cycles:
• The Folate Cycle
• The Methionine Cycle
• The Transsulphuration Pathway
• The BH4 Cycle / Neurotransmitter Metabolism
• The Urea Cycle
Let’s consider the result of impaired methylation. What does this mean to human health?
25
Impaired methylation may contribute to major conditions, including:
• Cardiovascular disease
• Unexplained miscarriages
• Problems during pregnancy
• Mood and psychiatric disorders
• Cancer
• Free radical damage (premature ageing)
• Diabetes
• Infertility
• Neural tube defects
• Adult neurological conditions
• Chronic fatigue syndrome
26
METHYLATION
FOLATE CYCLE
Folate is vitamin B9. Folate is ‘naturally’ occurring dietary folate and folic acid. Folic acid is a
‘monoglutamate’ form of the vitamin, which is found in supplements and fortified foods.
Folate requires vitamin B3 as a co-factor to convert it into a usable form of DHF.
Within the Folate Cycle a number of conversions take place (viewed in the table above), requiring active
enzymes within relevant genes and nutrients to complete. Absorption of folate may then be impacted
by variants on the GCPII gene, and the RFC1 or DHFR genes.
5-MTHF then feed both the Methionine and BH4 Cycles, therefore a complete breakdown and
utililisation of Folate is required in order to be made full use of.
Therefore, variants on the MTHFR can lead to low levels of transmitters and strain on the BH4 Cycle.
With the amount of BH4 then affecting the function of the urea cycle.
For management of good folate levels, ensure adequate intake of all B vitamins, particularly B2, B3, and
B6 as co-factors.
DHFR Dihydrofolate Reductase
DHFR Variant Result Description Rs1643649 A16352G Supports neurotransmitter synthasis
Rs70991108 19bp DEL
Anti-folate drugs such as methotrexate target DHFR to deplete cells of reduced folate resulting in the
suppression of purine and pyrimidine synthases.
Variants on the DHFR gene may down regulate activity and ay protect against certain cancers (colorectal
cancer and childhood leukaemia), similar to the action of methotrexate. However, the consequent
deficiency of folate can increase susceptibility to megoblastic anaemia, neural defects and spina bifida.
27
GCPII Glutamate Carboxypeptidase II
GCPII Variant Result Description Rs202700 C1561T Normal intestinal absorption of dietary folate
Variants are associated with down regulation of the gene resulting in impaired intestinal absorption of
dietary folate resulting in lower blood folate levels and consequent hyperhomocysteinemia.
MTHFD1 Methylenetetrahydrofolate Dehydrogenase 1
MTHFD1 Variant Result Description Rs1076991 C105T Associated with increased risk of NTD’s in
combination with G1958A
Rs1950902 R134K Risk of disruption to nucleotide synthesis and reduced 5-MTHF levels
Rs2236225 G1958A May impact 5-MTHF levels and increase demand for chlorine as a methyl-group donor
Variants have been linked to increased risk of folate sensitive neural tube defects and endometriosis
related infertility due to choline depletion.
MTHFR Methylenetetrahydrofolate Reductase (NAD(P)H)
MTHFR Variant Result Description Rs1801131 A1298C Reduced gene function may result in lower 5-
MTHF and BH4 depletion
Rs1801133 C677T Reduced gene function impacting 5-MTHF levels and THF and methionine regeneration
MTHF catalyzes the conversion of folate to ‘active folate’, which then donates to the Methionine Cycle
which support DNA synthesis and repair, vital for healthy cell division, as well as metabolism of
neurotransmitters, phospholipids and proteins such as myelin.
MTHFR activity can be supported by increasing the intake of folate (B9) and the cofactors B2, B3, B12
and zinc.
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RFC1 Reduced Folate Carrier 1
RFC1 Variant Result Description Rs1051266 A80G Reduced ability to take up, retain, and metabolise
folate – possible raised homocysteine levels
A transporter of folate gene, involved in the regulation of intracellular concentrations of folate.
SHMT1 Serine Hydroxymethyltransferase 1
SHMT1 Variant Result Description Rs1979277 C1420T
This is a B6 dependent enzyme.
TYMS Thymidylate Synthetase
TYMS Variant Result Description Rs2790 Neutral genotype – no impact on DNA synthesis
or repair
Variations on this gene impact DNA stability, replication and repair. Absence of which affects risk of
certain cancers.
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METHYLATION
METHIONINE CYCLE
AHCY S-Adenosylhomocysteinase
AHCY Variant Result Description i5000928 A344G Impact on conversion of SAH to homocysteine
Rs819147 AHCY-01 Impact on conversion of SAH to homocysteine
Rs819171 AHCY-19 Impact on conversion of SAH to homocysteine
Genetic deficiency of AHCY activity in humans has been reported in only a few cases, metabolic effects
of AHCY deficiency include elevated blood levels of SAH, SAMe and Methionine.
BHMT Betaine-homocysteine S-methyltransferase
BHMT Variant Result Description Rs3733890 R239Q Less effective ‘short cut’ conversion of
homocysteine to methionine
Rs567754 BHMT/2 No impact on short cut homocysteine to methionine conversion
Rs651852 BHMT/8 No impact on short cut homocysteine to methionine conversion
BHMT is not B12 dependent as in the ‘long’ route when recycling homocysteine to methionine. Rather
this is the ‘short’ route and is dependent on adequate levels of betaine and zinc.
The activity of this gene product can be affected by cortisol levels (stress) and may play a role in
ADD/ADHD by affecting norepinephrine levels.
FUT2 Fucosyltransferase 2
FUT2 Variant Result Description Rs1047781 A385T Secretor genotype – susceptibility to H.Pylori
infection and gastritis linked to reduced B12 absorption
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Rs601338 W143X Secretor genotype – susceptibility to H.Pylori infection and gastritis linked to reduced B12 absorption
FUT2 is the secretor gene within the gastrointestinal mucosa. Absorption of B12 requires the secretion
of the glycoprotein intrinsic factor.
The FUT2 secretor status has been linked with both H. pylori infection and gastritis.
B12 malabsorption and low levels of serum vitamin B12 have higher prevalence of H. pylori infection.
MAT1A Methionine Adenosyltransferase 1, Alpha
MTHFD1 Variant Result Description i5007205 C164A Associated with normal MAT activity and
conversion of methionine to SAMe
i5007206 C1070T Associated with normal MAT activity and conversion of methionine to SAMe
i5007207 T914C Associated with normal MAT activity and conversion of methionine to SAMe
i5007208 C790T Down regulation of MAT activity which may lead to hypermethioninemia
Rs1985908 T1297C Associated with normal MAT activity and conversion of methionine to SAMe
MAT serves to form SAMe, which is the master methyl donor. Variants on the MAT genes, particularly
inactive MAT activity may lead to hypermethioninemia, low SAMe and therefore slow methylation.
MTR 5-Methyltetrahydrofolate-Homocysteine Methyltransferase
MTR Variant Result Description Rs1805087 A2756G Neutral genotype – no impact on MTR or B12
levels
Variants of MTR can result in UP-regulation of the gene and increased usage and therefore deficiency of
methylcobalamin / B12. MTR activity can be supported by supplementing the methylated form of B12.
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MTRR 5-Methyltetrahydrofolate-Homocysteine Methyltransferase Reductase
MTRR Variant Result Description i6015189 H595Y Neutral genotype does not impact B12 or
homocysteine
Rs162036 K350A Reduced ability to recycle B12 impacting MTR conversion of homocysteine
Rs1801394 A66G Neutral genotype does not impact B12 or homocysteine
MTRR regenerates MTR with use of SAMe as donor. I also converts vitamin B12 into its methylated
usable form.
Variants in MTRR can result in down-regulation of the gene activity and high homocysteine levels.
PEMT Phosphatidylethanolamine N-Methyltransferase
PEMT Variant Result Description Rs7946 G5465A Potential for reduced do novo choline synthesis
and higher homocysteine
PEMT supports the conversation of the inactive to the active form of choline, a significant source
relative to dietary intake.
Oestrogen induces the expression of this gene, allowing premenopausal women to make more of their
required choline.
Variants in PEMT alter this endogenous synthesis of choline, impacting conversion of homocysteine to
methionine via the short cut. This may lead to high homocysteine, particularly when there are variants
on MTHFR, MTR and MTRR genes.
TCN2 Transcobalamin II
TCN2 Variant Result Description RS1801198 C776G Likely to have reduced ability to absorb
cobalamin (Vitamin B12)
This gene affects the absorption of B12 via it’s binding protein to cobalamin. Transporting it from the
intestine into the blood cells.
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METHYLATION
TRANSSULPHURATION CYCLE
CBS Cystathionine Beta Synthase
CBS Variant Result Description Rs1801181 A360A One variant allele may cause up-regulated CBS
Rs234706 C699T CBS activity
Rs234715 C12646A Normal genotype, normal CBS activity
Rs2851391 A13637G Partially impaired CBS activity may lead to impaired conversion of homocysteine
Rs4920037 C19150T Associated with normal CBS activity
CBS catalyzed the conversion of homocysteine from the Methionine cycle to cystathionine, the first step
in the transsulphuration pathway. Requiring vitamin B6 and heme as co-factors.
Variants on CBS cause the ‘gate’ between homocycsteine to cystathionine to be left open, draining
homocysteine, while preventing it from being recycled into methionine. This further depletes B6, B12
whilst preventing the generation of SAMe.
Homocysteine is instead pulled down and converted into ammonia and cysteine.
High levels of ammonia puts pressure on the urea cycle and causes low BH4, disrupting
neurotransmitter metabolism.
High cysteine converts to toxic sulphites, putting pressure on SUOX.
CBS should always be considered alongside variants on MTHFR, MTR, BHMT, MUT to determine risk.
CTH Cystathionine Gamma-Lyase
CTH Variant Result Description Rs1021737 G1112T Compromised CTH activity
CTH encodes an enzyme that converts cystathionine to cysteine. The second step in the third cycle,
transsulphuration pathway requiring vitamin B6 as a co-factor.
The most abundant antioxidant in the human body, Glutathione is synthesized via the CTH gene from
available cysteine. Glutathione is important for a variety of biological functions including protection of
cells from oxidative damage by free radicals, detoxification of xenobiotics and membrane transport. All
this is vital for health.
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GSS Glutathione Synthetase
GSS Variant Result Description Rs6060124 G11705T Associated with normal glutathione synthesis
Rs6088659 A5997G Normal GSS activity, normal glutathione synthesis
GSS catalyses the second step in the synthesis of glutathione synthesis. Variants on this gene may cause
glutathione deficiency.
MUT Methylmalonyl CoA Mutase
MUT Variant Result Description i6060254 G1595A Associated with low circulation of B12 and
elevated homocysteine
MUT is a mitochondrial enzyme that converts Co-enzyme A to Succinyl-CoA, with B12 as co-factor.
Succinyl-CoA is an important enzyme within the Krebs cycle, crucial for energy, heme and P450 enzymes
discussed in Phase I of detoxification above.
SUOX Sulfite oxidase
SUOX Variant Result Description Rs705703 C5444T No variant alleles, normal SOUX activity
Variants on SOUX may result in sulphite sensitivity and neurological abnormalities. When present with
an up-regulation on CBS this is more pronounced. Sulphites are ingested via foo that we eat, but also a
natural by-product of the methylation cycle. Sulphur dioxide can cause irritation in the lungs, severe
asthma attacks in those who suffer from asthmas, as well as nausea, hives, and even more severe
allergic reactions.
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METHYLATION
BH4 CYCLE / NEUROTRANSMITTER METABOLISM
COMT Catechol-O-methyltransferase
COMT Variant Result Description Rs4633 H62H Low COMT activity, susceptibility to mood swings
Rs4680 V158M Low COMT activity, inefficient breakdown of catecholamines
Rs769224 P199P Low COMT activity, enzyme activity
COMT is responsible to breaking down and inactivating catecholamines dopamine, epinephrine, and
norepinephrine. This is completed by transferring a methyl group from the SAMe, rendering the
molecule amenable for secretion.
Because SAH and SAMe complete for binding sites, then a build-up of SAH will also reduce COMT
activity.
Variants on COMT lad to a reduced function, with excess methyl groups causing irritability, heightened
stress responses, hyperactivity, abnormal behavior and heightened pain sensitivity.
The balance between norepinephrine levels and dopamine levels has been implicated in ADD/ADHD and
other conditions such as Parkinson’s disease.
Those with normal COMT activity and variants on VDR causing low activity will also have low dopamine
levels and increased need for methyl donors and dopamine precursors.
MAOA Monoamine Oxidase A
MAOA Variant Result Description Rs3027399 G82315C Associated with aggressive behaviour
Rs6323 R297R Low enzyme activity, higher levels of neurotransmitters in the brain is associated with outward anger, anxiety and higher risk taking
Rs769224 P199P Associated with less aggressive behavior especially together with GG genotype for rs6323
This gene influences dopamine, norepinephrine and serotonin.
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Nicknamed the Warrior gene, since variants on this gene have been associated with anger and
aggression due to slower neurotransmitter breakdown. Wild Type alleles on this gene are associated
with faster breakdown of neurotransmitters which have been linked to low mood.
A combination of MAOA and COMT variants may cause severe neurotransmitter imbalances leading to
mood disorders, poor memory and concentration and aggressive behavior.
The combination of rs3027399 G, rs6323 G, rs909525 T, indicate a ‘NON-Warrior’ haplotype, since there
is no suggestion of a slowing of this enzyme function.
MAOB Monoamine Oxidase B
MAOB Variant Result Description Rs1799836 A118723G May be susceptible to negative moods due to
inefficient norepinephrine catabolism
MAOB plays an important role in the metabolism of neuroactive and vasoactive amines, including
histamine, and noradrenalin in the central nervous system as well as peripheral tissues.
Preferentially this protein degrades benzylamine and phenylethylamine.
QDPR
QDPR Variant Result Description Rs1031326 A690G Possible BH4 deficiency
Rs11722315 G17953T Reduced BH4 synthesis
Variants on this gene result in BH4 deficiency. When considered alongside CBS up-regulation creates
excess ammonia this further depletes BH4
VDR Vitamin D Receptor
VDR Variant Result Description Rs1544410 Bsml Normal VDR activity, normal dopamine synthesis
Rs731236 Taql Normal levels of vitamin D3, normal dopamine production
Rs7975232 Apal Low VDR activity leading to low dopamine synthesis
This gene is responsible for the receptor site of vitamin D3, the active form of vitamin D. This receptor
mediates an increase in dopamine production.
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Variants of Taq1, BsmI and ApaI lead to lower vitamin D levels causing low dopamine production. This is
good for those with COMT variants since there will be less circulating dopamine in need of breaking
down.
Individuals with variants of COMT but normal VDR activity will have higher dopamine level and low need
and tolerance for methyl donors and dopamine precursors, and the greatest susceptibility to mood
swings.
UREA CYCLE
NOS3 Nitric Oxide Synthase 3
NOS3 Variant Result Description Rs1799983 D298E
Rs3918188 C19635A Partially compromised NOS activity may result in higher levels of free radicals and ineffective ammonia detoxification
NOS synthesizes nitric oxide from L-arginine with the help of BH4.
Without adequate BH4, NOW generates the free radicals peroxynitrite and superoxide instead of nitric
oxide.
Variants on NOS cause low enaymatic activity.
Together with up-regulated CBS, down-regulated SUOX and variants on MTHFR will have an additive
effect and cause excess ammonia.
SOD2 Superoxide Dismutase 2, Mitochondrial
SOD2 Variant Result Description Rs2758331 G816T Affects ability to neutralize superoxide
Rs4880 A16V Affects ability to neutralize superoxide
SOD2 variants can result in a predisposition to oxidative stress. Ensure adequate intake of the co-factor
manganese.
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FOOD AND NUTRIENT RESPONSES
FADS1 FATS / FAT GENE rs174548 Function; Acetylcholine, rs174537 Function: Arachadonic Acid; GLA conversion
rs174548 Function; Acetylcholine
CG C alleles are associated with increased phosphatidylcholine levels. G Allele is associated with lowered phosphatidylcholine and low acetylcholine levels. Homozygous GG is associated with higher requirement for choline and phosphatidylcholine. In those susceptible to depression, excessive supplementation of phosphatidylcholine can induce depression. 2-5p of lecithin is fine.
rs174537 Function: Arachadonic Acid; GLA conversion
GT GG allele is associated with enhanced conversion of DGLA to AA due to increased enzymatic efficiency, systemic inflammation and inflammatory disorders and higher arachidonic acid levels. GT alleles are associated with intermediate AA levels and somewhat higher LDL and cholesterol levels. TT is associated with low AA levels and lower LDL and cholesterol levels.
FADS2 Function: conversion of ALA to EPA
rs1535 AG
G Alleles are associated with lower conversion. Homozygous GG is a low converter with 29% poorer conversion of ALA to EPA. Heterozygous AG is an intermediate converter, with 18% poorer conversion of ALA to EPA
VITAMIN B6
NBPF3 rs4654748
CT
The C allele is associated with lower B6 plasma levels, and increase in dietary B6 intake. 46% of the population is CT, resulting in low levels. CC results in double the lower plasma levels than a healthy cohort.
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VITAMIN B12
rs602662 AG
AG and GG alleles result in 15% lower plasma B12 due to malabsorption.
rs492602 CT CC alleles is associated with higher plasma levels of B12 than normal
VITAMIN D VDR
Taq1 rs731236 TT
Associated with D3 receptor activity. C and G alleles are associated with a HIGHER requirement and appears to correlate more with the development of infectious and auto-immune and other non-skeletal health outcomes.
Bsm1 rs1544410 GG Decreased risk of low bone density disorder
Fok1 rs3948464 CC T allele has poorer calcium absorption compared to the C allele. The TT genotype has higher bone turnover and increased cone loss and is associated with a lower BMD and osteoporosis in the lumbar spine. Ensure adequate calcium and vitamin D intake and reduce caffeine. Test vitamin D levels regularly.
VITAMIN C SLC23A2
rs12479919 CC
T alleles are associated with low absorption or plasma levels of vitamin C
ZINC SLC30A8
rs13266634 CT
C alleles are associated with less active transporter leading to low zinc transportation and plasma levels
VITAMIN K KVKORC1
rs9923231 CT
CC alleles are associated with normal active vitamin K levels. T alleles are associated with reduced active vitamin K levels. CT is linked with Warfarin sensitivity.
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LACTOSE PERSISTANCE LCT
rs4988235 CT
Likely to be lactose intolerant as an adult.
VITAMIN E
rs6025 GG
GG Homozygous are at a normal risk associated with thrombosis. A alleles raise the risk of blood clotting, in particular, thrombosis and pre-eclampsia
IRON HFE / TMPRSS6 (Genetic Variation: C282Y & H63D ) Hereditary hemochromatosis is a genetic disorder in which there is excessive accumulation of iron in the body, leading to iron overload. In individuals with the disorder, the daily absorption of iron from the intestines is greater than the amount needed to replace losses. Since the normal body cannot increase iron excretion, the absorbed iron accumulates in the body. Individuals who carry the genes for hereditary hemochromatosis may have no symptoms or signs and the disease is treatable if detected early. Severe symptoms and signs of iron overload include sexual dysfunction, heart failure, joint pains, liver cirrhosis, diabetes mellitus, fatigue, and hypermelanotic pigmentation.
HFE rs1800562 GG A and G Alelle lead to lowered hepcidin levels and increased, diminished iron homeostasis feedback loop, and a potential of increased iron absorption. Avoid excessive dietary intake of iron rich foods.
HFE rs1799945 CC NORMAL (lower serum iron and hemoglobin levels and correlates with higher risk for iron deficiency and iron deficiency anaemia).
TMPRSS6 rs4820268 AG G alleles are associated with lower serum iron levels and correlates with higher risk from iron deficiency anaemia.
SODIUM ACE / AGT
AGT rs699 CT Associated with INCREASED risk of hypertension
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VITAMIN A: Beta-Carotene Conversion BCMO1
rs12934922 AA
Reduction of conversion from beta-carotene to vitamin A, may need preformed vitamin A.
rs7501331 CT Associated with LOWERED conversion of beta-carotene to vitamin A
rs11645428 GG Variant, reducing conversion leading to higher beta-carotene levels
rs6420424 AG Variant, reducing conversion leading to higher beta-carotene levels
rs6564851 GT Variant, reducing conversion leading to higher beta-carotene levels
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VERY HIGH SENSITIVITY: You have 10 variants. No refined carbohydrates or grains, max 20% of calories from carbs; 1.75-2.25 cups daily of fresh fruit,
squash, root vegetables (not white potatoes), legumes. Consume minimum 28g fibre daily. Eliminate grains for 6 weeks, 3 times a year.
CARBOYDRATE SENSITIVITY: ADRB2, PPARG, TCF7L2, ACE, FAB2 ADRB2 Variant Rs1042713 GG, 2
Commentary: The G allele is associated with obesity and insulin resistance in the presence of refined and excessive carbohydrate intake. Elimination of all refined carbohydrates and overall reduction in carbohydrate intake is recommended. For optimal weight loss, consider a high-fat diet.
PPARG Variant Rs1801282 CC, 2
Commentary: C allele plays a role in the unfavourable formation of fat cells and lipid metabolism as well as the development of type 2 diabetes. Elimination of all refined carbohydrates and overall reduction in carbohydrate intake is recommended.
TCF7L2 Variant Rs7903146, rs12255372 TT TT, 4
Commentary: The T allele is associated with impaired glucose homeostasis in the presence of refined and or excess carbohydrates. Elimination of all refined carbohydrates and overall reduction in carbohydrate intake is recommended. Higher risk of type 2 diabetes
ACE Variant Rs4341 GG, 2
Commentary: G allele indicates the SNP is deleted. Incrementing a reduction of ACE by 150% and 200% for both alleles respectively, which in turn increases the general sensitivity to carbohydrates. Elimination of all refined carbohydrates and overall reduction in carbohydrate intake is highly recommended.
COELIAC PREDISPOSITION: HLADQA1 / DQB1 rs2187668 Stabilised rs2395182 Stabilised rs7775228 Compromised rs4639334 No Call rs4713586 No Call rs7454108 Bad
GENETIC MACRONUTRIENTS
CARBOHYDRATE
CARBOYDRATE SENSITIVITY: ADRB2, PPARG, TCF7L2, ACE, FABP2
COELIAC PREDISPOSITION: HLADQA1 / DQB1
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GENETIC MACRONUTRIENTS
VERY High Sensitivity
Focus 1.75-2.75 cups daily of fresh fruit, squash, root vegetables (beets, carrots, etc. – not white potatoes), and legumes; consume a maximum, of 1/2 cup at a time and overall maximum of 20% of calories from carbohydrate daily. (2cups is roughly equivalent to 500ml in volume; ¾ cup is roughly equivalent to 200ml in volume Avoid grains for a period of 6 weeks three times a year, refined carbohydrate, fruit juice, and sugars (e.g. bread, pasta, biscuits, and including sweeteners like honey, agave, or brown rice syrup), limit foods naturally high in sugars (like bananas, dates, and dried fruit); eliminate dairy – use coconut milk as a substitute. 0.75 cup raw or frozen berries daily for antioxidants (berries are best!); ½ cup is about 70g of fruit. Eat meals 4-5 hours apart and incorporate a snack in between meals when going longer than 5-6 hours between meals’ always leave at least 2-3 hours between a meal and snack; for weight loss, consider intermittent fasting plan of two large meals per day (e.g. lunch and dinner) with no snacks. Eat a wide variety of fruit and carbohydrate sources from across the spectrum. Incorporate cinnamon, cinnamon tea, fresh ginger, and ginger tea into the diet to optimise insulin receptor sensitivity if tests well. Limit consumption of browned and burned carbohydrates.
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FATS / SATURATED FAT
OVER-ALL SENSITIVITY: ADRB2, ADRB3, APOA2, PPARG, TCR7L2, FTO, FABP2,
APOC3, LPL
SENSITIVITY: You have 4 variants. No processed trans/oxidized fats; dietary fat 30-45% of total calories; approximately 65-100g fat daily for women
SATURATED FAT SENSITIVITY: FABP2, FTO, TCF7L2 SENSITIVITY: You have (2) 1+ variant.
Saturated fat up to 8-10% of total calorie intake-preference for organic, grass-fed sources.
FAT SENSITIVITY: ADRB2, ADRB3, APOA2, APOC3, PPARG, TCF7L2, FTO, LPL ADRB2 Variant Rs1042714 GG, 0
Commentary: The C allele is associated with higher levels of obesity in the presence of dietary fats. Reduction of total fats and elimination of processed/ trans/ oxidative fats is recommended
ADRB3 Rs4994 TT, 0
Commentary: C allele is associated with higher levels of obesity in the presence of processed, trans and oxidative fats.
APOA2 Rs5082 TT, 0
Commentary: CC genotype demonstrated higher body mass index scores and a higher incidence of obesity, but only if they consumed a diet high in saturated fat. The C allele is associated with a greater inflammatory response to unhealthy fats. Elimination of processed/ trans / oxidative fate is highly recommended.
PPARG Rs1801282 CC, 2
Commentary: The C allele plays a role in the unfavourable formation of fat cells and lipid metabolism as well as the development of type 2 diabetes. Reduction of processed/ trans / oxidative fate is highly recommended.
APOC3 Rs5128, not in 23&Me No Call
Commentary: The C allele is associated with a impaired ability to transport triglycerides from the blood into the cells for use as energy along with obesity ad metabolic syndrome in the presence of excess dietary fats. Reduction of processed/ trans / oxidative fate is highly recommended.
TCR7L2 Rs7903146 TT, 2
Commentary: This gene codes for blood glucose homeostasis. Genetic variants are associated with type 2 diabetes. The T allele is associated with metabolic syndrome in the presence of excess dietary saturated fats. Reduction of saturated fats and elimination of processed trans/oxidative fats is recommended.
LPL Rs328 CG, 0
Commentary: CC Homozygous (but not Heterozygous) are associated with a somewhat increased sensitivity to dietary fats. Reduction of total fats and elimination of processed/trans. Oxidative fats is recommended.
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Follow up testing
Depending on the number of genetic markers present within your profile, you may wish to consider
some follow up testing. This can be completed at home easily, via Functional Medicine home test kits.
The required samples are returned to the lab via courier, and results emailed to you within 1-4 weeks.
Genetic polymorphisms / enzyme deletions heavily influence the outcome of health. The following are
tests which can measure the outcome of specific enzyme deletions which may be present in your profile.
GSH (reduced glutathione) to GSSG (oxidized glutathione); a ratio marker for oxidative stress and cellular
toxicity.
Heavy metal toxicity can be assessed using a comprehensive element profile (urine). This could also
assess nutrient elements.
Urinary d-glucarate can be used to asses exposure to industrial toxins or xenobiotics and indicates high
CYP450 activity.
Detoxification enzymes – reduced glutathione, glutathione peroxidase, SOD (superoxide dismutase) can
be measured.
Urinary porphyrins, by products of damaged haemoglobin, can be clues to damage done by chemical or
heavy metal toxins.
Urinary organophosphates – specific compounds such as sulphates, pyroglutamate and orotate can be
measured.
A comprehensive stool analysis can indicate dysbiosis, and can also detect beta-glucuronidase which can
cause reversal of glucuronidation.
Nutrition and Lifestyle
Substances that up-regulate Phase I, such as alcohol, smoking, caffeine, charred foods and certain
medications can have a deleterious effect upon the balance of P1 and P2 activity, because the Phase II
may not be able to keep up with the increased demand.
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The result would be an increase in activated intermediates and free radicals, which can react with and
damage proteins, RNA and DNA, further promoting a cycle of unbalanced detoxification in the
individual.
Your Healthy Detoxification Programme should include a number of the following
action steps:
• Exclude foods and that are likely to contain toxins or food allergens.
• Eliminate or reduce toxic household and personal care produce.
• Avoid excess exposure to environmental pollutants such as exhaust fumes.
• Optimise nutritional needs including adequate protein, nutritional cofactors and antioxidants.
• Encourage the use of organic.
• Ensure adequate hydration
• Include regular appropriate exercise; yoga, or massage to increase circulation and metabolism
• Use of steam baths, saunas or Peat mud baths to induce sweating
• Address gut infections and imbalanced ecology
• Reduce heavy metal exposure both in the environment and from within the body
Recommended