NUTRIGENETICS AND PERSONALZIED NUTRITION DUBAI 2020.pptx

Personalized nutrition for disease prevention.Using
nutrigenetics and nutrigenomics in clinical practice
MARIA VRANCEANU
UNIVERSITY OF MEDICINE AND PHARMACY CLUJ NAPOCA
ROMANIA
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Personalized nutrition for disease prevention. Using nutrigenetics
and nutrigenomics in clinical practice
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SCIENTIFIC EVIDENCES BASED?
YES or NOT?

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•irreversible brain damage and intellectual disabilities
within the first few months of life
•behavioral problems and seizures in older children
PAH (Phenylalanine hydroxylase)
gene

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GALT GENE

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BCKDHA, BCKDHB, DBT GENES

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Type 1 hemochromatosis results from
mutations in the HFE gene, and type 2
hemochromatosis results from mutations in
either the HJV or HAMP gene. Mutations in
the TFR2 gene cause type 3 hemochromatosis

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Signs and symptoms of a biotinidase deficiency can appear several days after birth. These
include seizures, hypotonia and muscle/limb weakness, ataxia, paresis, hearing loss, optic
atrophy, skin rashes (including seborrheic dermatitis and psoriasis), and alopecia. If left
untreated, the disorder can rapidly lead to coma and death.
Biotinidase deficiency is an inherited disorder in which the
body is unable to recycle the vitamin biotin.
BTD GENE

Learning objectives
 Understanding the molecular basis of nutrition
 Understanding the SNP affecting dietary requirement
 Critically consider and evaluate the SNP involved in diabetes predisposition,
cardiovascular diseases, early cognitive decline, inflammation, oxidative stress.
 Understanding how interpreting the SNP and how to use the result of genetic
test information to design bespoke diets, including the required food
supplements for the patient
Personalized nutrition for disease prevention. Using
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GENETICS
study of heredity in general
and of genes in particular.
Heredity is a biological process
where a parent passes certain
genes onto their children or
offspring.

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MENDELIAN AND CLASSICAL GENETICS
Mendelian inheritance
Law of segregation
During gamete formation, the alleles for
gene segregate from each other so that each
gamete carries only one allele for each gene.
Law of independent
assortment
Genes for different traits can segregate
independently during the formation of
Law of dominance
Some alleles are dominant while others are
recessive; an organism with at least one
dominant allele will display the effect of the
dominant allele.

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MOLECULAR BASIS OF INHERITANCE
Molecular Structure of Nucleic Acids: A Structure for Deoxyribose Nucleic Acid"
1st article published to describe the discovery of the double helix structure of DNA, using X-ray
diffractionn and the mathematics of a helix transform. It was published by Francis Crick and James
D. Watsonn in the scientific journal Nature on pages 737–738 of its 171st volume (dated 25 April
1953)

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The Human Genome Project (HGP)
International, collaborative research program.
Whole genome sequencing
All our genes together are known as our
genome.
The project formally launched in 1990 and was
declared complete on April 14, 2003
Craig Venter-Celera Francis Collins-NIH

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• Haplotype map (HapMap) of the human genome, to describe the common patterns
of human genetic variation.
• HapMap is used to find genetic variants affecting health, disease and responses to
drugs and environmental factors.
• The information produced by the project is made freely available for research

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A haplotype is a group of genes within an organism that was inherited together
from a single parent.
By examining haplotypes, scientists can identify patterns of genetic variation that are
associated with health and disease states.

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The most popular haplotype model is the Human Leukocyte Antigen (HLA) system,
with a fundamental role in the immune defense of the body
Many genetic diseases originate in an anomaly of HLA genes

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HUMAN DNA
MV DNA IS 99.9% THE SAME OF BARAK OBAMA DNA.

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GENETIC VARIATIONS
Difference in DNA sequences between individuals within a population.
occurs in:
• germ cells i.e.
• sperm and egg
• somatic (all other) cells.
• Variation in germ cells can be inherited, affect population dynamics, and ultimately evolution.
Mutations and recombination are major sources of variation.

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TYPES OF GENETIC VARIATION

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What are single nucleotide polymorphisms (SNPs)?
SNPs may help predict
• an individual’s response to certain drugs
• susceptibility to environmental factors such as toxins
• risk of developing particular diseases.
can also be used to track the inheritance of disease genes within families.
Future work : SNPs associated with complex diseases such as heart disease, diabetes, and cancer.

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The big dogate the cat and the fat rat
the end
The big hog ate the cat and the fat rat
the end

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SNP does not indicate a disease or health condition but can condition the body's responses in
different ways:
altering the expression of the genes and causing, as the case, production of a higher or lower
amount of the protein than the normal amount.
It can also alter protein efficiency by producing bad or unstable proteins.
C677T
CC
CT
TT
A1298C
AA
AC
CC

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SNPs
• susceptibility to some intolerances (lactose, gluten, caffeine, etc.)
• predisposition to a range of pathologies such as osteoporosis,
cardiovascular diseases, Alzheimer's, diabetes
• can create a dietetic resistance
• may influence the amount of detoxifying substances or
• inflammatory activity with serious health consequences.

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Why genetic testing is important?
GRS !!!
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One Size Does Not Fit All!
Genomic Background Will Help Identify Responders to Foods and
Components.
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Winston Churchill –heavy drinker, smoker, nerver
practiced sport
Died-aged 90
Jim Fixx
Fixx died on July 20, 1984, at age 52 of a fulminant heart attack. Fixx
was genetically predisposed—his father died of a heart attack at 43
after a previous one at 35, and Fixx himself had a congenitally
enlarged heart
Genes-Environment-Disease(GRS)
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Disease Threshold
Environment
Genes
Genes PLUS Environment cause disease
Pima
Mexico
Pima
Arizona
Caucasian
Simple diet
Phisical activity
Western diet
Sedentary
GENES →ENVIRONMENT→DISEASE
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Genetic polymorphisms affecting dietary requirements.
the genes can tell what to eat?

LCT gene
CC-intolerant
CT-tolerant
TT-tolerant
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LCT(Lactase) gene
provides instructions for making an enzyme called lactase. This enzyme helps
to digest lactose, a sugar found in milk and other dairy products.
Cytogenetic Location: 2q21.3
Lactose Intolerance – 4 types:
Congenital lactase deficiency- one of the approximately 30 rare recessive disorders that are relatively
common in Finland
Primary lactase deficiency- is genetic, only affects adults, and is caused by the absence of a lactase
persistence allele. In individuals without the lactase persistence allele, less lactase is produced by the body over
time, leading to hypolactasia in adulthood.
Secondary lactase deficiency- is caused by an injury to the small intestine. This form of lactose intolerance
can occur in both infants and lactase persistent adults and is generally reversible.
Developmental lactase deficiency- happens in babies who are born prematurely. It usually goes away on its
own, lasting for only a short time after birth.
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LCT-13910C>T; LCT-22018G>A
2 SNPs have been associated with lactase expression:
• C−13910 (C at position -13910 upstream of the gene LCT)
• G−22018 (G at position -22018) are related to lactase
• T−13910 and A−22018 are related to lactase persistence
In northern Europe, the GG genotype of the rs4988235 SNP in and the CC genotype of the
rs182549 SNP were identified as causal for lactose intolerance.
In North Africa and the Middle East, a different set of
are associated with lactose intolerance:
• CC for rs145946881
• AA for rs41380347
• GG for rs41525747.
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Living
with
lactose
intoler
ance
Try a lactose-free diet for 8 weeks. After 8 weeks, add foods with lactose back into your diet gradually and watch your results. This can give you a
clearer idea of what and how much of certain foods and beverages you can consume without problems.
People with lactose intolerance are generally more likely to tolerate hard cheeses, such as cheddar or Swiss, than a glass of milk. A 1.5-ounce
serving of low-fat hard cheese has less than 1 gram of lactose, while a 1-cup serving of low-fat milk has about 11 to 13 grams of lactose.
However, people with lactose intolerance are also more likely to tolerate yogurt than milk, even though yogurt and milk have similar amounts of
lactose.
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Gluten intolerance, celiac disease and NCGS
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Genetic predisposition plays a key role in CD and is strongly
associated with specific HLA class II genes known as HLA-
DQ2 and HLA-DQ8 located on chromosome 6p21.
Approximately 95% of CD patients express HLA-DQ2, and the
remaining patients are usually HLA-DQ8 positive.
However, the HLA-DQ2 allele is common and is carried by
approximately 35% of Caucasian individuals. Thus, HLA-DQ2or HLA-
DQ8 is necessary for disease development but is not sufficient for
disease development; its estimated risk effect is only 36-53%.
Global Prevalence of Celiac Disease 1.4%
Global prevalence of NCGS 6%
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ACTION PLAN!
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GSTM1 & GSTT1 (glutathione S-transferases) are involved in phase II of the detoxification process
by which toxins are removed from the body (via the conjugation of toxic molecules with
glutathione, facilitating their elimination).
According to genetic variation the enzyme activity is either present (Insertion or “I”) or absent
(Deletion or “D”).
GSTM1 null allele
Add extra portions of cruciferous vegetables and consume on average at least 3-4 portions per
week. It is also recommended that add frequent consumption of allium vegetables (garlic, onions,
etc) to the diet.
Gene Result Effect
GSTM1 D **
GSTT1 I
DETOXIFICATION FASE II
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GPX gene and selenium
is part of a family of enzymes that catalyze the
degradation of organic hydroperoxides resulting from
normal metabolic processes and ensure the
protection of proteins, lipids and nucleic acids against
the action of oxidizing molecules,
GPX is a selenium-dependent enzyme.
A selenium deficiency, even insignificant, affects the
activity of the enzyme and determines the
peroxidation of the membranes and the increase of
their permeability.
Polymorphisms identified in the GPX1 can increase
atherogenesis risk. Low levels of selenium can also
contribute to the development of autoimmune
disorders, such as psoriasis and thyroid disease.

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Major public health epidemic despite recent advances in both
pharmaceutical and technologic treatment options. According to 2017
International Diabetes Federation (IDF) statistics, there are
approximately 425 million people with diabetes worldwide.
Type 2 diabetes (T2D) has long been identified as an incurable chronic
disease. The best outcome that has been expected is amelioration of
diabetes symptoms or slowing its inevitable progression. Approximately
50% of T2D patients will need insulin therapy within ten years of diagnosis.
T2DM

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T2DM is a very complex disease, for which the hallmarks are -βcell failure and insulin
resistance (IR). A combination of genetic, epigenetic, environmental, and lifestyle
factors, such as diet, are responsible for the onset and development of T2DM.

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The total estimated cost of diagnosed diabetes in 2017 is $327 billion, including $237 billion in direct
medical costs and $90 billion in reduced productivity.
For the cost categories analyzed, care for people with diagnosed diabetes accounts for 1 in 4 health care
dollars in the U.S., and more than half of that expenditure is directly attributable to diabetes. People with
diagnosed diabetes incur average medical expenditures of ∼$16,750 per year, of which ∼$9,600 is attributed to
diabetes. People with diagnosed diabetes, on average, have medical expenditures ∼2.3 times higher than what
expenditures would be in the absence of diabetes.

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Schematic diagram of the role of nutritional, genetic and epigenetic factors in the development
of T2DM. Nutrients, dietary patterns and genetic makeup (SNPs) have a direct impact on T2DM risk.
Parental nutrition, prenatal and perinatal nutrition induce epigenetic modifications that increase the
susceptibility of T2DM development during adulthood. The epigenetic modifications can be inherited
to following generations. +: Increase; -: decrease

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Are you obese? Maybe
is the fault of your
grandfather!

Dutch Famine:Winter 1944-1945
In the Duch Famine (1944-1945) cohort, 60 years old adults prenatal exposure to famine
showed hypomethylationofwholebloodIGF2gene
Resource-richpostnatalenvironment,highplasmaglucoselevelswill coincidewith
insulin resistance, greatly increasing the risk for metabolic disease in laterlife
In mammals only the allele for insulin-like growth
factor-2 (IGF2) inherited from one's father is active;
that inherited from the mother is not

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Gene Result Effect
ACE II
PPARG Pro-Pro **
TCF7L2 TC *
ADRB2 Gly-Gly **
CLOCK TT
PLIN GA *
INSIG2 GC
Genes involved in T2DM
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ACE
Long name: Angiotensin I
converting enzyme
There are many studies to show the link between the angiotensin-
converting enzyme (ACE) insertion/deletion (I/D) gene
polymorphism and the prevalence of type 2 diabetes mellitus
(T2DM)
II ID DD
the I allele:
• lower ACE activity
• not increased
sensitivity
D variation:
• Increased activity of RAS
• increased sensitivity to refined
carbohydrates
• insulin resistance.
The negative effects of the D variant on
insulin sensitivity may be ameliorated by
regular exercise and low GL diet.
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ADRB2 (Gln27Glu)
Beta-adrenergic receptors are found in fat cells, liver and
skeletal muscle where they are involved in fat mobilization,
blood glucose levels and in vasodilation.
CC
(Gln-Gln)
CG
(Gln-
Glu)
GG
(Glu-Glu)
This genotype is not associated
with increased sensitivity to
refined carbohydrates or fats
Glu27 variant:
• increased sensitivity to refined
carbohydrates
• increased fat accumulation especially
visceral fat in women
• Higher BMI in women
• Strong yo-yo effects
Diet prescribtion: GL not more than 80/day
May benefit from higher intensity of
exercise for fat loss.
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TCF7L2
Long name:
Transcription Factor 7-
Like 2
implicated in blood glucose homeostasis and the SNP tested affects insulin
sensitivity.
The polymorphism has also been shown to affect weight loss according to diet type
with the TT homozygotes responding poorly to high fat/low carb diets. The T allele
may also make weight loss harder with standard diet & exercise protocols
TT genotype is linked to negative insulin/glucose balance the good news is that
these effects can be neutralised by the correct diet, reducing
weight if overweight and regular exercise.
CC CT TT
CC does not increase
sensitivity to refined
carbohydrates or saturated
fats. Not associated with
increased exercise
indications
CT indicates a reduction in
refined carbohydrates and
an increase in fibre can be
important in weight loss.
One copy of the T allele is
associated with a
moderately increased fat
sensitivity especially to
saturated fats.
Increased intensity
exercise may be more
beneficial and reduced
refined carbs: 8% from total
calories
TT indicates a reduction in
refined carbohydrates and
an increase in fibre can be
important in weight loss.
TT is associated with
significantly increased fat
sensitivity especially to
saturated fats. Increased
intensity exercise may be
more beneficial
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PPARG
This long named protein is a receptor found in the cell nucleus – PPARG is important in
the formation and development of adipocytes (fat cells)..
The SNP tested changes the amino acid at position 12 in the protein from Proline to
Alanine.
This gene enables survival during periods of food shortages through a mechanism
conserved over generations under the selection pressure of under-nutrition. This
nutrients-saving mechanisms in the growing individual, lead to excessive storage later
on and increased risk of metabolic disorders
Long name:
Peroxisome
Proliferator-Activated
Receptor Gamma
CC (Pro-Pro) CG (Pro-Ala) GG (Ala-Ala)
Individuals with CC genotype are
more sensitive:
• to refined carbohydrates and
saturated fats
• sedentary lifestyle
• Genetic predisposition to
obesity( OR:1.38)
• Increased risk of fat storage
around the organs
• Yo-yo effect
Caloric restriction is essential
higher proportions of PUFA and/or
MUFA in the diet compared to
saturated fats is linked to a lower
BMI
ProAla is not
associated with
increased sensitivity to
refined carbohydrates
or saturated fats
AlaAla is not associated
with increased sensitivity
to refined carbohydrates
or saturated fats
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“Diabetes reversal” is a term that has found its way into scientific articles and the lay press alike; “remission” has
also been used.
While the exact criteria are still debated, most agree that a hemoglobin A1c (HbA1c) under the diabetes
threshold of 6.5% for an extended period of time without the use of glycemic control medications would qualify
.
Excluding metformin from the glycemic control medications list, as it has indications beyond diabetes, may also
be a consideration.

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Despite the growing evidence that reversal is possible, achieving reversal is not commonly
encouraged by our healthcare system. IN FACT, REVERSAL IS NOT A GOAL IN DIABETES GUIDELINES.
Specific interventions aimed at reversal all have one thing in common: they are not first-line standard of care.
This is important, because there is evidence suggesting that standard of care does not lead to diabetes
reversal. This raises the question of whether standard of care is really the best practice.
A large study by Kaiser Permanente found a diabetes remission rate of 0.23% with standard of care.
A significant number of studies indicate that diabetes reversal is achievable using bariatric surgery

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Bariatric surgery
Long-term outcomes from bariatric surgery depend on multiple factors, including type of
surgery performed, patient comorbidities, patient readiness for lifelong dietary change, and ongoing
surveillance.
While bariatric surgery has been demonstrated to be safe it is important to recognize that it is not without
risks

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GENE –DIET INTERACTION IN T2DM
Diabetes→ the biggest global health burdens of the current century.
The International Diabetes Federation (IDF) Atlas 2015 →415 million adults suffer from
this disease and diabetes prevalence is constantly increasing.
the hallmarks are β-cell failure and insulin resistance (IR). A combination of genetic, epigenetic, environmental, and
lifestyle factors, such as diet, are responsible for the onset and development of T2DM
The nutrient gene interaction may modulate the gene expression via different mechanisms:
• Directly
• Through their metabolites
• By activating various signalling molecules of complex metabolic pathways

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Polyphenol-Gene Interactions in T2DM Pathogenesis
Large and heterogeneous group of plant products found in fruits, vegetables,legumes, cereals and chocolate
• Flavonoids
• Lignans
• phenolic acids
• stilbenes
BENEFICIAL EFFECTS OF POLYPHENOL-RICH FOODS IN
• lowering the risk of T2DM
• improving inflammation and glycaemia markers in Type 2 diabetic subjects .
Dietary polyphenolic compounds may exert hypoglycemic effects in multiple ways:
• diminished carbohydrate digestion and glucose absorption
• inhibition of glucose release,
• stimulation of insulin secretion
• protection of pancreatic -cells against glucotoxicity
• Increased glucose uptake in peripheral tissues by modulating intracellular signaling
• antioxidant activity
• inhibition of advanced glycation end product formation

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FLAVANONE (naringenin and hesperetin)
FLAVONOLS (quercetin and isorhamnetin), as well as the phenolic acid,
were associated with a lower risk of developing T2DM in a time-dependent manner
EGCG supplementation (1% in diet) in obese db/db mice improved glucose
Tolerance
increased glucose-stimulated insulin secretion from pancreatic –βcells
HUMAN?
Some studies have demonstrated that an acute, high dose of EGCG concentrated green tea supplement could
control postprandial hyperglycemia,
long-term studies in Type 2 diabetic adults did not reveal an hypoglycemic effect
Polyphenol-Gene Interactions in T2DM Pathogenesis

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RESVERATROL → reducing diabetic complications in many organs and tissues liver and pancreatic –
cells
• improvement of glucose homeostasis
• decrease in IR
• improvement in insulin secretion
• amelioration of metabolic disorders
• anti-inflammatory molecule in diabetes and other chronic diseases associated
with chronic activation of NF-kB

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CARBOHYDRATES < 49%

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GENES INVOLVED IN FATS METABOLISM AND CVR

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GENE APOA5
APOA5 is an important determinant of plasma triglyceride
levels. It is believed that APOA5 affects lipoprotein
metabolism by stimulating VLDL catabolism culminating in
reduction of plasma TG. APOA5 is a major gene that is
involved in triglyceride metabolism and modulated by
dietary factors and pharmacological therapies. Moreover,
genetic variants at this locus have been significantly
associated with both coronary disease and stroke risks.
There are two SNPs that modulate the effect of dietary
factors (-1131T >C and 56 C>G). -1131T >C is modulated the
effect of PUFA on triglyceride levels –
Carriers of the C allele show increased TG levels when n6
PUFA are high. Both rarer alleles have been associated with
increased risk factors of CVD (e.g. carotid intima thickness,
TG levels, etc).

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LPL gene provides instructions for making an enzyme called
lipoprotein lipase. This enzyme is found primarily on the surface of
cells that line tiny blood vessels (capillaries) within muscles and in
fatty (adipose) tissue.
Lipoprotein lipase plays a critical role in breaking down fat in the
form of triglycerides, which are carried from various organs to the
blood by molecules called lipoproteins.
Mutation in this gene are correlated with high level of triglyceride
and low HDL level.

VITAMIN B METABOLISM, METHYLATION AND HOMOCYSTEINE LEVELS
MTHFR
plays a critical role in homocysteine metabolism by catalyzing the conversion of
5, 10 methylenetetrahydrofolate to 5-methyltetrahydrofolate, the predominant circulatory form of
folate and the methyl-group donor in the B12-dependent remethylation of homocysteine to
methionine.
Two common polymorphisms of MTHFR gene, the thermolabile C677T and A1298C
polymorphism may contribute to hyperhomocysteinemia.
Reccomendations: increase vit B consumption
BASIC METHYLATION PROTOCOL
Galenical formulation
400 mcg of folate
3 mg of vitamin B6
5 mcg of vitamin B12
2.4 mg of vitamin B2
12.5 mg of zinc
250 mg of bethaine
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Kuwait – 37.9%
Jordan – 35.5%
Saudi Arabia – 35.4%
Qatar – 35.1%
Libya – 32.5%
Egypt and Lebanon – 32%
United Arab Emirates – 31.7%
Iraq – 30.4%
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Genetic variations contributes to the development of
obesity

LEP and LEPR genes-monogenic obesity
Congenital leptin deficiency is a condition that causes severe obesity
beginning in the first few months of life. Affected individuals are of
normal weight at birth, but they are constantly hungry and quickly
gain weight.
LEP gene mutations that cause congenital leptin deficiency lead to
an absence of leptin
This condition is inherited in an autosomal recessive pattern
Leptin treatment reduces food intake

LEPR-rs1137100 (K109R)
LEP-rs1137101 (Q223R)
The most studied SNPs associated with severe
obesity

• SNP (rs17782313)-is confirmed to be associated with overweight and obesity.
• The minor allele (C-allele) of this SNP is believed to have reduced MC4R expression
when compared to the major allele (T-allele).
• The loss of function MC4R mutations lead to its carrier’s increased appetite in
childhood.
• A typical feature of the affected individuals is:
• Hyperphagia
• insatiable appetite.
A typical meal of mutation carriers contains about three times the number of calories than
that in non-mutation carrying siblings.
• carriers of the C-allele of the MC4R SNP rs17782313 eat larger amounts of food,
snack more frequently, like foods containing more fat content, and are
having weak satiety when tested with eating behavior questionnaires (Choquet &
Meyre. 2011; Cecil et al., 2012).
MC4R-MELANOCORTIN 4 RECEPTOR
18q21.32

FTO rs9939609 T/A
Long name: Alpha-Ketoglutarate Dependent Dioxygenase
This gene is a nuclear protein of the AlkB related non-haem
iron and 2-oxoglutarate-dependent oxygenase superfamily but
the exact physiological function of this gene is not known.
Satiety can be described as the feeling of fullness after you eat.
The A/A genotype at rs9939609 in the FTO gene was
associated with "Difficulty in Feeling Full”
AA AT TT
Indicates a hunger for fats, wanting large
portions of food and greater snacking. By
eating excessively, the patient may
overstore these fats. If their results for
the FTO gene are either AA or AT they
could show an increased tendency to
obesity and hypertension.
Not associated

Fasting decreases while a high-fat diet increases FTO
expression levels specifically within the arcuate nucleus of the
hypothalamus. In keeping with this, reducing FTO expression in
the arcuate nucleus increases food intake, while
overexpressing FTO decreases food intake

CYP1A2 is the gene coding for the cytochrome P450 enzyme involved in phase I
(activation) of removing toxins-such as carcinogens of meat and smoke - and also
metabolises caffeine.
The genotype of the homozygous alleles A (AA) coding for the rapid version of the
enzyme witch activates more rapidly potentially toxic substances present in meat cooked
at high temperatures.
EPHX1 is a critical biotransformation enzyme that converts epoxides from the
degradation of aromatic compounds to trans-dihydrodiols which can be conjugated and
excreted from the body. Epoxide hydrolase functions in both the activation and
detoxification of epoxides.
Gene Results Limited grilled
meat
CYP1A2*1F AA **
EPHX1 Tyr/His *
DETOXIFICATION FASE I
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GSTM1 & GSTT1 (glutathione S-transferases) are involved in phase II of the detoxification process
by which toxins are removed from the body (via the conjugation of toxic molecules with
glutathione, facilitating their elimination).
According to genetic variation the enzyme activity is either present (Insertion or “I”) or absent
(Deletion or “D”).
GSTM1 null allele
Add extra portions of cruciferous vegetables and consume on average at least 3-4 portions per
week. It is also recommended that add frequent consumption of allium vegetables (garlic, onions,
etc) to the diet.
Gene Result Effect
GSTM1 D **
GSTT1 I
DETOXIFICATION FASE II
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GENETIC OF INFLAMMATION

Acute inflammation
begins within seconds to minutes following the injury of tissues.

Chronic Inflammation
~
Overload of proinflammatory
cytokines in the body which
leads to catastrophic effects
when released sistematically
in the body

Chronic Inflammation
SKIN AGING
KIDNEY AND LIVER DAMAGE
ARTHROSIS
OSTEOPOROSIS
SARCOPENIA
BRAIN AGING
OBESITY
INSULIN RESISTANCE
TUMORS
ATHEROSCLEROSIS-MI
IMMUNOSENESCENCE

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TNF this gene encodes a multifunctional proinflammatory cytokine that belongs to the tumor
necrosis factor (TNF) superfamily. This cytokine is mainly secreted by macrophages. It can bind to,
and thus functions through its receptors TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. This cytokine is
involved in the regulation of a wide spectrum of biological processes including cell proliferation,
differentiation, apoptosis, lipid metabolism, and coagulation.
This cytokine has been implicated in a variety of diseases, including autoimmune diseases, insulin
resistance, and cancer.
IL 6 This gene encodes a cytokine that functions in inflammation and the maturation of B cells. In
addition, the encoded protein has been shown to be an endogenous pyrogen capable of inducing
fever in people with autoimmune diseases or infections. The protein is primarily produced at sites of
acute and chronic inflammation, where it is secreted into the serum and induces a transcriptional
inflammatory response through interleukin 6 receptor, alpha.
The functioning of this gene is implicated in a wide variety of inflammation-associated disease states,
including suspectibility to diabetes mellitus and systemic juvenile rheumatoid arthritis.
CRP levels rise dramatically during inflammatory processes occurring in the body, due to a rise in IL-6
levels. It is thought to assist in complement binding to foreign and damaged cells and enhances
phagocytosis by macrophages, which express a receptor for CRP. It is also believed to play an
important role in innate immunity, as an early defence system against infections. CRP is used as a
marker for inflammation. Several studies suggest that raised CRP levels increase risk of diabetes (type
2), hypertension and cardiovascular disease. Levels may be increased by high intakes of trans-fat.
There is a SNP at position 219 in the gene (219 G>A) which affects CRP levels, the G allele is
associated with significantly higher levels of CRP

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Clinical monitoring
Get tested for chronic inflammation
 Omega 3 screening
-Ratio omega 6/omega3;
reference parameters: OMS-4:1 antiaging medicine 3:1 and
 C reactive protein
Reference parameters: OMS 0-10 mg/L
Antiaging medicine: < 1 mg/L
 hsCRP-stronger predictor of heart diseases than LDL cholesterol
References parameters in antiaging medicine < 0.8mg/L
 Fibrinogen
Reference parameters: OMS 150-400mg/dL
antiaging medicine < 280mg/dL

Omega
3
Inflammation
Plt aggregation
Omega
6
Inflammation
Plt aggregation

Food rich in omega 3
 Mackerel 5134 mg/100 grams
 Salmon 2260 mg/100 grams
 Cod liver oil 2664 mg in a single tablespoon
 Herring 1729 mg/100 grams
 Sardines 1480 mg/100 grams
 Anchovies 2113 mg/100 grams
 Oyster 672 mg/100 grams
 Walnuts2542 mg per ounce, which amounts to 7 about walnuts.
 Chia Seeds 4915 mg per ounce (28 grams).
 Flaxseeds 2338 mg per tablespoon of seeds, 7196 mg per tablespoon of
oil.
 Hemp Seeds 1000mg per tablespoon of seed
 Soybeen 1443 mg per 100 grams

OMEGA-3 AND BIOAVAILABILITY
 Very limited amount of Δ-6-desaturase in the digestive tract and no more than
5% of ingested ALA( alpha linolenic acid) can be converted in the final metabolites
EPA and DHA
 Δ-6-desaturase is more deficient in elderly, in diabetics, hypertensives and in
persosns who suffer from neurodegenerative diseases.
 Direct supplementation with bioavailable omega 3 is more useful
 Dosage: 2-3 g/day

Antiinflammatory herbs
Zingiber officinalis(ginger roots)
-suppresses prostaglandin synthesis by inhibiting
cyclo-oxygenase-1 and cyclo-oxygenase-2
-suppresses leukotriene biosynthesis, by inhibiting 5-
lipoxygenase
-association with the Alpina galanga (Zingiberaceae
family), is able to inhibit the induction of several genes
involved in the inflammatory response.
-6-Shogaol performs an action against neuro-
inflammation in animal models of Parkinson's disease,
in LPS-induced inflammation and in transient
ischemies.
-6-shogaol can however play a role in the inhibition of
activation of glial cells and in reducing memory
deficits in animal models of dementia

Curcuma longa
strong anti-inflammatory action
Suppresses genes that ratched up
inflammation COX2gene
-detoxifying and immunostimulating agent
-the curcuminoids are also able to exert an
antioxidant action, with the blocking of free
circulating radicals and the inhibition of the
formation of new ones.

Antiinflammatory diet
Abundant fruit and vegetables
Healthy fat: olive oil, avocado ,
nuts
Low glycemic load diet
Green tea
Turmeric
Ginger
Exercises
• Caloric restriction
decrease inflammation
• Intermitent fasting
decrease inflammation

Oxidative stress
113

Reactive oxygen species (ROS) are produced by living organisms as a result of
normal cellular metabolism and environmental factors, such as air pollutants or
cigarette smoke.
ROS are highly reactive molecules and can damage cell structures such as
carbohydrates, nucleic acids, lipids, and proteins and alter their functions.
Aerobic organisms have integrated antioxidant systems, which include enzymatic
and nonenzymatic antioxidants that are usually effective in blocking harmful
effects of ROS.
However, in pathological conditions, the antioxidant systems can be overwhelmed
114

Oxidative stress contributes to many pathological conditions and
diseases
115

Oxidants
Endogenous Sources of ROS
 ROS are produced from molecular oxygen as a result of normal cellular metabolism.
 ROS can be divided into 2 groups: free radicals and nonradicals.
 Molecules containing one or more unpaired electrons and thus giving reactivity to
the molecule are called free radicals.
 When 2 free radicals share their unpaired electrons, nonradical forms are created.
The 3 major ROS that are of physiological significance are
superoxide anion (O2
−.), hydroxyl radical (•OH), and
hydrogen peroxide (H2O2).
116

Exogenous Source of Oxidants
117

Antioxidants
The human body is equipped with a variety of antioxidants that serve to
counterbalance the effect of oxidants.
enzymatic
118

Nonenzymatic Scavenger of Antioxidant
Defenses
Scavenger against various
radicals
(HO •, ROO • and O2)
Reducing the tocopheryl
radical regenerates vitamin E
119

Glutathione
GSH is highly abundant in all cell
compartments and is the major soluble
antioxidant.
GSH detoxifies hydrogen peroxide and lipid
peroxides via action of GSH-Px.
GSH donates its electron to H2O2 to reduce it
into H2O and O2.
Reduced glutathione donates protons to
membrane lipids and protects them from
oxidant attacks.
GSH/GSSG ratio
is a major biomarker of oxidative stress
120

Vitamin E (α-Tocopherol)
 Lipid-soluble vitamin E is concentrated in the hydrophobic
interior site of cell membrane and is the principal defense
against oxidant-induced membrane injury.
 Vitamin E donates electron to peroxyl radical, which is
produced during lipid peroxidation.
 α-Tocopherol is the most active form of vitamin E and the
major membrane-bound antioxidant in cell.
 Vitamin E triggers apoptosis of cancer cells and inhibits
free radical formations.
121

Carotenoids (β-Carotene)
Carotenoids are pigments found in plants.
Primarily, β-carotene has been found to react with
peroxyl (ROO•), hydroxyl (•OH), and superoxide (O2
−.)
radicals.
Carotenoids show their antioxidant effects in low
oxygen partial pressure but may have pro-oxidant
effects at higher oxygen concentrations.
Both carotenoids and retinoic acids (RAs) are capable
of regulating transcription factors.
β-Carotene inhibits the oxidant-induced NF-κB
activation and interleukin (IL)-6 and TNFα production.
Carotenoids also affect apoptosis of cells.
Antiproliferative effects of RA have been shown in
several studies. This effect of RA is mediated mainly by
retinoic acid receptors and vary among cell types.
In mammary carcinoma cells, retinoic acid receptor
was shown to trigger growth inhibition by inducing cell
cycle arrest, apoptosis, or both
Βcaroten molecule 3D image
122

Effects of Oxidative Stress on DNA
ROS can lead to DNA modifications in several ways:
Degradation of basis
Single or double strand DNA break
purine, pyrimidine or sugar-bound modifications
mutations, deletions or translocations
cross-linking with proteins.
Most of these DNA modifications are highly relevant to carcinogenesis, aging, and
neurodegenerative, cardiovascular, and autoimmune diseases.
Tobacco smoke, redox metals, and nonredox metals, such as iron, cadmium, chrome, and
arsenic, are also involved in carcinogenesis and aging by generating free radicals or binding
with thiol groups.
Formation of 8-OH-G is the best-known DNA damage occurring via oxidative stress
123

Clinical monitoring
d-ROMs test
BAT test
(biological
antioxidant
potential)
 The d-ROMs test essentially determines the concentration of hydroperoxides (ROOH) in the
blood
 can be performed on samples of whole blood (generally finger prick capillary blood)
 the units of measurement for the test is expressed in U. CARR.
 normal range 250-300 uCARR
 One U. CARR is equal to 0.08 mg/dL of a solution of hydrogen peroxide.
124

• Measurement of Urinary 8-OHdG
• Measurement of F2-isoprostane
• Measurement of Malondialdehyde
Other test
125

Antioxidant therapy
Vitamine C
Vitamine E
Glutamine
Combined antioxidants (selenium, β-
carotene, vitamin C, vitamin E and
methionine)
Glutathione precursors [S-adenosyl
methionine (SAMe)]
Coenzyme Q10
Pycnogenol
Alfa lipoic acid
Resveratrol
Quercetin
Hesperedin
126

THE FUTURE?
127

NUTRIGENETICS AND PERSONALZIED NUTRITION DUBAI 2020.pptx

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