NUTRIGENETICS AND PERSONALZIED NUTRITION DUBAI 2021 draft.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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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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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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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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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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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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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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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?

Personalized nutrition for disease prevention. Using nutrigenetics and nutrigenomics in
clinical practice

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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INTOLERANTA LA FRUCTOZA
EREDITARA GENA ALDOB( ALDOLAZA B)
MALABSORBTIA FRUCTOZEI
incapacitatea celulelor de la suprafata intestinelor de a
descompune eficient fructoza.

DETOXIFICATION
PHASE I
• 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 *

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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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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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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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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%

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

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

NUTRIGENETICS
AND COVID-19
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Personalized nutrition for disease prevention. Using nutrigenetics and nutrigenomics in
clinical practice

The VDR gene is expressed in most
tissues of the body and has diverse
effects on different systems. One
role is in the regulation of the
intestinal transport of calcium,
others include though regulating a
variety of other metabolic pathways,
such as those involved in the
immune response and cancer.
VDR, GC, CYP2R1 variations and COVID-19

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Personalized nutrition for disease prevention. Using nutrigenetics and nutrigenomics
in clinical practice

Glutathione peroxidase is a
“selenoprotein”, i.e.
dependent on selenium for its
activity. Gpx1 is an anti-
oxidant enzyme that protects
the cell by removing
hydrogen and lipid peroxides.
GPX VARIATION, SELENIUM AND COVID 19

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Personalized nutrition for disease prevention. Using nutrigenetics and nutrigenomics
in clinical practice

IL6, TNF alpha variations and COVID 19
IL6 Rs1800795
G-174 C
IL6R Rs2228145
Asp358Ala
TNF Rs1800629
G-308A
CRP rs1205

THE FUTURE?
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