This document discusses genetic factors that influence obesity and eating behaviors. It begins by outlining learning objectives around understanding the molecular basis of obesity and evaluating genetic influences on food attitudes and satiety. It then provides background on the global prevalence of obesity in various countries. The rest of the document discusses several specific genes like LCT, TCF7L2, PPARG, and ACE that influence traits like lactose intolerance and response to dieting. It emphasizes that genetics can help tailor diets and lifestyle recommendations based on an individual's genetic profile to increase success with weight loss and management.

1. Dr. MARIA VRANCEANU
UNIVERSITY OF MEDICINE AND PHARMACY CLUJ NAPOCA
ROMANIA

2.  Understanding the molecular basis of obesity and eating
behavior
 Describe and evaluate the genetic factors influencing
attitudes to food and obesity.
 Critically consider the role of SNPs involved in controlling
eating and satiation
 Asses genetic explanation of food preferences.
 Genetic explanation for the success and failure of dieting.
Learning objectives

5. HIPPOCRATES 400 BC

6. 2018 A.D.

7. 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%

9. Why genetic testing is important?
GRS !!!

10. 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)

11. Disease Threshold
Environment
Genes
Genes PLUS Environment cause disease
PimaMexico
PimaArizona
Caucasian Simple diet
Phisical activity
Western diet
Sedentary
GENES →ENVIRONMENT→DISEASE

12. NUTRIGENE+
• Obesity
• Stress oxidative
• Detoxification
• Inflammation
• Metabolism of vitamins, salt, lipids, caffeine
• Vit D and Bone health
• Vit B, methylation and homocysteine
• Sleeping and eating behavior
• Lactose and gluten intolerance
• Caffeine metabolism
ASPECTS OF A PERSONALIZED
NUTRITION. GENETIC TESTING

13. Personal: GRS&Lifestyle
† Daily intake levels of nutrients recommended for the Italian population
(L.A.R.N.) - Revision 2012
* recommended quantity, modified with respect to the LARN table, based on the
genetic test result

14. 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.

15. ADAPTING DIET TO GENETIC PROFILE
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
nonpersistence
• 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
alleles are associated with lactose intolerance:
• CC for rs145946881
• AA for rs41380347
• GG for rs41525747.

17. LCT gene
CC-intolerant
CT-tolerant
TT-tolerant

18. Living with
lactose
intolerance
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.

19. Gluten intolerance, celiac disease and NCGS

20. 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%

21. ACTION PLAN!

24. Genetic variations contributes to the
development of obesity

25. DIETING!!!
Dieting and weight loss are common issues among people of all ages.
Up to 50 percent of women are on a diet at any given time, according to Judy
Mahle Lutter in her book “The Bodywise Woman.” Up to 90 percent of
teenagers diet regularly, and up to 50 percent of younger kids have tried a
diet at some point.
Weight Loss Industry: Americans spend more money in dieting, dieting
products and weight loss surgery than any other people in the world.
Dieting Extremes
According to data published by the University of Colorado, 35 percent of
people who start by dieting occasionally become addicted to dieting. As of
1990, the average dieting age for girls was 8 years old. That’s down from 14 in
1970.

28. One Size Does Not Fit All!
Genomic Background Will Help Identify Responders to Foods and Components.

29. Emerging research suggests that the ability to place weight loss
subjects on a diet that is matched to their genotype may increase both
adherence and health outcomes.

31. Gene Result Effect
ACE II
PPARG Pro-Pro **
TCF7L2 TC *
ADRB2 Arg-Arg
CLOCK TT
PLIN GA *
INSIG2 GC
Metabolism of carbohydrates
Sensitivity to refined carbs
2.6/10
Low sensitivity
Nutritional advices:
10% refined carbs
GL 100/daily
Fiber 25 gr

32. ACE
Long name:
Angiotensin I
converting enzyme
Angiotensin I-converting enzyme is a small enzyme that
plays an important role in blood pressure regulation and
electrolyte balance. Its activity leads to blood vessel
constriction and increased blood pressure. The variation
tested is the Insertion (I)/Deletion (D) variation in which a
piece of DNA is either present or deleted from the gene.
– the I allele is associated with lower ACE activity
II ID DD
the I allele is
associated with
lower ACE activity
which is not
associated with
increased
sensitivity
to refined
carbohydrates
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.

33. ADRB2 (Gln27Glu)
Long name:
Adrenoceptor Beta 2
(aka: beta-2- adrenergic
receptor)
Beta(2)-adrenergic receptors are expressed throughout the
body and serve as receptors for the natural stimulant
hormones called catecholamines epinephrine (adrenaline)
and norepinephrine. The polymorphisms tested result in
amino acid changes, which affect the activity of the receptor
and alter the response to these hormones. 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.

34. 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
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

35. TCF7L2
Long name:
Transcription Factor 7-
Like 2
TCF7L2 is a transcription factor (a protein which binds to DNA and affects the
expression of genes and the amount of various proteins produced) – it affects a
variety of genes. It has not been fully characterised but the protein has been
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 and it is associated with increased weight gain after
dieting. While the T allele, and in particular the 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
intensityexercise 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

36. 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

38. 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

39. 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
GSMT1 D **
GSTT1 I
DETOXIFICATION FASE II

40. 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

41. Gene
Result Effect
VDR CC
**
COL1A1 GT
*
VDR gene is coding for the vitamin D receptor which affects the production of
various proteins, some of which are involved in the use of calcium.
The genotyps heterozygous for the allele C (CT), and homozygous CC, have been
shown to influence the absorption of calcium and the bone structure.
COL1A1 gene provides instructions for making part of a large molecule called
type I collagen. A common variation in the COL1A1 gene appears to increase the
risk of developing osteoporosis.
Diet prescription= increasing amounts of vitamin D and calcium.
VITAMIN D METABOLISM

42. Personalized recommendations based on genetics profile
Personalized recommendations based on DNA profile alongside base diet
Variation in ACE, PPARG Low glycemic load (GL) diet in addition to extra exercise, specifically power-based
exercise such as step aerobics, spinning, at high intensity weight training.
Variation in LPL, FTO, APOA2,
APOC3
Restriction of saturated fats to no more then 16 g/day with concurrent increase in
unsaturated fat consumption, such as olive oil. Supplementation with niacin.
Variation in GSTM1 and GSTT1 Ensure consumption of an adequate intake of cruciferous vegetables - 200 g five times
per week. If both null genotypes were present, supplementation with broccoli
extract and allium was recommended.
Variation in GPX Consume foods rich in selenium such as Brazil nuts, fresh fish, meat, wheat germs,
brown rice, oats, and onion. In case of low plasma selenium, supplementation of
200mcg/day was recommended.
Variation in TNF and IL 6 Increased consumption of omega-3 rich foods. Green tea, turmeric, ginger, rosemary,
oregano were also recommended, along with supplementary omega 3 (1-2g/day)
Variation in MTHFR Increase consumption of folate-rich foods(dark leafy greens, asparagus, bean, peas,
lentils, avocado, okra). Supplementation with 400mcg folate, 3 mg B6, 5mg B12,
2.5 md B2, 12mg Zn, 250 mg TMG/betain
Variation in CYP1A2 and EPHX1 Increase consumption of antioxidants, such as grapes, blueberries, sweet potatoes and
orange vegetables. Also recommended to increase consumption of dark green
veggies, whole grain, and tea, along with a decreasein caffeine consumption to
200mg/day. Decrease consumption of grilled meat and fish to 1-2 servings per
week.
Variation in SOD2 and CAT Increase antioxidant consumption through diet, and add supplements containing
vitamin A(5,000 IU) vitamin C (250 mg) and vitamin E (200IU)
Variation in LCT-lactose
intolerance
Elimination of dairy, followed by a rotation diet.
Variation in VDR Keep caffeine below 2 cups coffee/day. Increase dairy component of diet (yoghurt,
cheese and low fat milk). If required add supplement containing 800 IU vitamin D

43. CONCLUSIONS
• Genetically matched diets and dietary advice may be useful in the
treatment of obesity and altered haematological markers of
metabolic health.
• Genetically tailored diets may reduce the risk of developing obesity
or type-II diabetes in non-obese individuals, although research in
this area is required to confirm this.
• The use of nutrigenetics could be an effective aid in long term
lifestyle changes leading to sustained weight loss and health
improvements.

44. •Is there a proven connection between
the test results and the condition which
the test predicts?
•How strong is this connection: is it
plausible, probable, or reliable?
•How large was the sample population
on which the association was based?
•Has the evidence for this association
been published in expert publications?
CHOOSING THE DNA TEST

45. THE FUTURE?

46. References:
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signatures of strong recent positive selection at the lactase gene. Am. J. Hum. Genet. 2004;74(6 ):1111–1120.
• Cagliani R, Fumagalli M, Pozzoli U, Riva S, Comi GP, Torri F, Macciardi F, Bresolin N, Sironi M. Diverse evolutionary histories for
beta-adrenoreceptor genes in humans. Am. J. Hum. Genet. 2009;85(1):64–75.
• Church C, Lee S, Bagg EA, McTaggart JS, Deacon R, Gerken T, Lee A, Moir L, Mecinovic J, Quwailid MM, Schofield CJ, Ashcroft
FM, Cox RD. A mouse model for the metabolic effects of the human fat mass and obesity associated FTO gene. PLoS
Genet. 2009;5(8):e1000599.
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Ali A, Natah S, Comas D, Mehdi SQ, Groop L, Vestergaard EM, Imtiaz F, Rashed MS, Meyer B, Troelsen J, Peltonen L.
Independent introduction of two lactase-persistence alleles into human populations reflects different history of adaptation to milk
culture. Am. J. Hum. Genet. 2008;82(1):57–72.
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hypolactasia. Nat. Genet. 2002;30(2):233–237.
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(Lond) 2008;32(Suppl 7):S55–61
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47. Vranceanu.Maria@umfcluj.ro
Thank you for your attention!