Yrd. Doç. Dr. Nesrin Erçelen

Beslenme ve Nutrigenetik: Dünyadaki
Güncel Uygulamalar
Yrd. Doç. Dr. Nesrin Erçelen
Bahçeşehir Üniversitesi, Tıp Fakültesi, Tıbbi Genetik ABD
• Nutrigenetik,
metabolizmanın kullanılan
diyete ve beslenme
alışkanlıklarına karşı verdiği
cevabın üzerine genetik
varyasyonların etkisini ve
besin maddeleri ile
biyoaktif yiyecek
içeriklerinin genetik
ekspresyona etkisini
inceleyen bilim dalıdır.
• Nutrigenetiği önemli bir bilim dalı yapan üç temel faktör
vardır;
– Bireylerin, besin maddelerinin biyo-yararlılığı ve metabolizmayı
etkileyen kalıtınmış genomu arasında büyük bir çeşitlilik vardır,
– insanların kültürel, ekonomik, coğrafi ve tat algısı farklılıklarına
bağlı büyük tercih farkları ve yiyecek/besin maddesi
bulunurluğu farkları vardır,
– beslenme bozukluğu (yetersizliği veya fazlalığı) gen
ekspresyonunu ve genom kararlılığını etkileyebilir ve gen
sekansında veya kromozomal seviyede mutasyonlara sebep
olarak anormal gen dozajlarına ve gen ekspresyonuna sebep
olarak hayatın çeşitli dönemlerinde farklı fenotiplerin
oluşmasına öncülük edebilir.
Nutrigenetik
• Genler, hücre çekirdeğinin iç faktörlerden
(hormonlar) ve dış faktörlerden (besin maddeleri)
aldıkları metabolik sinyallere göre açılıp
kapanabilirler.
• Evrimsel gelişimde organizmanın sindirdiği besin
maddeleri, kıtlık ve bolluk zamanlarında, sentez ve
depolama yollarını açıp kapatabilecek primitif
sinyaller olarak işlev göstermişlerdir.
• Böylelikle genomlar
beslenme
alışkanlıklarını da içeren
birçok farklı çevresel
uyarana göre
evrilmiştir. Bu yüzden
genetik bilginin
ekspresyonu, besin
maddelerine,
mikrobesinlere ve
yemeklerde bulunan
fitokimyasallara büyük
ölçüde bağlı olarak
düzenlenebilir
• Besin – gen etkileşimi üç yolla oluşur:
1) Direk etkileşim: besin maddeleri bazen bir reseptör ile etkileşerek
DNA’ya bağlanabilen bir transkripsiyon faktörü gibi davranabilir ve gen
ekspresyonunu indükleyebilir. Örneğin, A vitamini ya da A vitaminin
retinoid türevleri retinoid asit reseptör proteinleri ile etkileşerek
genlerin promotör bölgelerine bağlanarak transkripsiyonu aktive
edebilir veya baskılayabilir.
2) Epigenetik etkileşim: besin maddeleri DNA’nın yapısını
değiştirebilir ve gen ekspresyonu kronik olarak değişir.
Epigenetik mekanizmanın sürekli etkisi DNA metilasyonu,
asetilasyonu veya histon biyotinasyonu aracılığıyla yapılır.
Sonuçta ortaya çıkan epigenetik modifikasyon, kişinin hayatı
boyunca hatta gelecek kuşaklarında var olacak şekilde gen
ekspresyonunu değiştirebilir.
3) Genetik varyasyon: yaygın genetik varyasyonlar
(SNPler) genlerin fonksiyonlarını veya ekspresyonlarını
değiştirebilir. Bu üç mekanizma, değişmiş mekanizmalar
ile ve besinsel gerekliliklerin değişimi ile sonuçlanabilir.
Insülin Metabolizması
KLİNİK NUTRİGENETİK
• Nutrigenetiğin uygulamaları, genetik yatkınlığın,
beslenme ile ilgili müdahaleler ile hafifletilebilen
hastalıklara kullanımını kapsar.
• Gıda endüstrisini için nutrigenetiğin potansiyeli
bilimsel hedefler için formülize edilmiş güzel tatlı
ürünler sağlanmasıdır.
• Hali hazırda çeşitli besin maddeleri ile hastalıkları
iyileştirmek veya hastalıklardan korunmak üzere
zenginleştirilmiş fonksiyonel yiyecekler
bulunmaktadır. Son zamanlarda incelenen bir alan
da, ürünlerin omega-3 yağ asitleri ile
zenginleştirilmesidir
• Belirli bir hastalığa maruz kalmış bireylerin, ailelerin
ve alt grupların tedavisi için veya koruyucu ajanlar
olarak yiyecek ve içecekler geliştirilebilir. Örnek
olarak, pediyatride epilepsi hastası bireylerin
tedavisinde ketojenik besinler kullanılmaktadır.
• Artrit, astım, ülseratif
kolit, lupus vb. kronik
inflamatuvar
hastalarda olduğu gibi
koroner arter ve
hipertansiyon
hastalarında da arka
plan diyeti olarak
temel yağ asitlerinin
dengelendiği bir diyet
kullanılması çok
önemlidir.
• Çölyak (celiac)
hastalarında,
fenilketonüri
hastalarında ve diğer tek
gen hastalıklarında hali
hazırda spesifik yiyecek
ve diyetler
kullanılmaktadır.
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Personalized Health Management
•
•
•
•
Genetic counseling/examination
Biochemistry of blood
DNA analysis
Personel report
• Personalized health monitoring and treatment strategy
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Nutrigenetics
Pharmacogenetics
Medical treatment
Surgery treatment
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Genetic Counseling
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Family pedigree
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Genetic Testing
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Blood
sample is
taken
And sent to the
laboratory for
genetic testing
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APPENDIX: HOW TO READ THE GENOTYPE REPORT (EXAMPLE)
Gene
Gene
Symbol
GENE NAME X
GName X
Genotype description
Gene
Symbol
HOMOZYGOUS ALLELE 1
HOMOZYGOUS ALLELE 2
HETEROZYGOUS
GName X
GName X
GName X
Polymorphism
Allele 1 > Allele 2
Presence
of Allele 1
X
b>B
Genotype
Allele 1 > Allele 2
bb
b
/
/
/
Presence
of Allele 2
Presence
of Allele 1
-
X
X
BB
B
Presence
of Allele 2
X
X
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GENOTYPE REPORT
1. ARTERIOSCLEROSIS / LIPID METABOLISM
Gene
Gene
Symbol
Polymorphism
Allele 1 > Allele 2
Apolipoprotein A1
APOA1
G>A Pos. -75 Promoter
X
Apolipoprotein E
APOE
Cys>Arg Codon 112
X
Apolipoprotein E
APOE
Arg>Cys Codon 158
X
Cholesterol ester transfer protein
CETP
Arg>Gln Codon 451
Sterol element binding transcription factor
SREBF2
Gly>Ala Codon 595
X
Endothelial NO-Synthase
NOS3
T>C Pos. -786 Promoter
X
Endothelial NO-Synthase
NOS3
Glu>Asp Codon 298
X
Endothelial NO-Synthase
NOS3
Ins>Del Intron 4 (VNTR)
X
Gap junction protein alpha 4 (Connexin 37)
GJA4
Pro>Ser Codon 319
X
Matrix metalloproteinase 3 (Stromelysin 1)
MMP3
5A>6A Pos. -1171
Paraoxonase 1
PON1
Gln>Arg Codon 192
Presence
of Allele 1
Presence
of Allele 2
X
X
X
X
X
X
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7. Metabolism and Obesity
As for the blood pressure you display a high risk of left ventricular hypertrophy
due to the homocygoty of the GNB3. It is a signal protein, which works too
hard.
In addition I include a study, which gives sufficient risk explaining. Please keep
ypour blood pressure low!(<120/80)
“A common C825T polymorphism in the gene GNB3, which encodes the beta 3
subunit of heterotrimeric G proteins, was identified in cell lines from patients
with hypertension. The 825T allele is associated with increased intracellular
signal transduction. Many population-based and case-control studies in
different ethnicities have investigated an association between this
polymorphism and hypertension, obesity, and atherosclerosis. A critical
assessment of published studies suggests that 825T allele carriers have
an increased risk for hypertension combined with features of the
metabolic syndrome, such as dyslipidemia, hypercholesterolemia, insulin
resistance, and obesity. It is anticipated that this polymorphism will be
used in clinical practice to better characterize hypertension and for
individualized treatment regimens.”
For diet: low glyceamic diet(see below)
The ADRB2 variant increases the risk of obesity and metabolic syndrome. This
is to say as well regarding the PAI-1 . The MTHFR produces slightly increased
Homocystein levels. They can be cured by a mixture of Vitamin B12, B6, Folic
acid and Same.
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CORONARY ARTERY DISEASE (CAD)
The association of GENETICS and ENVIRONMENT
Good genes
Healthy
Low CAD
Unhealthy
Low CAD
Bad Genes
Low CAD
High CAD
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Polymorphisms
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Environmental factors
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Expression of genetic polymorphisms
Atherosclerosis and CAD
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Ageing Process and Symptoms
The ageing process occurs over
all the body and for everyone,
but the pace may be different
depending on the type of organ
or individual. Certain cells in our
tissues simply stop working
after a while. When enough
tissue is rendered dysfunctional,
we come face to face with the
debilitation of ageing. However,
these cell deaths do not happen
all at the same time. Some
tissues remain viable for many
decades, some wear out rather
quickly. And ageing does not
occur in the same way in every
human being. It turns out that
people's lifestyles also has
additional influence on ageing.
What is Personalized Medicine?
The Human Genome was
sequenced by the year 2000 at a
cost of about
$2.7 billion
Personalized Medicine is
the
Human Genome Project
“Dividend”
Personalized Medicine:
What is it?
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How Has Genomics Enabled
Personalized Medicine?
Genomics has led us to a better understanding of the
molecular signals of disease
Genes
Clinical data
Proteins
Metabolites
Molecular screens combined
with clinical data will point to more
precise treatment options for each
individual patient
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Modern Medicine
“DNA MEDICINE”
1- Individual patient
is taken care
2- Genetic
technology
3- Informative
consultation:
Patients give the
decision
The Future of Medicine
Newborn screening expands to
track hundreds or thousands of
genes, rather than dozens.
Information is used throughout
the individual’s life to manage
their healthcare.
Medical information on a smartcard
contains our unique molecular profile.
Healthcare providers will consult the
profile before treatments/drugs are
prescribed.
Blood and other samples drawn
during routine medical visits are
submitted for molecular
screening for a large number of
cardiovascular, cancer,
neurological and other diseases
that may develop
U.S. Department of Energy Human Genome Program
http://www.ornl.gov/hgmis
U.S. Department of Energy Human Genome Program
http://www.ornl.gov/hgmis
SNPs and HUMAN POPULATION
Number of
SNPs
Possible genotypes
(bi-allelic
calculation)
Number of
people
(8 billion people)
10
1.024
7.812.500
15
32.768
244.141
20
1.048.576
7.629
25
33.554.432
238
30
1.073.741.824
7
33
8.589.934.592
<1
All calculations are based on the assumption,
that these SNPS are not „linked“
What is Personalized Medicine?
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Current Practice
Personalized Medicine
One size fits all
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Trial and Error
The right treatment for
the right person at the
right time
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Major Drugs Ineffective for Many…
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Hypertension Drugs 10-30%
ACE Inhibitors
Heart Failure Drugs 15-25%
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Beta Blockers
Anti Depressants 20-50%
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Cholesterol Drugs 30-70%
Statins
Asthma Drugs 40-70%
Beta-2-agonists
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…And Harmful to Some
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Just in hospitals: about 6.7% of patients (2.2 million)
experience serious adverse drug reactions
Serious adverse drug reactions in even smaller
percentages of treated populations have led to the
withdrawal of several drugs from the market
Baycol
Fen-Phen
Lotronex
“Are good drugs going to the wrong people?”
Propulsid
Tysabri
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Vioxx
OSTEOPOROSIS
HYPERTENSION
Col1A1 Type I collagen
Angiotensin Converting Enzyme- (ACE)
 Vitamin D Receptor – VDR
 Angiotensinogen- (AGT)
 αββ-Adrenergic Receptor - (ADRA2B)
β-Adrenergic Receptor- (ADRB1)
BLOOD CLOTTING RISK
Prothrombin- F2
PAI 1- Plasminogen Activator
Inhibitor Type I
Factor V Leiden
Glycoprotein IIIA – GPIIIA
MTHFR GENE
S
N
P
METABOLISM AND OBESITY
Protein β 3-subunit- (GNB3)
Neuropeptide Y (NPY)
ββ-Adrenergic Receptor- (ADRB2)
βββ-Adrenergic Receptor- (ADRB3)
Cholesterol Ester Transfer Protein-(CETP)
Sterol Regulatory Element Binding
Transcription Factor 2 (SREBF2 )
Endothelial NO-Synthase- (NOS3)
Gap Junction Protein alpha 4 (GJA4)
Matrix Metalloproteinase 3 (MMP3)
Paraoxonase 1- (PON1)
G
INFLAMMATION
Interleukin
6 - (IL-6)
Interleukin 10- (IL10)
DETOXIFICATION
Glutathione
S-transferase pi- (GSTP1)
Glutathione S-transferase M1 -(GSTM1)
Preimplantation Genetic Diagnosis
Embryo
Fetus
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IMAGES of FISH ANALYSIS
PB Probe mixture :
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Chromosome 13
Chromosome 16
Chromosome 18
Chromosome 21
Chromosome 22
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Blastomere with Trisomy 13
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x3
x2
x2
x2
x2
PERSONALIZED
MEDICINE
REGENERATIVE
MEDICINE: STEM
CELL
PREVENTIVE
GENETIC
DIAGNOSIS