Sunarti Department of Biochemistry Faculty of Medicine Universitas Gadjah Mada

INTRODUCTION
Nutrigenomic is the study of how foods affect our genes and how individual genetic differences can affect the way we respond to nutrients in the foods we eat. Under certain circumstances and in some individuals: diet can be a serious risk factor for a number of diseases. The degree to which diet influences the balance

between healthy and disease states may depend on:

an individuals genetic makeup.

 Nutrigenomics applies high-throughput molecular biology techniques:

1. Genomics 2. Transcriptomics determines patterns of gene expression in

response to a nutrient.

The transcriptome is the complete collection of RNA

transcripts produced from the DNA in a genome.

3. Proteomics studies effect of nutrients on protein synthesis,

protein structure, and patterns of protein expression.

from the transcriptome, including all subsequent modifications that the proteins may undergo

The proteome is the full complement of proteins produced

4. Metabolomic techniques analyze profile and function of metabolites

Metabolomics is the study of the sum total of

endogenous and exogenous metabolites in a cell, an organ, or in body fluids, and is the newest of the

omic technologies.

The comprehensive data handling is finally

accomplished by bioinformatic tools .

Genomics, transcriptomics, proteomics, and metabolomics as analytical tools in molecular nutrition

Spectrum of Human Disease

Metabolic syndrome
Environmental Multifactorial (Environmental and Genetic Factors) Genetic

Infection Nutrition deficiency Congenital Abnormality

Chromosome

Abnormal Single Gene

Common Chronic Disorders on adult

Metabolic Syndrome.
The metabolic syndrome (MetS) is a constellation of

factors associated with increased risk of cardiovascular disease (CVD) and type 2 diabetes (T2D)
MetS is a clustering of metabolic risk factors,

including:
high blood pressure (BP) central obesity insulin resistance

atherogenic dyslipidemia (ADL)

hyperglycemia

Nutrigenomic and Blood pressure

The prevalence of hypertension varies among race or ethnic

groups. The varied prevalence is associated with culture or genetic background or interaction between genetic and environment or nutrition factors. The increase of nutrition risk factor such as high salt intake solely does not necessarily elevate blood pressure to abnormal level. However, the combination of high salt intake and other factors such as genetic tendency will increase blood pressure to abnormal level

Hypertension-related gene and diet interaction

The most widely studied genediet association is that

of the MTHFR gene and folic acid.

The gene has a common single nucleotide

polymorphism at position 677 in the coding region of the methylenetetrahydratefolate reductase (MTHFR) gene.

MTHFR directs folate from the diet either to DNA synthesis or to homocysteine remethylation.

 The C677T polymorphism of MTHFR results in the

insertion of a valine residue in place of an alanine residue in the enzyme, which lowers both the stability and the activity of the enzyme
Low MTHFR activity reduce remathylation reaction of

homocysteine to methionine so leads to hyperhomocysteinemia.

Hyperhomocysteinemia cause oxidative-stress In the oxidative-stress, free radical reacts with NO that

cause low NO level in the circulation

Remathylation reaction of homocysteine to methionine

Effect of Nutrient to Homocysteine Level

Folate status has an important role in regulating plasma

homocysteine level. Interaction between MTHFR C677T mutation and folate status determines total plasma homocysteine level Individuals with TT genotype have risk of hyperhomocysteinemia although they have marginal folate deficiency, whereas individuals with CC genotype have risk of hyperhomocysteinemia only when they have severe folate deficiency In the individuals carry TT genotype and limited folate intake, the rate of homocysteine synthesis is twice faster than that in the individuals carry CC genotype

Relation of Blood Folate Levels and Risk of Hypertension

C677T mutation in MTHFR gene
OR=1,36
OR=2,30

Hipertension

Folate deficiency

OR=1,40

 The C677T mutation-related MTHFR part was involved in

binding of folate to MTHFR enzyme which can be stabilized by enough folate consumption in individuals carry CT genotype.
The folate will prevent the release of flavin co-factor from

MTHFR enzyme. Therefore, the subjects with CT genotype did not show hyperhomocysteinemia if they dont have folate deficiency.

Hyperhomocysteinemia & Hypertension

Hyperhomocysteinemia
Oxydative Stress Inhibition of DDAH activity
ADMA Degradation of NO Bioavailability NO Endothelial dysfunction

Releasing of NO from endothelial cell

Impaired vasodilation
Hypertension

DDAH: Dimethylarginin dimethylaminohydrolase ADMA: Asymmetric dimethylarginine

Other Genes that Influence Developing of Metabolic Syndrome

Many genes involved in regulating glucose and blood

pressure. Among those genes are genes KCNJ11E23K coding for -cell K+ channels involved in the entry of glucose into cells Gene angiotensin converting enzyme (ACE) related to the production of angiotensin II Gene endothelial nitic oxide synthase (eNOS) involved in the production of nitrite oxide. Angiotensin II and nitric oxide in blood is very determining blood pressure in humans.

Other Genes that Influence Developing of Metabolic Syndrome

PPARG encodes for the ligand-binding transcriptional peroxisome

activatorreceptor gamma which is important for adipose tissue differentiation and activation of a number of genes involved in glucose and lipid metabolism A polymorphism, Pro12Ala (P12A), is association with Type 2 DM and metabolic disorders The PPARG PP genotype has been reproducibly associated with increased insulin resistance whereas the A-allele shows protection against Type 2 DM

ADRB1 G389R
The -adrenergic receptors are key regulators of

catecholamine-mediated lipolysis in humans.

The 1- and 2-adrenergic receptors (ADRB1 and

ADRB2) are expressed in several tissues and are the predominant -receptor subtypes in cardiac myocytes and adipocytes.
An amino-acid substitution of a glycine (G) by

arginine (R) at position 389 would have decreased lipolysis and therefore be more prone to weight gain.

 Variants in PPARG and ADRB1 showed also an additive

association on the MetS risk.

Both risk variants were associated with an increase in

triglyceride concentrations over time

Whereas the ADRB1 variant also was associated with

an increase in fasting plasma glucose concentrations.

The association with triglyceride levels can most likely

be explained by effects on adipogenesis and lipolysis.

 APOA5 gene involved in triglyceride metabolism and

modulated by dietary factors

Cryptic APOA2 gene has potential roles of this

apolipoprotein on dietary intake, body mass index and postprandial lipidemia

Fat mass and obesity-associated (FTO) gene.

PUSTAKA
Mine Y, Miyashita K, Shahidi F. Nutrigenomics and

Proteomics in Health and Disease Food Factors and Gene Interactions. 2009. Wiley-Blackwell, USA.
Rimbach G, Fuchs J, Packer L. Nutrigenomics. 2005 CRC

Press. Boca Raton.

Sunarti. Interaksi polimorfisme genetik

metilentetrahidrofolat reduktase dan metabolisme folat pada hipertensi esensial. 2007. Program Doktor Ilmu Kedokteran dan Kesehatan, Fakultas Kedokteran, Universitas Gadjah Mada, Yogyakarta

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