SunartiDepartment of Biochemistry

Faculty of MedicineUniversitas Gadjah Mada

INTRODUCTIONNutrigenomic 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 individual’s genetic makeup.

Nutrigenomics applies high-throughput molecular biology techniques:

1.Genomics2.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. The proteome is the full complement of proteins

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

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

Environmental

GeneticMultifactorial(Environmental and

Genetic Factors)

Infection

Congenital Abnormality

Common Chronic Disorders on adult

Nutrition deficiency ChromosomeAbnormal Single Gene

Spectrum of Human Disease

Metabolic syndrome

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 obesityinsulin resistanceatherogenic dyslipidemia (ADL) hyperglycemia

Nutrigenomic and Blood pressureThe 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

The most widely studied gene–diet 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.

Hypertension-related gene and diet interaction

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-stressIn 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 levelIndividuals 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

OR=1,40

C677T mutationin MTHFR gene

Folatedeficiency

Hipertension

OR=1,36

OR=2,30

Relation of Blood Folate Levels and Risk of Hypertension

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 don’t have folate deficiency.

Hyperhomocysteinemia & HypertensionHyperhomocystei

nemiaOxydative

StressInhibition of DDAH activity

A D M A

Releasing of NO from endothelial cell

Degradation of NO

Bioavailability NO

Endothelial dysfunction

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 β-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 activator—receptor 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 G389RThe β-adrenergic receptors are key regulators of

catecholamine-mediated lipolysis in humans.

The β1- and β2-adrenergic receptors (ADRB1 and ADRB2) are expressed in several tissues and are the predominant β-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.

PUSTAKAMine 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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