Lecture 11 Gene and nutrition

Obesity

Hyperlipemia Hypertension

Oxidation Ripo protein

Non-esterified fatty acid

rise in bloodhyperinsulinemia

Insulinresistance

Abnormal glucose

tolerance

Salt collect.Sympathetic nerve tension

Geneticfactor

Lifestyle relatedfactor

　 Right figure shows the structure of DNA (deoxyribonucleic acid). All genetic codes of the living thing are decided by how of four kinds of bases such as A, G, C, and T to queue up. Only in the array of only two kinds of 0 and 1, the computer is the same as can show all sentences and figures　 All genetic codes of one cell are called a genome, and the same genome as each one of 60 trillion that make the body exists. Because the genome is a blueprint of the whole body, the cloned sheep can make it from sheep's one soma. Nutrigenomics is a compound word of Nutrition (nourishment) and Genomics (genome analysis)

Double stranded of DNA is mutually copied and is inherited

Hydrogen bond

G-C ：３

A-T ：２

Hydrogen bond

Single-standardDNA

Double-standardDNAPhosphoric

acid

DNA of parents cellDNA of

Child cellDivision

Direction of DNA strand

Gu

an

ine

Cy

tos

ine

Gu

an

ine

Cy

tos

ine

Cy

tos

ine

Gu

an

ine

Th

ym

in A

de

nin

e

Base

Ad

enin

e

Nu

cleotid

e

Yasuo KAGAWA et at al. “Core, molecular biology of human body” MARUZEN, 1997, p.2

The corresponding bases are united

It dissociates into single stranded DNA

Complementary Chain DNA against up

Pentose

Pentose

Base

Phosphoricacid

Identical twin's identity frequency of the attack is higher than that of fraternal twins. Monovular brother's one side is a possibility of the prevention of the high rate because it doesn't get sick

Both brotherly appearance of

disease frequency of twin

Statistical,

significant difference

Identical twin

（ Men62 　Women63 ）

Homosexual fraternal twins

（ Men86 Women92 ）

　　　ｐ value

ＢＭＩBlood sugar rise for

120 minutes

Systolic pressureDiastolic blood pressure

Value of HDL cholesterol

0.68

0.52

0.55

0.47

0.61

0.28

0.26

0.17

0.07

0.26

<0.001

<0.05

<0.001

<0.01

<0.001

Article ： P.Poulsen et al. Diabetologia 44:537-543 (2001)

An increase in disease by making of meal European-style

Men Women

Hyperlipemia(To Cerebral infarction

Cardiac infarction)

Hyperlipemia(To Cerebral infarction

Cardiac infarction)

Abnormal glucose

Tolerance(To diabetics)

Abnormal glucose

Tolerance(To diabetics)

Fre

qu

ency

per 1961 per 1961 Kyushu University the second internal medicine department Hisayama laboratory

Hyperlipemia:Total cholesterol

Comparison of 3 groups (40 or more) in Hisayama-machiAge

adjustmentperson

Relation between strength to alcohol and gene

Lysine

Lysine ThreonineThreonineGlutamic

acidValin

Normal type

Amino acidOf enzyme

Deletion form

single nucleotide

polymorphism

From father from mother

Strong Normal type / Normal type

Middle Deletion form / Normal type

Weak Deletion form /Deletion form

Base

Distribution of aldehyde dehydrogenase multi type and consumption of ethanol. It is small in a lot of Japanese Yayoi Kinki, China, and Hokuriku that is

Tohoku

Okinawa

gene

Northkyushu

Kanto

Shikoku

Hokkaido

South kyushu

Chugoku

Hokuriku

Kinki Chubu

frequency

HokkaidoTohoku

KantoChubu

HokurikuKinki

ChugokuNorth

Kyushu

ShikokuSouth

Kyushu

Amount of Alcohol consumption

Ethanol

Each prefecture investigated for 5000 Japanese or more in total

Year/person)

Feature of gene polymorphism related to nourishment in Japanese

1.The hunger tolerance: Light obesity is a diabetic and infarct: βARs and UCPs.

2. The salt receptivity: It is high blood pressure by 10g or more on the salt

the first: TT type of AGT. 3. Alcoholic receptivity: The weak person is a cancer of the esophagus

in alchol: Two types of ALDH2. 4.No lactose tolerance: Limit 500ml of for drinking milk: Adult lactase

loss5.A passive, joint character: Guidance politely :: The SS type of

SerotoninT. 6.Folic acid and Epijeneticcs: Acknowledgment syndrome and cerebral infarction: TT type of MTHFR7.The amount of the pancreatic island secretion: It is diabetic

constitution half of Caucasian: Multi type of SOCS2. 8.Detoxication Nou uniqueness: Racial difference of food function element effectiveness: CYP multi type9.Haplotype of mitochondria: New mongoloid feature

DNA reproductionRNA transcript

Protein translation

polymerase

ProteinRibosome Amino acid

Translation

Change of nucleotide sequence

Processing

Yasuo KAGAWA et at al. “Core, molecular biology of human body” MARUZEN, 1997, p.16

Peptide bondProcessing Of inteprer

product

Transfer RNA

DNA

Disease and gene information

Gene type

Aminoacil

Addition (Cap, Poly A)

Splicing

Synthesis of biological

material

Activity Structureof living

body

Reaction ofS period

(DNA Polymerase α)

Messenger RNA

Synthesis protein (Start, Extension, Conclusion)

The processing abnormality of the translation product

(Proinsulin syndrome)Prepeptide cleavage of membrane protein

Repli-cation

Trans-cription

Abnormal regulationOf expression

(Steroid hormone action, etc)Processing abnormal

Of the translation product(Thalassemia, etc )

energy

(Mutation)

Abnormal aminoacid (missense

mutation)Abnormal conclusion

Deletion (Frameshift)

Chromosome)

Metabolic abnormalityDysfunctionMorphological defect

Abnormal proteinEnzyme deficiencyReceptor deficiency

Transportor deficiency

Peptide bond

Conformation ← 　 Chaperonin

Peptide cleavage, Glycosylation, Residue modificationTargetalization for membrane (1st-5th screening)

Self prolification

Phenotype

Extraction and

detection method of

DNA

Yasuo KAGAWA et at al. “Core, molecular biology of human body” MARUZEN, 1997, p.20

Double-strandedDNA

Autoradiography orFluorescence intensity

detection

Denatured protein

Cell

Heat annealingHybridization(Molecular hybridization)

Phenol extraction, Ethanol precipitation, Protein-cutting enzyme

SingleStranded

DNAor RNA

Complementary strand DNA

Alkali denaturationor heat

denaturation T means Uwhen RNA

Probe DNA Radioactive phosphoric acid

or fluorescent dye

Base peculiar hydrogenuniting formation

　　　　　Environmental factors（ Nutrient, Function element, Exercise ）

Universal set body in each cell (ohm)

Amount of ratio in cell (profile) Analysis

DNA 　　　　：　　 Genome

Gene multi type （ SNP etc ）

Individual difference

Genomics

　　　　　　　　　　Transcript

RNA 　　　　：　 Transcriptome

Gene expression profiling

(mRNA synthesis amount) Transcriptomics

Proteomics

Metabolomics

　　　　　　　 　　Translation

Protein 　　　：　Proteome)

Protein appearance file

(enzyme and receptor, etc.)

　　　　　　Vicissitude

　　　　　　　

Metabolite profile

(blood sugar, serum lipid, and lactic acid, etc.)

Metabolites 　： Metabolome

Diversity of action appearance

The mind and body's all activitiesLifestyle disease and aging

*epigeneticsDifference of cell

bioinformatics

Outline of Nutorigenomiccs

Yasuo KAGAWA. “Easy nourishment study”, Kag

awa Nutrition Publishing, 2006, p.163.

Obesity

Hyperlipemia Hypertension

Oxidation Ripo protein

Non-esterified fatty acid

rise in bloodhyperinsulinemia

Insulinresistance

Abnormal glucose

tolerance

Salt collect.Sympathetic nerve tension

Geneticfactor

Lifestyle relatedfactor

Lifestyle-related diseases prevention and mongoloid gene polymorphism

Appearance of disease and obesity of lifestyle disease

Mongoloid hunger resistant gene multi type

Globalization of lifestyle of Corcasoid

Cancer

Hypertension

Obesity

Diabetics

Alzheimer type dementia

Lifestyle disease being found for gene related to appearance of disease

C type of CYP1A1, etc

T type of Angiotensinogen, etc

Arg type of β Adrenaline receptor

Apo E4 type, etc

Uncoupling protein 3 (UCP 3) etc

Obesity factor

ObesityLife style factor Hereditary determinant

Excess nutrient

Monobasic multi type

Tryptophane

Arginine

Decrease in amount of body activity

β3 adrenaline receptor

Mutation

Amount of consumption

energy

Amount of intake energy

Amount of metabolizing at rest and

β3 adrenaline receptor multi type

R/W W/W0

500

1000

1500

2000

(kcal/day)

P<0.01

R/W W/W

Kagawa Nutrition University

Students:175

Attendance lecture in Nutrition clinic(KAGAWA Nutrition University) : 127

(Average age 21) (Average age 50)

NS

Source ： Prof. Kazuhiro UENISHI （ Nutrition physiology, KAGAWA Nutrition University ）

Obesity gene multi type in Nutrition clinic (KAGAWA NutriObesity gene multi type in Nutrition clinic (KAGAWA Nutrition University)tion University)

Receptor of not enzyme but biomembrane and multi type of transportation bodyReceptor of not enzyme but biomembrane and multi type of transportation body

①β3 Adrenaline receptor （ β3AR ） Trp64Arg

② 　 uncoupling protein ２（ UCP2 ） 45bp insertion/deletion

③ 　 uncoupling protein ３ （ UCP3)C-55T

White adipocyte

β3AR

UCP2

β3AR

Brown adipocyte

UCP1

Frame muscle cell

UCP3

Non-esterified

fatty acid

β2AR

Both film proteins concerning energy transduction

Increase and decrease of amount of metabolizing of Japanese obesity gene multi type at frequency and rest. There are a lot of multi types of the receptor and the transportation body, and a multi type of the enzyme is few

Name of gene

The gene multi type remainder radical and position

Difference of amount of resting metabolismKcal/a day

Frequency of aryl on

Japanese ％

β3-AR Trp64Arg -200 (Arg aryl) 26 ％β2-AR Arg16Gly +300 (Gly aryl) 16 ％UCP1 a-3826g -100 (G aryl) 40 ％

UCP2Insert/Del

-200 (Loss) 35%

UCP3 c-55t -100 (t aryl) 63%

Kir6.2 Glu23Lys +100 (Lys aryl) 41%

LEPRGln233Arg

-100 (Arg aryl) 85%

RAGE g1704t -350 (t aryl) 14%

MTP g-493t -100 (t aryl) 21%Toshihide YOSHIDA, 「 Obesity treatment 」 , Available from <http://metab.kuhp.kyoto-u.ac.jp/IKAI/report/no8.html>, (accessed 2007-12-11)

Racial difference of gene concerning nourishment

Amount of energy place main point

Milk tolerance

Alcohol metabolism

Farming culture

Caucasian

Strong

Multi type concerned energy

Japanese

Type of tolerance hunger

Weak

Rice farmingStock raising

Type of energy consumption of large

amount

SOCS2(supressor of cytokine signaling 2) difference of multi type gene

The Japanese develops diabetes easily because of slight obesity. The insulin secretion is few

Comparison of Japan-US diabetic patients

Rate of obesity Insulin immunity

Japan

Japan

USUS

Fasting glucose

It is a big difference. the condition physiology and the expression type

When the number of risk factor possession exceeds three, Metaboric syndrome becomes 31 dangerous times the healthy individual

Number of risk factor possesion andappearance disease odds rate

05

101520253035

0 1 2 3 4～Number of risk factor possesion

App

eara

nce

dise

ase

odds

rat

e 発症ｵｯｽ 比゙

Risk factor・ Obesity・ hypertension・ High levels of sugar・ Hyperlipemia

Risk is not mere addition

Appearance diseaseOdds rate

Kidney disease and losing sight can be prevented by meal and exercise even

due to diabetic by the gene polymorphism

Adiponectin

Adiponectin

Normal value of blood sugar Diabetics and abnormal glucose tolerance

Data after it passes of 20 years or more of attending a lecture

Keiko YANAGISAWA, Sayuri AIDA, Yasuo KAGAWA et at al (Nutrition Clinic, Kagawa nutrition university)

Frequency of aryl of gene polymorphism

that promotes hypertension

45

81Japanese

Caucasian

Angiotensinogen

　　　　 　Ｔ 235

50

69Japanese

Caucasian

Aldosterone synthase 　　　　 　Ｔ -344

25

52Japanese

Caucasian

G proteinβ ３（ Na-H pump ）ﾟ　　　　 　Ｔ 825

15

57Japanese

Caucasian

α adducin　　Ｔ rp460

(Ishikawa, Hypertension 2001)

(Ishikawa, Am J Hypertens 1998)

(Tsujita, Hypertens Res 2001)

(Ishikawa, Am J Hypertens 2000)

（ unit ：％）

One nitric oxide synthetic enzyme gene T786C multi type doesn't become hypertension in case of the salt intake 11.7g or less/a day either

115

120

125

130

135

140

145

150

<7.5g 7.5-9.2g 9.2-11.7g >11,7g

TT typeTC/ CC type

TC/CC type that 17% of 281 Japanese of

average age 45 year becomes high blood

pressure easily

Miyaki. K. et al. “Salt Intake Affects the Relation Between Hypertension and the T-786C Polymorphism in the Endothelial Nitric Oxide Synthase Gene” Am J. Hypertension. 18(12), 2005, 1556-62

Hypertension appearance of disease rate and Angeotenshinorgen gene polymorphism after three years intervention examinations

45

2825

44

3236

32

41

32

0

10

20

30

40

50 typeＴＴ typeＴＭ typeＭＭIn

ciden

ce rate of

hyp

ertensio

n (%

)

Obesity level (BMI) is ameliorable in no administering even if there is a gene polymorphism related to four kinds of obesitys in the guidance of the nutritional clinic

26.4 25.524.6 23.9

- 1.7 - 1.7

20.0

25.0

30.0

35.0

-3

-2.4

-1.8

-1.2

p＜p＜

26.2 25.524.5 23.9

- 1.7 - 1.7

20.0

25.0

30.0

35.0

-3.0

-2.4

-1.8

-1.2

p＜ p＜

26.1 25.924.4 24.2

- 1.8 - 1.7

20.0

25.0

30.0

35.0

-3.0

-2.4

-1.8

-1.2

p＜ p＜

25.8 26.124.1 24.4

- 1.7 - 1.7

20.0

25.0

30.0

35.0

-3.0

-2.4

-1.8

-1.2

p＜0.0001

p＜

ns

β3AR

野生型群（ n=91 ）変異型群（ n=56 ）

ns

UCP2

野生型群（ n=105 ） 変異型群（ n=42 ）

変異型群（ n=83 ）野生型群（ n=64 ）

nsnsUCP3 FABP2

野生型群（ n=59 ） 変異型群（ n=86 ）

（㎏ /m2 ） （㎏ /m2 ）

（㎏ /m2 ） （㎏ /m2 ）

After attending vs before a lecture is attended, the order authorization with the sign and wild type group vs mutation type

group of Wilcoxon are U authorization of Mann-Whitney

Beforelecture

Afterlecture

（㎏ /m2 ）

（㎏ /m2 ）

（㎏ /m2 ）

（㎏ /m2 ）

Amount ofchange

Wild typeMutation

typeWild type

Wild typeWild typeMutation

type

Mutation type

Mutation type

　　　

180

200

220

240

260

Before after Before after

Wild group(n=105 ）

Mutation type group （ n=42 ）

Total cholesterol

50

70

90

110

130

Neutral fat

Before after Before after

Wild group（ n=94 ）

Mutation type group

（ n=34 ）

(mg/dl) (mg/dl)

210±36

197±36

241±53

225±46 97±42

75±25

115±48

80±25

p=0.0007p=0.0005

p=0.0417p<0.0001

p<0.0001

p<0.0075

p<0.0001

Serum lipid improvement of both of escape after movement is guided of nourishment of deficiency/deficient this type zygotic

mutation type of post protein 2

Thailand Health Profile 2000

During this 15 years:Heart diseases x 5.1Diabetes x 7.5Diabetes x 7.5Cancer x 1.3

DiabetesDiabetes

Heart disease

Cancer

The Heart Disease and diabetes increasing suddenly by the The Heart Disease and diabetes increasing suddenly by the change to Western Europe lifestyle also in Thailandchange to Western Europe lifestyle also in Thailand

95

70

46

25

7

25

40

56

52

30

91

11

5

14

19

6

63

7

89

98

42

2

5

2

Okinawa (n=100)

90

81

66

56

25

31

36

73

81

8

31

12

70

94

3

7

4

36

26

18

9

6

2

1

3

1

Thai (n=212)

99

91

69

12

9

30

96

88

40

68

26

51

12

71

96

9

1

20

3

1

1

3

3

1

Palau (n=118)PPAR2

LEPR ex6

Apo E

AGT M235T

AGT a-20c

UCP2

UCP3p

3AR

LEPR ex14 71

65

72

27

33

45

69

41

81

35

52

15

58

86

7

41

4

7

12

26

27

2

4

14

2

2

2

Mongol (n=252)

The gene multi type frequency between Asians is similarThe gene multi type frequency between Asians is similar(By the research of “Kagawa Nutrition University High-tech research Center”(By the research of “Kagawa Nutrition University High-tech research Center”

Mongoloid receptivity gene Lipid, salt, sake, milk, movement, stress, and medicine

Lifestyle disease and mongoloid receptivity gene

Action alternately Appearance of diseaseB

A

The agreement with the genetic test has increased overwhelmingly as for the public opinionAsahi Newspaper, March 12, 2006 morning newspaperThe Ministry of Education, Culture, Sports, Science and Technology specific area research

Information on the gene was considerably established. (The percentage of those to whom the person who doesn't know DNA understands 1% and the meaning is 55%. )It was answered that the genomic study applied to themedical treatment agreed by 70%, was opposite 1%, and itwas not able to be said that 29% was either. The percentage of those who had answered that it wantedto receive the genetic test to judge the easiness of themedicine to be effective was 66%. It was a positiveresponse to apply the result to the medical treatment

(It questions about 4,000 general people in Japan, 2005.11)

The person of 73% hopes for the genetic test

The Ministry of Economy, Trade and Industry:New health enhancement service investigation with genome base

(February, 2006)

I want to receive it by all means. I want to receive it somewhat. I do not want to receive it. I do not want

never to receive it

Do you want to receive the genetic test?

Because the resistance power strengthens economically advantageously as for a saving gene multi type by an appropriate lifestyle guidance, too it

is ethical to notify a multi type

A multi type is diversity in the normal person group, and it is not sick. Arg multi type of the β3 adrenaline receptor of the saving gene can be ..200kcal.. few during a day. General food is 1kcal=1 yen, and the possibility of the living at the disaster is high in one home. the holder of the saving saving gene during 360,000 yen/year

Because it is notified that it is a holder of the saving gene, and is prevented the lifestyle disease as well as a general person if guidance is received, it is not disadvantageous.

It is misunderstood to have advertised that discrimination happens because it is disadvantageous the saving gene.

Because the saving gene is inspected, and the notification is profitable to prevent the lifestyle disease, the report that fuels opposite and the uneasiness to the genetic test is unethical.

I want to promote checkup to a possible genetic test and the guidance of the treatment prevention

Approval or disapproval of ethics of gene medicine

Patient MeGene therapy 　 (the first generation) to fatal disease (terminal cancer etc.)

Patient MeGene therapy to quality decrease (the second generation) in important life

Patient Me

Legal promotion of whole nation's genetic test in Iceland etc

Patient MeGene therapy transmitted by descendant like mitochondria import in the United States.

Patient MeFreedom of gene manipulation that improves able-bodied person's mind and body's ability and features, etc

○×

Others

○×

Others

（ Medical student's result of the survey ）

Ratio of cultivation area of the world of genetically modified agricultural products in the world

0

20

40

60

80

100

120

140

160

Non genetically modifiedGenetically modified

Soybean Cotton Colza Corn55％

21％

16％

11％

(Million ha)