A Study on some polymorphisms of human leptin receptor gene in Koreans

임상노인의학회지 제 1권 제4호

2000

Korean J Clin Geri Vol. 1, No. 4 December

口 원 저 口

A Study on some polymorphisms of human leptin receptor gene in Koreans

Bong-Keun Choe,

T띠」Young

Yoon, Joon-Myung Choi,

Soon」Young

Park, IJong-Joon Lew

Department of Preventive

Me,벼~cine,&.뼈ol

of Medicine, Kyung Hee University

lnsto ‘ iJC:tion : L€ptin is an adipocyte-derived blood borne satiety factor that acts on its cognate leptin receptor(Ob-R) in the l\ypothalamus, thereby

regrula미ig

food intake and energy

얹:penditure.

To exlore whether mutations in the Ob- R gene cause

φesity

in humans, we have searched for mutations in the gene for Ob-Rb, a biologically active receptor isofonn, in

o뾰se

korean subjects.

Methe얘 :

Genomic DNA was extracted from whole

blo여

stored at the time of colletion, and used for subsequent analyses. PCR-RFLP

없ialysis

was performed for

genot째,ing

at codons 2Z3 and 1019.

ResUt : In obese subjects, allele frequencies of the polymorphic site at the codons 2Z3 and 1019

(GlnZ정.Arg

and Prol019pro) were 91 and Erl%. In non-obese subjests, they wre 92 and 86%. The odds ratio

(않%

confidence interval) for obesity of

ArgZ경

and prol019

외lele

were 0.9 (0.3-2.6) and

1.1

(0.5-2.5) , respectively. No significant

이fference

was

obseπed

in the clinical characteristics among the genotype groui:s. Diastolic blood pressure of subjects with he Gln/Gln and Gln/

Arg

in the non -obese.

There are no significant

띠fference

in TC, TG, HDL-C

때d

LDL-C among the Ob-R genotype groui:s.

Conch.회on

: Diastolic

blo여

pressure of subjects with the Gln/Gln and Gln/ Arg in the obese was signifi- cantly higher than that of those with Gln/Gln

ar띠

Gln/

Arg

in the non -obese.

Hypertension is associated with obesity. Further

stu띠$

are

req버red

to

cl따ity

the association

양tween

polymorphism of Ob-R gene and hypertension.

Keywords : Obesity,

Re때n

receptor, PCR - RFLP,

p얘morp비sm,

Diastolic

pr'얹sure,

Hypertension

and non - insulin dependent diabetes mellitus (NI- Introduction DDM)

.1i

Nowadays obesity

뼈s

reached epidemic

proportions and is threatening to become a global Obesity arises from complex interactions be- epidemic.

zi

What is causing the dramatic rise in

때een

genetic and environmental factors, confer- overweight among the population? Although rese-

미ig

a higher

디sk

of cardiovascular and

met.ab이ic

arch advances have

뼈매ighted

the importance of

disorders such as hypertension, hyperlipidernia, molecular genetic factors in determining

indi까d-

ual susceptibility to

O뾰sity,

the landmark discov- eries of leptin, uncoupling proteins and neurope- ptides involved in

body

weight

reg띠ation,

cannot explain the obesity epidemic. Our genes have not changed substantially during the

맹st

two dee- ades.

πle

culprit is an environment which pro- motes

beha띠ors

that cause obesity.3l Obesity can

a디se

only when energy intake exceeds energy expenditure. Our current environment is charac- terized by an essentially unlimited supply of con- venient, relatively

ine자iensive, highly

palatable, energy-dense foods, coupled with a lifestyle re- quiring only low levels of physical

acti띠ty

for subsistence. Such an environment promotes

비gh

energy intake and low energy

e짜ienditure.

Genetic make up

외so

plays a role in that it determines the strength of an

m띠찌du외’s

physio- logical defense against gaining and maintaining

often obese individuals have very

비gh

circulating levels of leptin, the OB gene product.9·10l It has

뾰en

recognized that leptin is an adipocyte - de- rived blood - borne satiety factor that acts on OB - R in the hypothalamus, thereby regulating food intake and energy

e짜ienditure.

OB- R gene mutation or polymorphism may contribute to human obesity. Therefore,

many

studies of the OB- R gene in humans were per- formed , and some

reve외ed

several sequence polymorphism in African - American, Caucasians and Pima Indians.11 · 1 2J

In

t비S

study, we investigated relationship be- tween OB - R gene polymorphism and clinical characteristics in Korean

ad버ts.

Methods

an obese

m아r

fat level. Genetic factors are crit- Subjects ically importance for determining how different

in

di찌duals

respond

wit비n

a given environment.

T때S

is

뾰st 피ustrated

by the differences in

mφr

weight

와nong U떠i띠d따ls U띠ng

in a com- mon environment. The

molec버ar

pathogenesis of obesity is, however, largely unknown. The

띠scov­

ery of leptin, the obese (ob) gene product,

뼈S

provided a

usef버

molecular tool to elucidate the pathophysiology of obesity and obesity-associated diabetes. ‘

^-6)

The recent identification and

developn웅nt

of

p이yrrorphic

markers within candidate genes, and

associa디ons

of alleles at candidate loci

뼈s

proved an informative and practical method for

analy강ng

polygenic quantitative traits in animal models and human population.

^{1‘ 8)}

Studies conducted in rodent models of

o뾰sity

have demonstrated that mutations in either the OB gene (ob/ob mice) or OB-R, the leptin rece- ptor gene (dh/dh mice, Zucker fa/fa rats, Kole- sky rat) . A defect in the OB gene in

m비kely

to represent a major cause of obesity in humans as

만le

subjects examined in this study were Ko- rean

ad버ts

in Seoul.

Blo여 S없nples

were collect- ed as part of a population - based survey. In- formed consent was obtained from subjects be- fore the

blo여

was collected.

Obesity index ( (

(re외

weight - standard weight) I

standard weight) × 100) was

calc띠ated

using the standard weight for Korean

ad버잉

and deter- mined according to

쟁e

gender and

stat따e.

Non -obesity was defined as obesity index between

a>% and + a>%. Obesity was defined as

o뾰sity

index of more than +a>%.

Body

mass index (BMI) was

c외C띠ated accor띠ng

to the formula ,

(re외

weight

(kg)

/height2 (M2) ) . Blood pressure was measured by an auto- hemodynamonleter in the sitting position

따ter

5 min rest.

Laboratory tests

Blood samples were obtained in the morning

after an overnight fast. Total cholesterol (TC),

Bong-Keun

α10e

et

외 :

A Study on sorre JX>lyroorphisms of human

lep마1

recept;or gene in Koreans

A:Gln223Arg

AJA AJG GIG

42lbp 294bp 127bp

B:Pro1019pro

G/G GIA A/A

99bp 7lbp 28bp

Fig.I IA - B Genotyping of the polymorphic alleles in th Ob - Rb gene by PCR- RFLP at codons 223(nucletide668) (A) and 10I9(3057) (B), where A to G and G to A transversions occurred, respectively. PCR- RFLP analyses were performed using upstream and down- stream sequence - specific primer(for Gln223Arg) or upstream and downstream mutated sequence -specific primer(for Pro1019pro) as described in Subjects and methods. The re- striction site created (Msp I (A) and Hind II (B)) in polymorphic alleles were depicted.

Polymorphic nucleotides are shown bold. Gel electrophoresis of the PCR products after di- gestion with restriction enzymes.

180 160 140 120

100

80 60 40 20

0

SBP(때n뼈) DBP(빼벼) 口 N。n-o'oose

NA. NG 'rJpe •

α〕ese

A/A. NG 'rjpe

Figure 2. Comparison of blood pressure in Gln223Arg genotype in female.

SBP: systolic blood pressure; DBP:diastolic blood pressure.

(* p-value <0.05 tested by ANCOVA)

triglyce디de

(TG), fasting glucose level and

비힐l

- significant was

establis뼈d

at the p<0.05 level.

density Jipoprotein cholesterol (HDL) were measu-

red by an

autoan외yzer.

Results

Polymerase chain reaction (PCR) - restriction

fragment length polymorphism

(RFLP) Characte「istics

Genomic DNA was extracted from whole blood stored at the

따ne

of collection

(Wi않rd

Genomic DNA Purification

때t, Prom앵a

Corporation, Madi- son, WI, USA) , and used for subsequent

와mlyses.

Obtained genomic DNA was used as templates in PCR with upstream and downstream

primer잉

se- lected to

amρJify

sequences corresponding to exons 2 to 20 of the human Ob-Rb gene ac-

cor띠ng

to the

G없IBANK data없nk(US않깡7-

U59263).

The reaction profiles were as follows ;

denat따a­

tion at 94 for

4않, ann없파ig

at 55 for 45s, and extension at 72 for 90s, for 54 cycles. All PCR products were

없mlysed

by agarose gel electro- phoresis.

PCR- RFLP analysis was performed using pub-

lis뼈d

oligonucleotied sequences and PCR conditi- ons to amplify the region of interest within the appropriate genes.

'3l

PCR- RFLP analysis was performed for geno- typing at codons

2경 ar띠

1019.

πle

PCR

p띠ners

were sequence - specific and/ or mutated for con- venience. The PCR products were

이gested

with

빠n

Ill and Hind II at

c여ons 짧

and 1019, respectively, and were

a떠Jysed

as described

(뀐g.

1) 14)

Statistical analysis

All data are expressed as mean

士standard

de-

끼ation

(s.d.) . One-way analysis of variance (ANOV A) , unpaired t- test, analysis of

cova디­

ance (ANCOV A) test were used to

es따nate

the effects of each

gen따rpe

on quantitative and

qualita디ve

variables.

Statisti않l

analyses were performed using SAS 6.12 software. Statistical

Table 1 present physical and clinical characte- ristics of the subjects. Number(%) of subjects with obesity, non-obesity were 58 (51.3%) , 55 (48.

7%), respectively.

Genotype and allele frequencies of

t따

Ob-R gene and effect of the Ob-R genotype on obesi-

@

πle 띠st다bution

of the Ob - R genotype, allele frequencies and odds ratio for obesity are shown in Table 2-1, 2-2, 3-1, 3-2 .. In male obese subjects, allele frequencies of the polymorphic site at the codons 223 and 1019 (Gln223Arg and Prol019pro) were 92 and 89%. In non-obese

subκcts,

they were 90 and 90%. The odds ratio (95% confidence interval) for obesity of

ArgZ정

and prol019

외lele

in

m외e

were 0.8(0.1-5.5) and 1.1 (0.2-4.9) , respectively. There were no interac- tion between Gln223Arg and Prol019pro

geno앙R

for obesity prevalence (Table 4) . Clinical charac- teristics of subjects according to Gln223Arg and Prol019pro genotype of the Ob-R gene and obesity are shown in Table

4-1 ∼4-4.

No signif- icant difference was

obseπ'ed

in the clinical characteristics among the genotype groups.

Systolic blood pressure (SBP) of subjects with the Gln/Gln and Gln/ Arg in the female obese was significantly higher than that of those with Gln/

Gln and Gln/ Arg in the non -obese (p=0.024).

Serum lipid value, according to the Gln223 and

Prol019pro genotype of the Ob-R gene are show

in Table 4 and 5. There are no significant diffe-

rence in TC, TG, HDL-C

뻐d

LDL-C among the

Ob - R genotype groups.

Bong-Keun

α10e

et al : A

Stuφr

on

so~ I빼rmrphisrrs

of human leptin receptor gene in Koreans

Table 1. Physical and clinical characteristics of study populations by gender and obese sta tus .

Male Female

Non-obese Obese Non -obese Obese

n 20 26 35 32

Age (y) 49.4± 13.7

43.8 土 13.3 41.9 土

14.8 i 52.2± 12.5i

Height(cm) 168.3± 6.5 167.1± 7.0 155.5± 6.0 155.1± 6.7 Weight (kg) 62.0± 5.5t 73.6± 8.4 ’ 53.6± 4.9

^、

65.6± 8.0i Obesity index(%)

4.7 土

4.6t 19.7 ±10.0

^•

4.9± 3.0 i 23.8± l0.4i BMI(kg/m2 ) 21.9± 1.5

•

26.3± 2.2 ’ ^{22.2± l.3 i} 27.2± 2.3i SBP(mmHg) 137.0±20.2 137

^‘

7± 18.2

120.6 土16.6

135.2± 18.2

DBP(mmHg) 85.3± 11.1 90.0± 15.9

76.3 士 10.2

85.9± 11.5

FBS(mg/띠) 87.7 土 16.2

102.4±35.6 92.9±28.0 89.8±20.4

TC(mg/dl) 195.2±28.9 195.5±34.6 184.2±28.1 193.8±36.3

TG (mg/dl) 140.4± 15.l

157.1 土 67.0

83.6 土 44.4 i 118.3 土 59.1 i

HDL(mg /dl) 46.2± 6.0 46.9± 7.2 48.2± 6.4 46.3± 7.3

LDL (mg/dl) 121.0±33.2 117.2±38.3 119.3±30.5 123.9±42.8

data are

mean 土 s.d.

MBI, body mass indes; SBP, systolic blood pressure; DB P, diastolic blood pressure ; FBS, fasting blood sugar; TC, total cholesterol; TG, triglyceride ; HDL, high - swnairy lipoprotein; LDL, low - density lipoprotein.

t

i

p value< 0.05 tested by unpaired t - test in same gender.

Table 2 - 1. Human leptin receptor gene Gln223Arg polymorphism in male.

Genotype Allele

Odds

rati이95%CI)

Group frequency

A/A A/G G/G Gln223 Arg223 Gln223 Arg223

All (n =46) 0(0.0%) 6(13.0%) 40(87.0%) 0.065 0.935 Non - obese (n =

2이

0(0.0%) 2(10.0%) 18 (90.0%) 0.100 0.900

Obese (n = 26) 0(0.0%) 4(15.3%) 22(84.7%) 0.076 0.924 1.0 0.8 (0.1- 5.5)

Table 2- 2. Human leptin r eceptor gene Gln223Arg polymorphism in female.

Genotype Allele

Odds ratio (95%CI)

Group freq uency

A/A A/G G/G Gln223 Arg223 Gln223 Arg223

All(n=67) 2(3.0%) 9(13.4%) 56(83.6%) 0.097 0.903 Non-obese(n=35) 1 (2.8%) 5(14.3%) 29(82.9%) 0.100 0.900

Obese (n = 32) 1 (3.1%) 4(12.5%) 27(84.4%) 0.093 0.907 1.0 0.7 (0.2- 3.2)

The

띠scovery

of leptin, the obese (ob) gene Di scussion product, has

pro띠ded

a useful molecular tool to elucidate the pathophysiology of obesity and

만1e

molecular pathogenesis is largely

m뻐1own.

obesity-related

이seases.15i

It has been recognized that leptin is an adipo-

cyt.e-de디ved

blood - borne satiety factor that is involved in the regulation of food intake and en- ergy

e짜ienditure.16J

The leptin receptor (OB-R) is a single transmembrane protein that belongs to the gp 130

fam바

of cytokine receptor super-

fam바.11J

Recently other researchers have demon- strated that Ob- R is also mutated in genetically

O뾰se

Zuker fatty <fa/fa)

m잉

and obese sponta- neously

이rpertensive

Kolestky (fak !fa ’‘) rats.1BJ For

a따]ysis

of the Ob-R gene in humans, previous

Stu이es reve외ed sever외

sequence

polymorp비sms

in the Ob-Rb gene with no obesity-causing mu- tation in black African - American, Caucasians and Pima lndians.11· 12l No sequence variants were located in functionally defined

dom외ns.

Genetic

e찌dence sh애ed

that ob, db,fa, and fak,

외l

of which code for leptin or Ob-R, are autosomal recessive mutation in rodents.11 ·1 2J In the present study, 4 amino acid substitutions (Lys109Arg, Gln223Arg, Lys656Asn, and

Al뼈76Asp)

were founded to be homozygous but were

이sσibuted

in both obese and non - obese subjects.

πle

amino acid change at codon 492(Ser492Thr) was found to

뾰

only heterozygous.

I띠ividually,

the OB gene and

Gln2잃.Arg

poly- morphism were not associated with the obese.

There was an association between the Pro1019Pro polymorphism and

띠astolic

blood pressure. In addition,

indi띠du외S

with homozygous for the common alleles of

외l

three polymorphism exhibited significantly higher fasting insulin con- centration than individuals without the polymor- phisms. The allele frequencies for the three pol- ymorphisms investigated were compared to fre- quencies for observed in several populations.

A frequency of 89% was observed for Arg allele of the Gln223Arg

p이ymorphism

in the Na-

따uan

subjects.

T매S

is not sinlilar from previous studies conducted in Japanese and Pima Indian populations where the frequency of this

외lele

was found to be

appro잉mately

85% and 75%

respectively.1 9J It is, however, somewhat higher than the frequency reported for British males, 44

%. Previous reports have suggested that allele frequency of the Arg2Z3 of the Ob-R gene was higher in

Ja탱nese(O없8-0.872)

than in Caucasi-

킹lS (0.421-0.44이

and in Pima

In띠ans(0.75이_

12.

²⁰⁾

These studies showed that allele frequency varies

없nong

ethnic groups and that the polymorphism is not associated with obesity. Further studies are needed to determine associations between the

p얘morp비sm

of the Ob- R gene and obesity.

The frequency of the pro allele for the Pro1019Pro

polymorp비sm, appro잉mately

80%,

외so

appears to be sinlilar in the Nauran

pop띠a­

tion to that seen in other populations. Frequen- cies of 88% and 85% were observed for this allele in Japanese and Pima Indians populations, respectively, the frequency in the Korean popu- lation was 86%.

안le

OB and Ob-R

gen얹

have

뾰en

mapped to human chromosomes 7q31 and lp32, respectively.

These genes lie in regions identified through ge- nomewide scans as containing loci important in the development of obesity and type 2

띠abetes.

Strong evidence of

파뼈ge

has recently

뾰en

demonstrated for insulin precursors and the OB region. 2 1 J The relationship

descri뾰d

may be abse- nt in other populations either

양cause

of

띠ff

er- ent haplotype combinations at the Ob- R gene or

뾰cause

the markers tested may not themselves be functional polymorphisms. While the function-

외ity

of these polymorphisms needs to be investi- gated, the lack of physiological functions at these polymorphic sites would not necessarily rule out the possibility of the presence of

피lkage

disequilibrium between these marker and closely linked functional polymorphisms.

In the

C따rent

study, the DBP subjects of with

the obese A/ A type was significantly

미양'ler

than

t뼈t

of those with the non -obese A/ A type before

Bong-Keun

α10e

et

외 :

A Study on soire

I얘rrorp비srrs

of human leptin receptor gene in Koreans

Table 3-1. Human leptin receptor gene Pro1019pro polymorphism in male.

Genotype Allele

Odds ratio (95%CI)

Group freq1:1ency

G/G G/A A/A Pro1019 Pro1019 Prol019 Pro1019 All(n=46) 0(0.0%) 10(21.7%) 36(78.3%) 0.109 0.891

Non-obese(n=20) 0(0.0%) 4(20.0%) 16(80.0%) 0.100 0.900

Obese(n=26) 0(0.0%) 6(23.1%) 20(76.9%) 0.115 0.895 1.0 1.1 (0.2-4.9)

Table 3 - 2. Human leptin receptor gene Pro1019pro polymorphism in female.

Allele

G/G G/A A/A

frequency

Prol019 Pro1019 Prol019 Pro1019 Odds ratio (95%CI) Genotype

Group

때 m 씨 때

nU nU nU

m %%%

%n

깎

”

a

mω

%%…·

m강 이ω%ω mωn

9

%%%

nU nU nU nU nU nU

멧

m

잉

--nd

끼 꽁

=

얘 빼 빼 m

m

뾰

A N O

0.851 0.843

0.860 1.0 0.9(0.3-3.1)

Table 4. Odds ratio of interaction between Gln223Arg and Pro1019pro genotype for obesity prevalence.

Pro1019pro

G/G, G/ A type A/ A type Gln223Arg A/G, A/A type

G/G type

1.0

2.9(0.5 ∼

15.9)

6.5

(0.7 ∼ 59.6) 1.7(0.3 ∼

8.2)

Table 5 - 1. Association between the Gln223Arg polymorphism and clinical characteristics in male.

Non-obese Obese

A/A,A/G A/A,A/G P-value

type(n=2) (n=4)

SBP

125.0 土

7.1 138.8±14. 4 0.624

DBP

85.0 土

7.1

102.5 土 11.9

0.805

TC

187.0 土 28.3 203.3 土 32.4

0.806

TG 72.0± 5.7 120.8±63.8 0.905

HDL 45.5± 4.9 42.3± 5.1 0.732

LDL 127.1±34.4 136.9±42.3 0.736

Data are

mean 土 s.d.

‘ 'ANCOV A, adjusted for age and BMI, was used for comparisons of the two groups.

SBP, systolic blood pressure; DBP, diastolic blood pressure; TC, total

ch이esterol;

TG, triglyceride;

HDL,

^미gh

- density lipoprotein; LDL, low - density lipoprotein

Table 5- 2. Association between the Gln223Arg polymorphism and clinical characteristics in male

Non-obese Obese

G/G type G/G type P-value

type (n= 18) (n=22)

SBP 138.3±20.9 137.1±19.1 0.079

DBP 85.3±11.6 87.7± 15.6 0.325

TC 196.l ±29.6 194.0±35.5 0.456

TG 147.9 ±38.3 163.7±66.8 0.265

HDL 46.2± 6.2

47.7 土

7.3 0.439

LDL 120.3±34.0 113.6±37.5 0.758

Data are mean± s.d. 'ANCOV A, adjusted for age and BMI, was used for comparisons of the two groups.

SBP, systolic blood pressure; DBP, diastolic blood pressure; TC, total cholesterol ; TG, triglyceride;

HDL, high - density lipoprotein; LDL, low - density lipoprotein

Table 5-3. Association between the Gln223Arg

p이ymorphism

and clinical characteristics in female.

Non-obese Obese

A/A, A/G A/A, A/ G P-value

type(n=6) (n=5)

SBP 110.8±12.8 143.0±25.9 0.024

DBP 70.8± 6.6 89.0± 18.5 0.141

TC 191.8±20.1 182.0±21.6 0.680

TG 95.5±62.1

97.8 土 44.3

0.418

HDL 46.5± 4.5 47.8± 4.4 0.662

LDL

126.2 土 23.4

114.6±27.1 0.833

Data are mean

土 s.d.

aANCOVA, adjusted for age and BMI, was used for comparisons of the two groups.

SBP , systolic blood pressure; DBP, diastolic blood pressure; TC , total cholesterol; TG, triglyceride ; HDL, high -density lipoprotein; LDL, low-density lipoprotein

adjm tments for age, gender and obesity index (Table 7) . It is of interest that Widen et al.

22>

Hypertension is associated with obesity, further studies are required to clarify the association between polymorphism of Ob-R gene and hype- rtension.

c。nclusi。n

In the present study, investigation into the re- lationship between polymo[phisms in the Ob-Rb gene, a leptin receptor gene, and clinical findings

in a sample population of Koreans classified into the control and obese group;

뼈sed

on the crite- ria set by the Japanese Society of Obesity has led to the following conclusions. First of

떠I,

no difference in the prevalence of obesity has

뾰en

associated with the different polymorphisms in the leptin receptors. Secondly, no relavance was observed between variations in the levels of cho-

l않terol,

low- and

비gh

- density lipoproteins, and neutral fat, associated

깨th

obesity, and the le- ptin receptor polymorphisms studied.

Addition외ly,

members of the group; with the phenotypically

Bong-KetID

α10e

et

외 :AStuφr

on sorre polyrmrphisms of human Jeptin receptor gene in Koreans

Table 5 - 4. Association between the Gln223Arg

p애morphism

and

c피rical

characteristics in female

Non-obese Obese

G/G type G/G type P-value

type(n=29) (n=27)

SBP 122.6± 16.7 133.7± 16. 7 0.412

DBP 77.4± 10.5 85.4± 10.1 0.322

TC 182.6±29.5 196.0±38.3 0.566

TG 81.1±40.8 122.0±61.4 0.896

HDL 48.6± 6.8

46.0 土

7.8 0.860

LDL

117.8 土 31.9 125.6 土 45.3

0.575

Data are mean

土 s.d.

‘ 'ANCOV A, adjusted for age and BMI, was used for comparisons of the two groups.

SBP, systolic blood pressure; DBP, diastolic blood pressure ; TC, total cholesterol; TG, triglyceride;

HDL,

피gh

- density !ipoprotein ; LDL, low - density !ipoprotein

Table 6-1. Association between the Pro1019pro polymorphism and clinical characteristics in male

Non -obese Obese

G/G, A/G G/G, A/G P-value

type (n=4) (n=6)

SBP 128.8± 6.3 135.8±12.0 0.303

DBP 82.5± 9.6 86. 7± 9.3 0.554

TC

199.8 土 27.1 208.3 土 23.2

0.987

TG 87.5±21.5

163.7 土 99.6

0.985

HDL 44.3± 3.3 45.7± 5. 5 0.776

LDL 138.0±27.6 129.9±23.9 0.974

Data are mean

土 s.d.

‘ ' 'ANCOV A, adjusted for age and BMI, was used for comparisons of the two groups.

SBP, systolic blood pressure ; DBP, diastolic blood pressure ; TC, total

ch이esterol;

TG, triglyceride;

HDL, high - density !ipoprotein; LDL, low - density !ipoprotein

Table 6-2. Association between the Pro1019pro polymorphism and clinical characteristics in male

Non-obese Obese

A/A type A/A type P-value

type (n= 16) (n=20)

SBP 139.1 ± 22.1 138.3±20.0 0.108

DBP 85.9± 11.6 91.0± 17.4 0.892

TC 197.1± 30.0 191.6±36.9 0.562

TG 153.6 ± 113.9 155.2±57.2 0.127

HDL 46.6± 6.5 47.3± 7.7 0.821

LDL 116.7± 33.8 113.3±41.4 0.893

Data are mean

土 s.d.

'ANCOV A, adjusted for age and BMI, was used for comparisons of the

^’

two groups.

SBP, systolic blood pressure; DBP, diastolic blood pressure; TC, total cholesterol ; TG, triglyceride;

HDL,

비gh

- density lipoprotein; LDL, low - density !ipoprotein

Table 6-3. Association between the Pro1019pro polymorphism and clinical characteristics in female

Non-obese Obese

G/G, A/G G/G, A/G P-value

type (n= 11) (n=9)

SBP 123.2±21.6 136.7 ±22.8 0.903

DBP 77.3±11.5 90.6± 15.7 0.509

TC 175.8±16.0 178.8±20.l 0.778

TG 81.7±52.7 124.4±74.6 0.945

HDL 49.4± 5.2 48.7± 7.9 0.637

LDL 110.1±16.1 105.2±25.3 0.725

Data are mean± s.d. 'ANCOV A, adjusted for age and BMI, was used for comparisons of the two groups

^’

SBP, systolic blood pressure ; DBP, diastolic blood pressure; TC, total

ch이esterol;

TG , triglyceride;

HDL, high density lipaprotein; LDL, low - density lipaprotein

Table 6- 4. Association between the Prol019pro polymorphism and clinical characteristics in female

Non-obese Obese

A/A type A/A type P-value

type (n=24) (n=23)

SBP 119.4± 14.1 134.6± 16.7 0.581

DBP 75.8± 9.7 84.1± 9.1 0.345

TC 188.0±31.7 199.7±39.7 0.679

TG 84.5±41.2 115.8±53.6 0.703

HDL 47.7± 7.0 45.3± 7.1 0.933

LDL 123.4±34.7 131.2±46.4 0.629

Data are mean

土

s.d. 'ANCOVA, adjusted for age and BMI, was used for comparisons of the two

grou뼈.

SBP, systolic blood pressure ; DBP, diastolic blood pressure; TC, total

ch이esterol;

TG, triglyceride;

HDL , high - density lipoprotein; LDL, low - density lipaprotein

wild - type polymorphisms for the Gln2Z3Arg

gηn­

otype (A/ A or A / G) demonstrated higher systolic

요

blood pressures than those of the obesity group did (p=0.024).

약

연구배경

:

비만은 산업사회에 있어 주요한 건강운제이고 그 이환률도 급증하고 있다. 비만은 꽉히 고혈압, 지 방간, 고지혈증, 퇴행성 관절엽, 당뇨병 (NIDDM), 심혈관 질환 및 대사질환 퉁과 밀접한 관계가 있어 비만을 하나의 질환으호 인식하고 치료할 필요가 었다. Le며n은 지방세포에서 유래된

satiety

factor로 음식섭취와 에 너지소비 조절에 관여한다 -Leαm은 cyto때e 수용체 supezfa띠]y의 하나언

leptin

수용체

(Ob-R)

에 작용하는 데 크게 5가지의 isoform을 가지고 있다. 그 isoform총l] 뇌의 시상하부에서는 Ob-Rb의 isoform이 존재한다.

최근 leptin과 Ob-R은 에너지 향상성

(energy

homeostasis) 을 조절하는 시챔}부와 지방세포에서의 feed뼈ck

Bong-Keun

α¥>e

et al : A Study on

so~

po!yroorphisrrn of

hur때n lep미1

receptor gene in Koreans

system에 중요한 작용을 하고있다고 보고되고 있다.

방 법

:

1999년 11월 1일부터 am년 8월 31 일까지 한국인을 대상으로 일본비만학회에서 제시한 기준으로 비만군과 정상군으로 분류하여 한국인에서의 lepψ1 수용체 유전자 중

Ob-Rb

유전자의 다형성과 임상자료와 의 관련성에 대하여 조사하였다.

결 과:

1.

비얀유전자 수용체의 다형성에 따른 비만 유병률은 차이를 보이지 않았다.

2.

비얀유전자 수용체의 다형성에 따른 비만과 관련 있는 콜레스테롤, 저농도 지질단백질, 중성지방, 고밀도 지질단백질은 유의한 차이를 보이지 않았다.

3.

유전자 다형성중

Allele

빈도는 Gln2잃:Arg,

Prol019pro

모두 빈도의 차이는 보이지 없t으나

Piim

인디언 과 일본인보다는 발현율이 높았다.

4. Gln2Z3Arg

과 ProlOl않0 사이의 비만 유병률에 대한 유전자 상현1용은 통계척i로 연관성을 찾을 수 없었다.

5.

남녀로 구분하여 비만유전자 (Ob-R) 의 다형성에 따른 임상자료를 비교한 결과 수축기 혈압에서 차이를 보였는데, 여성비만군의

Gln223Arg

유전자중

A/A, A/G

형태다형성을 보인 군의 혈압이 높았다 φ=0.0'24) 중심단어 :비얀유전자수용체, 비얀유전자다형성, 유병률, 수축기 혈압

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