Association Between Vitamin D Receptor Gene Polymorphism ... - JASN

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60.9%,. P = 0.02, respectively), and the BB genotype and the. B allele were significantly more frequent in the low PTH group than in the high iPTH group. (32.3%.
Association Between Vitamin D Receptor Gene Polymorphism and Relative Hypoparathyroidism with Chronic Renal Failure ELVIRA JAUME

FERNANDEZ,* ALMIRALL,

*Nephrology

Service

Human

gene

polymorphism

renal

failure,

pmolfL

on

low

and

of Basic Unit,

of vitamin had

function

serum

PTH

group)

[iPTH]

levels

Sciences,

cies

were

significantly

who

and

all

0.0 1 8, respectively).

uais.

total

As

a result

criteria

in

levels,

serum

low

group

120)

and

tion rum

in those

dialysis

applied.

The

BsmI

pression

and

density

menopausal this

with

the

stability

genotype,

the

various

the

ultimately

have

an

increased (2,3).

is

transcriptional

These

and

of a specific

the

unknown,

other

allele

the activity

allelic

frequen-

can

B and gene

molecular B allele

clinical

b

ex-

Recent

(3-6)

have

were

lower

(14.7%

60.9%,

P

renal

faiiure.

The

lower

RNA

suggest

that

consequences

in bone.

January

2.

1997.

Accepted

March

14,

group

ratio,

than

in the

genotype

has

VDR

sible

been

density

For

parathyroid

to renal

these in the

the

wide

parathyroidism

observed

could in the

VDR

in chronic

in the parathyroid

upregulates

VDR

effect

Among

(7,8). to calcitriol

(9).

No

but

other

in uremia

definite

there cells

reason

is evidence of uremic

be at least degree

in patients

expres-

of hyperparathy-

reasons, we investigated VDR gene could determine that

Thus,

the VDR

ascertained,

variation

0.05,

=

1997)

in the parathyroid

cell function

for

the

group

8: 1546-i552,

pathogenesis

failure

high versus

and

function

cells

in the

0.85 b allele

the

respectively).

synthesis,

role

secondary

resistance

with

of parathyroid

important

(10,1 1). differences

Nephrol

0.3;

the group

and 41 .2%

BB

bb

in the

interval,

0.06,

the

an antiproliferative

resistance an

ease

of a patients

whether ailelic differences in partially

respon-

of secondary

with

for

end-stage

hyperrenal

dis-

(ESRD).

and Methods

Patients

1997.

Correspondence to Dr. Elvira Fern#{225}ndezNephrology versitari de Lleida Arnau de Vilanova, Rovira Roure

odds

and

parathyroid

of caicitriol

exerts

roidism

Soc

pre-pro-PTH

and

Materials Received

than

confidence

=

0.02,

=

influences

interaction

factors,

this

P and

P

39.1%,

(J Am

inhibits

sion,

in post-

group

genotype

iPTH

34.4%,

the

0.01). Conversely, in the low iPTH

bb

low

population,

36.4%;

P =

and

=

1.9;

respectively),

versus

polymorphism

piays

basis for has been

0.02,

58.8%

indicate with the with low

in the

before

0.037

were significantly more frequent in the low PTH in the high iPTH group (32.3% versus 12.5%, P

gene

cell

P

the was

of patients =

iPTH

versus

and

distribution

(P

low

the

versus

population

selected

ratio,

group

3’ re-

untranslated

final

odds

iPTH

and

total

19.7%;

Renals,

group

criteria

over-represented

frequencies

=

iPTH

to 0.82;

In addition,

than

criteria

or messenger

observations

as

by

genotypic

(14.7%

0. i).

=

control

the

in the

0.11

was

versus

P

both

of osteoporosis

Although

largely

to 4.3;

B allele

consequences.

risk

(23.3%

=

conforma-

in the

population interval,

Vilanova;

Sistemes

healthy low

frequent

de

Spain.

exclusion

In the

less

genotype

high

served

in a large population of healthy adults serum levels are higher in individuals (1). This genotype is also associated and

BB

(n

determined

locus defines in the VDR

functional

dialysis

fragments. Sethe BB genotype

and

in the

was

confidence

final

final

exclusion

in genotypic

identified

the

population

vitamin D receptor (VDR) may determine differences

to increased

the presence

or bb

when

several

population

of PCR amplified in patients with

differences

women

(2).

and

genotype

aluminum

dialysis),

control

dialysis

Bb

and

phenomenon

linked

on

of 34 patients

170-patient

on

serum

time

A healthy

polymorphism

observations that osteocalcin BB genotype

and

analysis were lower

No

gion of the alleles that

based

patients,

VDR gene polymorphism was the BsmI enzyme and single-strand

population

were

bone

of the

groups. with

polymorphism iPTH levels

than

levels,

32 patients.

162

exclusions

(diabetic

consisted

included

control digestion

subsequent

groups calcium

iPTH

iPTH

of

both

the in the

applying

had serum iPTH levels >60 pmoiIL (the high iPTH group) were selected out of a total dialysis population of 170 individ-

Lleida;

However,

different

after

M. PIULATS,t

Arnau

Sabadell,

between

group.

Lleida de

TaulI

found

iPTH

60

TBE

Polymorphism

ethyienediamine

Diagnostics

excluded

patients

in

group,

chemiluminometric

iPTH

>2.2

61 patients

we

from

levels

iPTH group. Because time favoring the development

hyperparathyroidism,

excluded

later

.tmolIL.

excluded left

iPTH

phosphorus,

levels

>2.75

group,

group).

we

(normal

high

Ciba-Corning in each

aluminum

levels

the

iPTH

calcium,

group,

mmollL.

iPTH

serum

12 pmoiIL


0.

fl C .-

.

C)ECCa ;a-, C) .0 C)60.C C C)> -6 .0O_ 0. U

C) V C)11 C) c,C) C ,,

.0 C

VDR Gene

A

100

80

-

60

-

40

-

ANOVA

20

0

-

-

80

-

60

-

60

-

40

-

20

-

F1

j_

IF0

20

0-

0bb

F0

I

I

BB

Bb

GENOTYPE Figure selection

1. Serum criteria

expressed

intact other

as mean

Table

2 shows

control

confidence

genotypic

subjects

and

exclusion criteria time on dialysis, included

95%

allelic

as an exclusion

criterion.

throughout.

tween reached

and

statistical

applied 49.1%;

criteria

16.6

to 48.1%;

2.79

to

were Bb,

allele

a defect

B and

absolute

values

considered

low

be-

iPTH

no exclusion

an

of

in

population

the

odds

low

and was

of belonging

the

criteria

low

bb,

low iPTH homozygous

genotype.

group

than

with

iPTH

19.7%,

odds

ratio,

34.4%,

P

tiveiy),

and

P = 0.01).

significantly group P detected

1.9, CI, 0.85

and 41.2%

the BB

genotype

higher

in the

(32.3% =

to 4.3;

=

0.02,

between

versus

versus

60.9%,

and

the B allele

low 12.5%,

respectively).

the low

group

PTH

P

=

Thus,

iPTH

0.05,

P

in the

risk 36.4%.

the BB when versus

in the versus

mary

were applied (A), criterion (C).Values

when are

influence

bb

and 58.8%

and

determining

hyperparathyroidism

BB

patients

roidism,

the

cystica,

fail

severe

has

its histologic

develop

only

others

to promote

adynamic neous

adequate

frequency different

disease

( 16, are

studies,

to the

memt

of severe

related

with

reasons

disease

use

of calcium

wide variaWhereas

iPTH

and

well

bone

secondary

that

result

for this

heteroge-

The

growing

defined. has

fibrosa levels

finally

been

in

attributed,

compounds

hyperparathyroidism

the duration

in

as phos-

of renal

has

failure

and

time

been

cor-

on dialysis

(8).

The

aim

of our

study

explain

why

that purpose

geno-

not

of

largely

hyperparathy-

elevated

17). The

severity

were

in osteitis

turnover

frethe

phate binders; high-dose caicitriol therapy; changing dialysis populations that are older and have more diabetic patients; and aluminum intoxication (18). On the other hand, the develop-

high versus

and failure

counterpart

modestly

pri-

higher However,

patients, there are hyperparathyroidism.

bone

of adynamic

renal

and uncontrollable

behavior

bone clinical

nonfamilial

development to

develop

which

with

VDR

parathyroid

a significantly the b allele (15).

secondary

were

association

detected

turnover,

to modify

Patients

have

genotype

on bone

shown

and function.

background in ESRD.

respec-

was

the bb genotype.

recently

hyperparathyroidism

genetic response

in the

the

cell differentiation

influences

dialysis

0.02,

and

has been

genetic

2 shows

frequency than

to its known

were

In addition,

a positive

group

bb

association

and

some

versus

0.1).

negative

group

CI,

Conversely,

P

In addition polymorphism

of the

decreased

(14.7%

but

iPTH

14.7%,

and the b allele frequencies were lower than in the high iPTH group (14.7%

0.06,

=

I

Bb

Discussion

quency

group was for the

total

a significant

group

to 0.82;

the

low

unknown until now. In ESRD tions in the degree of secondary

and alleles

in

stronger

CI,

Figure

of genotypes

a

the

32.4%,

was over-represented in the low iPTH group with the total dialysis population (32.3%

the bb genotype low iPTH group

I

BB

when no selection criteria was included as a selection

group

and both patient groups of the final found that the bb genotype was less

iPTH

0.3, CI, 0.11

(BB,

to 69.6%;

bb

associated

to the

ratio,

genotype compared

36.1

The final of subjects

and frequencies

total dialysis population selected population. We frequent

for analysis

CI,

0.018). excess

=

by

was

in the

when

52.9%,

P

26.6%;

characterized

39.1%,

distribution

and

between

found

(BB, 23.5%, CI, 14.4 to 32.5%; Bb, 38.8%, CI, 28.4 to bb, 37.6%, CI, 27.3 to 47.8%; P = 0.037) and when all

exclusion

iPTH

were

and the high iPTH group. The in the low iPTH group of values

significance

type

no

criteria, except on dialysis was

in genotype

observed

when

No differences

Differences

expected

in healthy

groups

when exclusion and when time

between healthy control subjects BB genotype was more frequent patients

patient

0,220

=

of the mean.

frequencies

various

applied; applied;

(CI)

p

GENOTYPE

in patients with the BB, Bb, or bb genotype, were used (B), and when time on dialysis

interval

and

in the

were were

0bb

GENOTYPE

PTH (iPTH) levels than time on dialysis

±

1

I

-

ANOVA

Ii I Ii I

0 -

0.

Bb

One-way

80

40

1549

-

0,065

0

E

BB

p=

ANOVA

T

T

I1 I

I

100 One-way

I

0.

Hypoparathyroidism

C

-

= 0,079

p

0

E

and Relative

B

100 One-way

Polymorphism

primarily

group previous

some

patients

in mind, on

had

the

levels studies

was

to determine

to the different Hopefully, this

basis

>60

behave

we defined of

to correlate

one

way

two groups

their

pmolIL.

the

iPTH

Such strongly

contribution

of

patterns of parathyroid could, at least partially, or another.

levels.

levels with

With

of ESRD The

have

been

patients, high

iPTH

found

the histologic

in pat-

I 550

Journal

Table

of

the

Genotype

2.

American

and

Society

allele

of

frequencies

in healthy

Healthy Control Subjects (11= 120)

Category

Nephrology

control

A (n = Lown=85

subjects

and

in the various

134)

B (n =

Highn=49

patient

groupsa C (n = 66)

106)

Lown=6l

Highn=45

Lown34

Highn=32

Genotype BB

16 (13.4%)

20 (23.5%)

7 (14.2%)

15 (24.6%)

1 1 (32.4%)

4(12.5%)

Bb

67 (55.8%)

33 (38.8%)

25 (51.0%)

26 (42.6%)

24 (53.3%)

18 (52.9%)

17 (53.1%)

bb

37 (30.8%)

32 (37.6%)

17 (34.6%)

20 (32.7%)

16 (35.6%)

5 (14.7%)

1 I (34.3%)

0.037

0.846

0.109

0.822

0.018

0.929

P versus control subjects P low

versus

5 (1 1.1%)

0.292

0.078

0.064

high

Allele B

99 (41%)

b

141

P versus

(59%)

73 (43.7%)

39 (41.9%)

56 (44.7%)

34 (38.0%)

40 (58.8%)

25 (39.0%)

97 (56.2%)

59 (58.1%)

66 (55.2%)

56 (62.0%)

28 (41.1%)

39(60.9%)

control

0.732

0.805

0.567

0.398

0.01

0.752

subjects P low

versus

0.615

0.237

0.02

high a

Genotypic

(A);

when

and

allelic

exclusion

frequencies

criteria

(C). The BB genotype

in healthy

except

time

was more

control

on dialysis

frequent

subjects

were

and

applied

in the low ‘PTH

(B);

group

in the various and

patient groups, when compared with those of the healthy control subjects, exclusion criteria. Differences in allele frequencies between the low iPTH significance in the final selected population.

tern

of osteitis

terized ing

fibrosa

cystica

by refractoriness that

impact

usually

indicates

of time

(16, 17). This

to high-dose disease

on dialysis

parathyroid hyperplasia, with