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