Influence of Vitamin D Receptor Gene Polymorphisms on Mortality
Risk in Hemodialysis Patients
Maria Paz Marco, MD, Lourdes Craver, MD, Angels Betriu, MD, Joan Fibla, PhD,
and Elvira Ferna ´ ndez, MD
● The BsmI polymorphism of the vitamin D receptor (VDR) gene influences mineral metabolism and the course of
cancers and infections. The poly-A polymorphism is in linkage disequilibrium with BsmI and could be responsible
for clinical associations attributed to BsmI. The objective of this work is to study the influence of VDR polymor-
phisms on survival of 143 prevalent hemodialysis (HD) patients followed up for 4 years. Chi-square test was used to
study the association between survival and these polymorphisms. Cox analysis was performed, adjusting for
comorbid conditions in the entire HD population, groups of patients on HD therapy for less than 5 and 3 years before
entering 4 years of observation, patients without diabetes, and patients treated with calcitriol. Survival was
analyzed by means of Kaplan-Meier according to BsmI genotypes. Results showed a strong influence of the BsmI
polymorphism on survival. The bb genotype was overrepresented among survivors (45.7%) compared with
nonsurvivors (21.6%), and Cox analysis showed a significant influence of age, diabetes, calcitriol treatment, and
BsmI polymorphism in all groups (in the entire population, Exp(B): BB, 3.9; and Bb, 3 with respect to bb), and also of
phosphorus in patients without diabetes and calcitriol-treated patients. Survival means by Kaplan-Meier were as
follows: BB, 983 days; Bb, 1,152 days; and bb, 1,290 days (log-rank P 0.01). The BsmI polymorphism influences
survival in HD patients, whereas the poly-A and FokI polymorphisms do not.
© 2001 by the National Kidney Foundation, Inc.
INDEX WORDS: Calcitriol; vitamin D receptor (VDR); hemodialysis (HD); mortality; hyperparathyroidism; 1,25-
dihydroxyvitamin D
3
.
I
T IS WELL ESTABLISHED that vitamin D is
a potent immunomodulator. Lower vitamin
D levels have been associated with poorer prog-
nosis in human immunodeficiency virus–in-
fected patients
1,2
and a greater occurrence of
tuberculosis in exposed patients.
3
Demonstration
of the inhibitory role of 1,25-dihydroxyvitamin
D
3
in experimental autoimmune diseases
4-7
and
the fact that it has been proven to prolong allo-
graft survival
8
are evidence of the importance of
1.25-dihydroxyvitamin D
3
in the immune sys-
tem. Moreover, receptors for 1.25-dihydroxyvita-
min D
3
have been found in human peripheral-
blood monocytes and active lymphocytes of rats
and humans.
9-12
In addition, vitamin D has an antiproliferative
and differentiating effect, shown in vitro in vari-
ous cell lines that express vitamin D receptor
(VDR), such as breast cancer cells.
13,14
In hu-
mans, an inverse relationship between vitamin D
level and tumor cell growth has been reported.
14
Recently, an association was described be-
tween 3'VDR gene polymorphisms and the preva-
lence
15,16
and aggressiveness of prostate
15
and
breast
17
cancers and the prevalence of certain
immune diseases, such as type 1 diabetes melli-
tus
18,19
and systemic lupus erythematosus.
20
Antiproliferative properties of vitamin D also
have been shown in the cardiovascular system.
In vitro, 1,25-dihydroxyvitamin D
3
inhibits vas-
cular smooth muscle cell growth,
21
and both
vitamin D and retinoic acid reduce endothelin-
induced secretion of atrial natriuretic peptide.
22
On a clinical level, calcitriol treatment reduced
left ventricular hypertrophy in hemodialysis (HD)
patients.
23
HD patients begin to show a relative defi-
ciency of 1,25 dihydroxyvitamin D
3
from early
stages of chronic renal failure,
24,25
and this may
be influenced by BsmI VDR gene polymor-
phisms.
25
Therefore, enough evidence exists to
hypothesize that lower levels of 1,25-dihy-
droxyvitamin D
3
or variations in VDR function
induced by polymorphisms at the 3' and 5'
regions of the VDR gene may have a role in the
From the Nephrology Service, Hospital Universitari Ar-
nau de Vilanova; and the Departments of Medicine and
Basic Medical Sciences, University of Lleida, Spain.
Received December 29, 2000; accepted in revised form
May 25, 2001.
Supported in part by grants La Paeria of the University of
Lleida and Fondo de Investigaciones Sanitarias (FIS) no.
00/1009. Joan Fibla and Elvira Ferna ´ndez are senior coau-
thors.
Address reprint requests to Elvira Ferna ´ndez, MD, Servi-
cio de Nefrologı ´a, Hospital Universitari Arnau de Vila-
nova, Rovira Roure 80, 25198 Lleida, Spain. E-mail:
efernandez@arnau.scs.es
© 2001 by the National Kidney Foundation, Inc.
0272-6386/01/3805-0006$35.00/0
doi:10.1053/ajkd.2001.28582
American Journal of Kidney Diseases, Vol 38, No 5 (November), 2001: pp 965-974 965