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Original Studies |
Departments of Clinical Physiopathology (L.G., L.B., L.M., R.M., M.L.B.) and of Obstetricts and Ginecology (G.L., A.M.B)., University of Florence, 50139 Florence; and Institute of Medical Pathology (S.G., C.C., S.M., A.M.), University of Siena, Siena, 53100 Italy
Address all correspondence and requests for reprints to: Maria Luisa Brandi, M.D., Ph.D., Endocrine Unit, Department of Clinical Physiopathology, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The cause of the discrepancies remains to be determined, and in part,
it may be caused by the limited sample size of many studies. Indeed,
relationships between VDR gene alleles and osteoporotic risk, mediated
through differences in BMD, are unlikely to be observed in relatively
small samples. A potential confounder in all such studies may be given
also from the health-based selection bias, with the tendency to exclude
osteoporotic women. Currently, the few association studies, in which
the prevalence of VDR genotypes in osteoporotic and nonosteoporotic
patients are compared, have been carried out in small samples, with
limited statistical power (12, 15, 16, 18). Heterogeneity also is
likely, with different major genes segregating in different patient
samples. In this regard, other polymorphic genes, such as those
encoding for estrogen receptor (ER), collagen type I 
1, and
interleuchin 6 recently have been linked to variation in BMD (19, 20, 21).
These genes could either positively or negatively modulate VDR gene
effect, with a different power, which needs to be individually
evaluated. In addition, environmental factors also could reciprocally
interact with genetic factors. Recently, dietary calcium intake has
been reported to contribute to the expression of the VDR gene effect,
both on BMD (10, 11) and on intestinal calcium absorption (22).
Finally, linkage disequilibrium with another bone metabolism-related
gene on chromosome 12 (i.e. Collagen 2 A1 and retinoic acid
receptor genes) cannot be excluded.
Being aware of the constant interaction between genetic and environmental factors in bone mass determination, the present study was performed to evaluate, for the first time, in a large and ethnically homogeneous group of postmenopausal women of Italian descent (stratified for BMD in normal, osteopenic, and osteoporotic patients): 1) the relationship of VDR and ER gene polymorphisms with BMD, after controlling for multiple confounders; and 2) the possibility of an interaction between VDR and ER genotypes with bone mass, assuming that variation of BMD is influenced by multiple genes.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Patients eligible for the study were selected among 1500
consecutive postmenopausal women who, in 1995, attended the metabolic
bone diseases outpatient clinics in Siena and Florence for osteoporotic
risk evaluation. For all subjects, a detailed medical history was
obtained, and dietary calcium intake was assessed by a sequential
self-questionnaire, including foods that account for the majority of
calcium in the diet. Among this group of women, 866 had associated
conditions known to affect bone metabolism and were excluded from
analysis. These were diseases known to influence bone mass (98 women),
use of bone active drugs (303 estrogen replacement therapy, 198 vitamin
D metabolite, 96 bisphosphonate, 59 calcitonin, and 7 fluoride) or use
of drugs that could potentially affect bone metabolism (55
glucocorticoid, 34 thyroid hormone, and 16 antacid). Eighty-nine women
also were excluded because of their different ethnical origin. Blood
was available for DNA isolation in 426 of the remaining 545 subjects.
The age range of the studied women was 47–76 yr, with a mean
(±SEM) age of 57.7 ± 0.43 yr. On the basis of BMD
measurements and according to WHO criteria (23), 40% of the 426
subjects had osteoporosis, 26% had osteopenia, and 34% were normal.
General characteristics of the population are presented in Table 1
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Genomic DNA was isolated from EDTA blood samples by a standard
phenol-chloroform extraction procedure, and 8 µg of DNA were digested
for 6 h in a vol of 50 µL with, respectively, 40 U of
ApaI, Bsm I, TaqI, PvuII, and
XbaI restriction endonucleases (Boehringer Mannheim, Milan,
Italy) at temperatures recommended by the manufacturer. The digested
DNA was size-fractionated using 0.7–1% agarose gel electrophoresis
and transferred to nylon-based filters (GeneScreen Plus, NEN Research
Products, Boston, MA) by standard techniques (24). Filter membranes
were prehybridized, then hybridized with the 32P-labeled
probe for 18 h at 65 C, washed, and autoradiographed for 24–48 h
at -80 C in intensifying screen. For identifying the RFLPs, we used,
as probes, a 2.1-kilobase complementary DNA (cDNA) coding region of the
human VDR (25) and a 1.8-kilobase cDNA coding region of the human ER
(26). The probes were radiolabeled with
[32P]deoxycycidine triphosphate using a random priming
labeling kit (Boehringer Mannheim, Milan, Italy). The RFLPs were coded
as B-b (Bsm I), A-a (ApaI), T-t
(TaqI), P-p (PvuII), and X-x (XbaI),
uppercase letters signifying the absence and lowercase letters the
presence of the restriction site.
Bone densitometry
Lumbar BMD (L2-L4), measured by dual-energy x-ray absorptiometry (Hologic QDR 1000/W) was available for all the 426 studied women. The long term in vitro precision at this site measured on spinal phantom was 0.4% in Siena and 0.6% in Florence; the in vivo precision was 0.9% in both centers. Dual-energy x-ray absorptiometry BMD scans at the upper femur were available for 230 of the 426 women (113 osteoporotic, 58 osteopenic, and 59 normal), with in vivo coefficients of variations of 1.1% in Florence and 0.9% in Siena. Cross-calibration studies on the precision of measurements between the 2 centers were previously performed both in vitro (using a single anthropomorphic lumbar spine phantom) and in vivo, on 50 patients, covering most of the clinically observed spinal density range. A correction factor was not considered necessary.
Because of the influence of extravertebral calcification on spinal bone mass measures, each woman underwent a lateral lumbar spine x-ray examination to be scored for spinal osteophytosis (SPO), according to Orwoll (27), and for facet joint osteoarthritis (FOA) on a four-point scale (0 = none, 1 = mild, 2 = moderate, and 3 = severe), according to Masud (28). Vascular calcifications were not evaluated for their reported limited impact on spinal density measurements (27, 28, 29).
Statistical analysis
Data were expressed as mean ± SEM, with
P < 0.05 accepted as the value of significance. The
frequency distribution of VDR genotypes in osteoporotic, osteopenic,
and normal groups were compared using cross-tabulation and standard
2 tests. Differences in antropometric characteristic,
spinal BMD, and femoral BMD among the different VDR and ER genotypes
were tested using ANOVA. Similar comparisons were done after adjusting
mean BMD values for potential confounding factors such as age, height,
weight, years since menopause (YSM), SPO, and FOA scores, using
analysis of covariance. Between groups, differences among genotype
groups were tested using Tukey’s test. All statistical analyses were
performed using STATGRAPHICS (Manugistic Inc., Rockville, Maryland) and
Statistica 5.1 (Statsoft Inc., Tulsa, Oklahoma).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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No significant departures from Hardy-Weinberg equilibrium were observed for ApaI, Bsm I, and TaqI RFLPs. The distribution of genotypes was similar to that of other studies, in Caucasians. When the 3 RFLPs at the VDR gene locus were considered together in all subjects analyzed, 7 major genotypes were recognized: AaBbTt (n = 157), AABBtt (n = 71), aabbTT (n = 56). AABbTt (n = 49), AabbTT (n = 47), AAbbTT (n = 17), and AaBbTT (n = 13).
Clinical characteristics of patients, in relation to the VDR genotype,
are shown in Table 2. Sixteen women
having rare genotypes (n < 5) were excluded from analysis.
Results indicated that subjects in the seven most common genotypes were
well matched for age and did not significantly differ for YSM, height,
weight, and dietary calcium intake. After correcting for potential
confounding factors, a statistically significant segregation of VDR
genotypes with lumbar BMD was detected (P = 0.01,
analysis of covariance), with mean corrected BMD values at the lumbar
spine significantly higher in women with aabbTT genotype, compared with
those with either AABBtt or AaBbTt genotype (P < 0.05,
Tukey’s test). A similar, but not significant, trend was observed for
femoral neck BMD, with a 6% higher BMD value in aabbTT than in AABBtt
genotype (data not shown).
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Genotype determinations for osteoporotic, osteopenic, and normal groups
are summarized in Table 3. We observed a
significantly increased prevalence of AABBtt genotype in osteoporotic
and osteopenic patients, compared with nonosteoporotic
(2 = 14.7; P = 0.0006). On the contrary,
aabbTT and AabbTT genotypes were significantly overrepresented in
nonosteoporotic vs. osteoporotic women (2 =
8.75, df = 1, P = 0.003 for aabbTT genotype; and
2 = 6.05, df = 1, P = 0.04 for
AabbTT genotype). Cross-tabulation testing resulted statistically
significant (2 = 41.9, df = 14, P =
0.0004).
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PvuII and XbaI RFLPs allele frequencies in this Italian population followed Hardy-Weinberg equilibrium. When we combined the 2 RFLPs we recognized six genotypes: PpXx (n = 174), ppxx (n = 126), PPXX (n = 73), Ppxx (n = 25), PPXx (n = 17), and PpXX (n = 11). Three genotypes (PPxx, ppXX, and ppXx) were not detected in the population examined in this study.
The clinical characteristics, by ER genotype, of the 426 studied women
are given in Table 4. There were no
significant differences in age, weight, height, YSM, and dietary
calcium intake across genotypes. Analysis of the ER genotypes, in
relation to adjusted BMD values, did not reveal any significant
effect.
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2 analysis on the genotypic frequencies revealed no
significant increased prevalence of any of the six ER genotypes in
osteoporotic, osteopenic and nonosteoporotic groups (data not
shown).
Combined effect of VDR and ER genes RFLPs
Sixteen major association groups were detected combining VDR and ER genotypes: AABBtt-PPXX (n = 9), AABBtt-PpXx (n = 29), AABBtt-ppxx(n = 25), AaBbTt-PPXX (n = 31), AaBbTt-PpXx (n = 70), AaBbTt-ppxx (n = 43), aabbTT-PPXX (n = 8), aabbTT-PpXx (n = 27), aabbTT-ppxx (n = 14), AaBbTt-Ppxx (n = 10), AABbTt-PPXX (n = 14), AABbTt-ppxx (n = 12), AABbTt-PpXx (n = 18), AabbTT-PPXX (n = 12), AabbTT-ppxx (n = 8), and AabbTT-PpXx (n = 23).
As shown in Fig. 1, when mean adjusted
lumbar BMD values were calculated among women grouped by ER and VDR
genotypes, we observed a statistically significant difference of
approximately 0.26 g/cm2 between the two opposite
association AABBtt-PPXX and aabbTT-ppxx (0.713 ± 0.05 vs.0.970 ± 0.03 g/cm2, P < 0.05,
Tukey’s test). Furthermore, a trend for higher BMD values was detected
between ppxx and PPXX subjects with the same VDR genotype
(P = 0.08, AABBtt-PPXX vs. AABBtt-ppxx;
P = 0.07, aabbTT-PPXX vs. aabbTT-ppxx).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Present data from a large and ethnically homogeneous population showed a significant segregation of VDR genotypes with lumbar BMD, in the Italian population, as previously shown in Australian women (5, 6). Women in the AABBtt genotype group showed a spinal BMD 13% less than those with aabbTT genotype. Such a difference persisted even after adjustment of BMD values for the potential influence of SPO and FOA. The magnitude of this effect between extreme homozygotes was approximately 0.1 g/cm2, slightly lower than that reported by Morrison et al. (5, 6). A similar trend was observed for femoral neck BMD, but with no statistically significant difference between genotypes. How can we reconcile these evidences with the lack of segregation of VDR alleles with BMD in several patient samples (13, 14, 15, 16, 17)? One possible cause of discrepancy could be related to the relatively small samples of many other studies being not powerful enough to adequately assess the VDR gene allele effect on bone mass. This explanation does not apply to two recent studies that have looked specifically at the relationship between VDR genotypes and BMD in large samples of postmenopausal women (17, 30). The first study (30), of Uitterlinden and co-workers, reported a weak association between low bone mass and a particular VDR genotype, AAbbTT, which is different from the one reported to be associated with low BMD, by our and other groups (4, 5, 6, 7, 8, 9, 10, 11, 12). In the 426 analyzed Italian women, individuals with AAbbTT genotype showed BMD values that were intermediate, between those with aabbTT and AABBtt genotypes. However, Uitterlinden et al. limited their analysis to the femoral neck BMD, a site with predominantly cortical bone, whereas the genetic effect on bone mass seems to be stronger at sites with higher proportions of trabecular bone (2, 3, 4, 5). In the second study (17), no significant relationships between VDR genotypes and BMD (measured at the spine, hip, and forearm) were detected in 268 French postmenopausal women, with frequency distribution of VDR genotypes quite different from that previously reported both by the same authors (14) and in other Caucasian populations of European ancestry (30, 32). Moreover, the contribution of VDR polymorphisms, both in Dutch and French studies, may have been masked by the relatively high calcium intake (17, 30). Indeed, environmental factors, such as calcium intake, are known to differ widely between populations and have been shown to contribute to the genetic influence of VDR genotypes on BMD (10, 11), rates of bone loss (10, 11), and intestinal calcium absorption (22). Consistent with the work of Dawson-Hughes et al. (22), we recently observed a significantly reduced fractional absorption capacity of strontium in a group of calcium-depleted women with AABBtt genotype, with respect to those with aabbTT genotype, suggesting a segregation of the VDR AABBtt genotype with a lower intestinal calcium absorption efficiency (32). For all these reasons, it is possible that the influence of VDR genotypes on bone metabolism could be observed only among populations with a relatively low calcium intake, as in the Italian population (33). Interestingly, in this sample of Italian postmenopausal women, we also observed a statistically significant increase in prevalence of both AABBtt genotype in the osteoporotic group and aabbTT and AabbTT genotypes in the nonosteoporotic group, in agreement with a possible segregation of the ABt homozygous haplotype with a higher risk of developing osteoporosis. Similarly, 2 other studies showed a disproportionate representation of the B allele in osteoporotic subjects, compared with a control group; but in both of them, these differences did not reach statistical significance (12, 18). By contrast, Looney and co-workers referred no large overrepresentation of the BB genotype in a group of North American severely osteoporotic women, compared with age-matched controls (15). However, all these previous studies were conducted in a limited number of subjects, with a consequent limited statistical power to test the hypothesis of a prevalence of a given genotype in osteoporotic subjects (12, 15, 16, 18).
The present study extends observations relating VDR genotypes and demonstrates that the addition of ER genotype to VDR genotype determination may provide a tool to identify, more precisely, individuals with a reduced bone mass. The magnitude of the effect of combining both VDR and ER genotype determination on lumbar BMD reaches approximately 2 SD and is significantly greater than that obtained from the analysis of the single ER or VDR gene effect. From this study, it also seems that the ER genotype PPXX confers some reduction in spinal BMD only when combined with VDR AABBtt genotype, without showing a segregation with BMD values by itself. Kobayashi et al. recently reported a statistically significant association of ER Px haplotype with a lower BMD in postmenopausal Japanese women, independent of VDR genotype (19). It is possible that these differences are related to the relative differential distribution of VDR and ER genotypes between populations of European and Asiatic ancestry. In fact, the PPxx genotype, representative of 8% of the Japanese population, was not detected in any of the 426 women examined in this study, whereas VDR genotype AABBtt, which in our Italian population is associated with the lowest BMD values, is extremely rare in the Japanese population (8, 16, 34). For this reason, a hypothetical segregation of BMD with polymorphisms at the ER gene locus could be more easily detectable in Asiatic women (where just 2 VDR genotypes, AabbTT and aabbTT, account for almost 80% of the total population) than in Caucasian populations of European ancestry, which exhibit high heterogeneity in VDR gene polymorphisms.
The epistatic effect between the ER and the VDR genes on BMD determination may be biologically fundamental, supporting a relevant role of the ER gene locus on BMD. Analysis of larger sample populations will make it possible to ascribe the ER gene locus either to the major gene family or to the polygenic aggregate, whose members are recognized among loci whose genetic effect is individually small. This approach, however, may be considered useful in future complex models of segregation analysis for osteoporotic risk.
In conclusion, in this homogeneous population of Italian postmenopausal women with a relatively low calcium intake, the allelic changes at the VDR gene locus are responsible for an important portion of the genetic component of spinal BMD. The results from the association analysis of ER and VDR genotypes effect on lumbar BMD suggest that the ER RFLPs could play a role, as well, exerting an additional contribution to bone mass determination. Other polymorphic genes and environmental factors could further modulate the expression of ER and VDR allelic effect on bone mass, making the picture as complicated as it is in nature.
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Acknowledgments |
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Received April 8, 1997.
Revised July 28, 1997.
Revised October 21, 1997.
Accepted November 11, 1997.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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1 gene. Nat
Genet. 14:203–205.[CrossRef][Medline]
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