Human Molecular Genetics, 2000, Vol. 9, No. 13 2043-2050
© 2000 Oxford University Press
Evidence of a linkage disequilibrium between polymorphisms in the human estrogen receptor 
gene and their relationship to bone mass variation in postmenopausal Italian women
1Endocrine Unit, Department of Clinical Physiopathology, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy, 2Scuola Superiore S. Anna, Pisa, Italy, 3Institute of Internal Medicine, University of Siena, Siena, Italy and 4Department of Internal Medicine University of Florence, Florence, Italy
Received 25 April 2000; Revised and Accepted 16 June 2000.
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ABSTRACT |
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Bone mineral density (BMD), the major determinant of osteoporotic fracture risk, has a strong genetic component. The discovery that inactivation of estrogen receptor
(ER) gene is associated with low BMD indicated ER as a candidate gene for osteoporosis. We have investigated the role of three ER gene polymorphisms [intron 1 PvuII and XbaI RFLPs and TA dinucleotide repeat polymorphism 5' upstream of exon 1] in 610 postmenopausal women. There was a strong linkage disequilibrium between intron 1 polymorphic sites and also between these sites and the microsatellite (TA)n dinucleotide polymorphism, with a high degree of coincidence of the short TA alleles and the presence of PvuII and XbaI restriction sites. No significant relationship between intron 1 RFLPs and BMD was observed. A statistically significant correlation between (TA)n repeat allelic variants and lumbar BMD was observed (P = 0.04, ANCOVA), with subjects with a low number of repeats (TA < 15) showing the lowest BMD values. We observed a statistically significant difference in the mean ± SD number of TA repeats between analyzed women with a vertebral fracture (n = 73) and the non-fracture group, equivalent to 2.9 (95% CI 1.56–5.72) increased fracture risk in women with a low number of repeats (TA < 15). We conclude that in this large population sample the (TA)n dinucleotide repeat polymorphism at the 5' end of the ER gene accounts for part of the heritable component of BMD and might prove useful in the prediction of vertebral fracture risk in postmenopausal osteoporosis. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSAKNOWLEDGEMENTSREFERENCES |
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Osteoporosis is a multifactorial disease characterized by a decrease in bone mineral density (BMD) and a microarchitectural deterioration of bone structure, leading to a higher susceptibility to fractures (1). Although there are several environmental influences on BMD, such as diet and physical exercise, a genetic contribution to the pathogenesis of osteoporosis has recently been recognized (2–5). Evidence from twin and family studies suggest that genetic factors play an important role in the multifactorial pathogenesis of osteoporosis, accounting for 50–70% of the inter-individual variation in bone mass (2–4). Given the complex biology of the skeleton, it is likely that bone mass is under the control of a large number of genes many of which exert relatively small effects on BMD, whereas a few contribute substantially to variations in this trait. Among several candidate genes, it has been assumed that the vitamin D receptor (VDR) gene is a major locus for genetic effect on bone mass, and polymorphisms in this gene appeared to predict spinal and femoral BMD in an Australian population (5). However, agreement on this relationship is not universal among different populations, some finding positive associations (6–10) and others reporting no significant effect (11–14). Various suggestions have been made to account for these discordant findings, including ethnic or environmental differences among populations, differences in age, menopausal status, the involvement of other genes and the inadequate sample size of many studies. A potential confounder in such studies may also be recognized in the health-based selection bias, with the tendency to exclude osteoporotic women.
Since the discovery that inactivation of the estrogen receptor (ER) gene is associated with low BMD, both in animal models (15,16) and in humans (17), this gene has been postulated as a candidate gene for osteoporosis. It is possible that heterogeneity in bone mass and bone metabolism after menopause may reflect different responsiveness to lower circulating levels of estrogen in the postmenopausal period because of the genetic variation in the ER gene.
Both intronic polymorphisms (recognized by the restriction endonucleases PvuII and XbaI) and polymorphic variable number of (TA)n repeats upstream of the ER gene have been associated with BMD in the Japanese population (18–19). The relationship between these polymorphisms and BMD was not widely studied in larger samples and similar studies in other populations yielded conflicting results (10,20–26). In the present study we examined the relationship between ER polymorphisms (PvuII, XbaI and TA dinucleotide repeats) with lumbar BMD and with the occurrence of vertebral osteoporotic fractures in 610 postmenopausal women of Italian descent, stratified for BMD into normal, osteopenic and osteoporotic groups.
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RESULTS |
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Allelic frequencies
The frequency distribution of genotypes were in Hardy–Weinberg equilibrium. Table 1 shows the allele frequencies and heterozygosity index for intron 1 PvuII and XbaI polymorphisms in our population of unrelated postmenopausal women of Italian descent. The distribution of PvuII and XbaI genotypes was very similar to what was previously reported in Caucasian populations of European ancestry (22,25,26), and this differed significantly from what was observed in populations of Asiatic ancestry (19–21,23,24). The frequency distribution of (TA)n dinucleotide repeat polymorphism upstream of the ER
gene in the 610 women (1220 chromosomes) is plotted in Figure 1, and did not differ significantly from other European and Asiatic populations (18,27), showing two peaks at 14–15 and 20–21 repeats.
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Allelic associations of PvuII/XbaI restriction fragment length polymorphisms (RFLPs) with (TA)n repeats
As previously reported (10), PvuII (P, PvuII-negative sites; p, PvuII-positive sites) and XbaI (X, XbaI-negative sites; x, XbaI-positive sites) polymorphisms were tightly linked so that a higher than expected number of PP women were XX homozygotes and a higher than expected number of pp women were xx homozygotes (Table 2). The distributions of the TA repeats in PP versus pp and XX versus xx homozygotes is illustrated in Figures 2 and 3. A consistent linkage disequilibrium was detected between the intronic PvuII or XbaI polymorphisms and the number of (TA)n repeats upstream of the ER
gene (
2 = 363.46, P < 0.000001 for PvuII and 2 = 308.08, P < 0.000001 for XbaI), with a lower number of repeats being linked to PvuII- and XbaI-positive sites and a higher number of repeats being linked to PvuII- and XbaI-negative sites. Whereas the majority of PX alleles had a higher number of repeats (mean ± SEM, 19.28 ± 2.2), the px alleles were predominantly associated with a lower number of repeats (mean ± SEM, 15.01 ± 1.9). This difference was highly significant [P = 0.0001, analysis of variance (ANOVA)].
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Effect of PvuII and XbaI intron 1 RFLPs on lumbar BMD
When we combined the two intron 1 polymorphisms together, six major genotypes were recognized: PpXx, ppxx, PPXX, Ppxx, PPXx and PpXX. Three genotypes (PPxx, ppXX and ppXx) were detected at a very low frequency in this Italian population. There were no significant differences in age, weight, height, years since menopause (YSM) and dietary calcium intake across genotypes. Analysis of the intron 1 ER
genotypes in relation to adjusted BMD values did not reveal any significant effect. A trend for a higher prevalence of the ppxx genotype in the osteoporotic group as well as in women with vertebral fractures was observed. Accordingly, mean lumbar BMD values were 3.5% lower in women with the ppxx genotype with respect to those with PPXX genotype [0.881 ± 0.02 versus 0.848 ± 0.01, PPXX versus ppxx, respectively; P = 0.09, analysis of covariance (ANCOVA)]. However, none of these differences reached statistical significance.
Effect of (TA)n repeat polymorphism on lumbar BMD
A statistically significant correlation between (TA)n repeat allelic variants and lumbar BMD values was observed (Fig. 4). Lumbar BMD values significantly decreased with the increase in the number of repeated TA dinucleotides (P = 0.04, ANCOVA). Similarly, linear-regression analysis showed a positive correlation between the mean number of TA repeats and lumbar BMD values (r = 0.15; P < 0.05). According to the distribution pattern of TA alleles in our population (Fig. 1), showing two major peaks at 14–15 and 20–21 repeats and a low distribution of intermediate 16–19 repeat alleles, we grouped the recruited women into three groups: (i) group H including alleles with a high number of TA repeats (TA 
20); (ii) group M including alleles with a medium number of TA repeats (15 < TA < 20); and (iii) group L including low TA alleles (TA < 15). As shown in Figure 5, lumbar BMD values were significantly lower in subjects with a low to medium number of repeats (groups L and M) than in subjects with a number of repeats equal to or higher than 20 (group H). No significant differences in age, weight, height, YSM, dietary calcium intake as well as in the degree of spinal osteophytosys and facet joint osteoarthritis were observed among women in these three groups.
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15). The number of subjects in each group is given inside the columns.After antero-lateral spinal x-ray analysis we detected 79 vertebral fractures in 73 of the 610 women. All but two vertebral fractures were observed in the osteoporotic group of women. Two fractures occurred in osteopenic women, their lumbar BMD was at the lower limit of osteopenia (with a T score of –2.4 and –2.3, respectively), and they both showed a low TAn repeat genotype. Table 3 presents the clinical characteristics of fracture and non-fracture groups. Interestingly, the mean ± SD number of TA repeats was significantly higher in women with a vertebral fracture than in controls (Fig. 6), equivalent to a relative risk of 2.9 (95% confidence interval 1.56–5.72; P < 0.05) in subjects with a low number of repeats (TA < 15). As shown in Table 3, the age and the number of YSM were significantly higher in the fracture group with respect to the non-fracture group or to osteoporotic subjects without fractures (data not shown), confirming that the aging process is an important determinant of osteoporotic fracture risk. No statistically significant differences in age and YSM were observed among women with a high, medium or low TAn repeat genotype in the whole sample or separately in osteoporotic, osteopenic and normal groups. The latter observation excludes the possibility that the relationship between the low TA repeat genotype and a higher fracture incidence is due to the presence of older women in that genotype and not to a true effect on bone mass. Indeed, among the fracture group, women with the low TAn repeat genotype were younger than those with the high repeat genotype. When the analysis was restricted to the osteoporotic group of women the number of TAn repeats did not significantly differ between osteoporotic women with a fracture and osteoporotic women without fractures. Moreover, statistically significant decreased BMD values were observed in osteoporotic women with a low TAn repeat genotype with respect to osteoporotic women with a high TAn repeat genotype.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSAKNOWLEDGEMENTSREFERENCES |
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Postmenopausal osteoporosis is a multifactorial disease in which genetic determinants are modulated by hormonal, environmental and nutritional factors. Since low BMD values are considered a major independent risk factor for osteoporotic fractures, their genetic regulation has been the focus of several studies. Many candidate genes have been implicated in the determination of BMD and in the pathogenesis of osteoporosis, spanning from those encoding cytokines to those encoding calciotropic hormones, their receptors and bone matrix proteins. However, the absence of a clear Mendelian inheritance pattern (at least for a subset of cases), makes extremely difficult, if not impossible, the a priori determination of the number of genes involved and their effects.
The gene encoding the vitamin D receptor (VDR) was the first to be proposed as a major locus for the genetic effect on bone mass, and was originally claimed to contribute to almost 75% of the genetic variation in BMD in twin and in general population studies (5). Not all of the studies published to date agree on a clear relationship between polymorphic VDR alleles and BMD. Moreover, the molecular basis for the VDR genetic influence on bone mineralization has not yet been clarified.
Polymorphisms of other candidate genes, such as those for collagen type 1 1 (28–30), interleukin-6 (31), TGF-ß (32), apolipoprotein E (33) and calcitonin receptor (34–36), have been related to BMD in some studies. Independent studies have not always confirmed these observations and certainly other genes, with great or even greater effects both on BMD and bone metabolism, are awaiting mapping and identification.
Given the central role of estrogens in bone metabolism, genes encoding estrogen receptors are certainly important candidates for the determination of osteoporotic risk. The clinical observation of an osteoporotic phenotype in a man with a disruptive mutation of the ER gene (17), as well as the report of decreased BMD values in mice lacking functional ER (15,16) but not in those lacking ERß (37), further supports the hypothesis that ER is a major candidate gene for osteoporosis. Osteoblast, osteoclasts and bone marrow stromal cells bear estrogen receptors and are modulated by estrogen (38,39). It is possible that common allelic variants of the ER gene, causing differential responsiveness to estrogen, exists in the general population, and that compensatory hyperestrogenism can initially overcome the resistance resulting in normal phenotype. This compensatory balance could be altered later on by aging or by a condition like menopause, leading to clinical disorders such as osteoporosis. Both intronic polymorphisms (recognized by the restriction endonucleases PvuII and XbaI) and polymorphic variable number of (TA)n repeats upstream of the ER gene have been associated with BMD variation in the Japanese population (18,19). The relationship between these polymorphisms and BMD has not been widely studied in larger samples and similar studies in other populations failed to confirm these data (20,25). In a previous preliminary study of the Italian population we did not observe any significant association between intron 1 polymorphisms at the ER gene and lumbar or femoral BMD values (10). The results that we obtained in the present analysis clearly indicate the need for analyzing larger population samples before reaching final conclusions. Indeed, examination of ER polymorphisms on a larger sample of postmenopausal women was performed and the investigation was also extended to the microsatellite dinucleotide (TA)n repeat polymorphism lying 5' upstream of exon 1. The observed ER (TA)n genotype distributions were similar to those previously reported in the Caucasian population of both European and Asiatic ancestry (18,27). A statistically significant association between women grouped according to different (TA)n repeat genotypes and lumbar BMD was observed: the highest number of TA repeats resulted in the highest BMD values. This finding is in partial agreement with a previous report on 144 postmenopausal Japanese women, in which subjects bearing a low TA repeat genotype (called C-genotype, defined by 12 TA repeats) showed a significantly lower Z score of spine BMD and higher urinary deoxypyridinoline levels than those with the other genotypes (18). Similarly, in this Italian population, women with the 12 TA repeat genotype showed the lowest BMD values measured at the lumbar spine. In contrast, no statistically significant association between intron 1 XbaI or PvuII polymorphisms and lumbar BMD values was observed in the selected population. To further determine the role of ER (TA)n dinucleotide repeat polymorphism as a risk factor for osteoporosis we evaluated the distribution of genotypes in women with or without an osteoporotic vertebral fracture. Interestingly a significantly increased prevalence of low TA repeat genotypes in women in the fracture group with respect to controls was observed.
In this study, we report for the first time a high degree of linkage disequilibrium between PvuII and XbaI polymorphisms and the variable length of dinucleotide (TA)n repeats, next to the promoter region of the ER gene. Women with the PPXX genotype showed a significantly higher mean number of repeats than those with the opposite ppxx genotype. No comparable data are actually reported for other populations. The discovery of such a high degree of linkage disequilibrium in a group of 610 postmenopausal women may have important implications. In fact, a differential degree of linkage disequilibrium among different ethnic populations may partly explain previous discrepancies among ER polymorphism studies. The reduced BMD levels in pp homozygotes reported in some studies, but not in others, might reflect random differences in (TA)n alleles between groups, or even a systematic difference due to allelic association. When we calculated BMD levels in PP and pp groups from the respective frequencies of (TA)n alleles, by linear-regression analysis, results demonstrated that the reduced BMD levels in pp are probably caused by the reduction of (TA)n repeats. Accordingly, the highest BMD values were observed in PP women with a high number of repeats and the lowest BMD values were observed in pp women with a low number of TA repeats.
The results from the present study clearly indicate that there is a relationship between (TA)n dinucleotide repeat at the ER gene locus and BMD. However, whether the molecular mechanism(s) underlying how bone mineralization is affected by the variation in the number of dinucleotide repeats is still unclear. For this three hypotheses can be proposed: (i) the dinucleotide TA polymorphism directly affects the levels of expression through transcriptional regulation; (ii) the dinucleotide polymorphism may be linked with exonic polymorphism with a direct implication on ER protein function; and (iii) the ER gene polymorphism may be linked with mutation of another unidentified gene adjacent to the ER gene which directly or indirectly causes low BMD. The central role that estrogens play in bone metabolism leads to speculation that alterations of the expression of the ER gene as well as alteration in ER protein function might have pathological consequences for bone tissue. Previous studies on the structure and organization of the human ER gene indicate that it is a complex genomic unit exhibiting different and partly unknown modulation (40,41). It is still unclear whether the different modulation of the ER gene in functionally different estrogen target cells occurs at the gene transcription level by the use of distinct promoters, alternative splicing of large RNA precursors or a combination of these mechanisms. At least three different promoters have been identified in this gene (40–48). The proximal promoter was the first to be characterized and was termed promoter A. This promoter contains a TATA box and a CAAT element (Fig. 7) and possesses a single site of transcription initiation (42). Subsequently, sequencing of upstream genomic DNA revealed the presence of an additional exon, denoted exon 1', and of an additional promoter, denoted promoter B (43,44). Several sites of transcription initiation from this promoter have been suggested (40–47). The existence of a previously unidentified upstream promoter, termed promoter C and located >21 kb upstream of promoter A, has been postulated recently (41,48). Transcription of the hER gene from these three promoters yields different mRNA isoforms with unique 5'-untranslated regions, but identical coding regions. Isoforms originating from both promoters A and B were found to be expressed in breast and uterus, whereas expression of the C promoter-transcript has been predominantly detected in liver (48,49). In bone cells expression of only the B promoter-mRNA has been detected (49). Correct expression of the ER gene in different tissues is likely to be required for estrogens to have a direct effect on estrogen target tissue development and function. Thus, it is important that the tissue-specific expression of estrogen receptors is tightly regulated. Because of its position, between promoter A and B regions, it is possible to speculate that allelic variations due to different (TA)n dinucleotide repeat length might have physiological relevance, in particular in bone, by affecting promoter usage. Interestingly, a novel regulatory element, resembling a steroid response element has been recently identified in the 5'-flanking region of the human ER gene, just ~220 bases downstream of the (TA)n repeat microsatellite region (50). This regulatory element is composed of two 7 bp sequences (underlined in Fig. 7) which together form a perfect inverted palindrome, similar to an estrogen-responsive element and to other known cis-acting elements, separated by a 21 bp spacer region. By transient transfection analysis it has been demonstrated that this sequence acts as a strong enhancer element in several cell lines (50).
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In conclusion, this study shows a significant correlation between (TA)n repeat polymorphism and lumbar BMD in a large cohort of postmenopausal women of Italian descent. Confirmatory studies in other populations as well as the discovery of a functional molecular mechanism are required before this polymorphic TA microsatellite at the ER
locus may be considered a marker for predicting bone loss and for making possible early therapeutic interventions in women at high risk for osteoporosis. |
MATERIALS AND METHODS |
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Subjects
The study was not population based. Patients were selected among women who attended the metabolic bone diseases outpatient clinics in Florence and Siena, Italy, 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. Women with a history of bone disease other than primary osteoporosis or who had used bone-active drugs or drugs that could potentially affect bone metabolism were excluded from analysis. Subjects were also excluded if their parents or grandparents were not of Italian descent. On the basis of BMD measurements and according to World Health Organisation criteria (1), blood samples from 240 osteoporotic, 189 osteopenic and 181 non-osteoporotic women were available for DNA isolation. The age range of the 610 women studied was 50–73 years, with a mean (± SEM) age of 58.2 ± 5.9 years. General characteristics of the population are presented in Table 4.
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Bone densitometry and fracture assessment
Lumbar BMD (L2–L4), measured by dual-energy X-ray absorptiometry (Hologic QDR 1000/W, Waltham, MA) was available for all the 610 women studied. The long-term in vitro precision at this site measured on spinal phantom was 0.6% in Florence and 0.4% in Siena; the in vivo precision was 0.9% in both centers. Cross-calibration studies on the precision of measurements between the two centers were previously performed (10). A correction factor was not considered necessary.
The documentation of vertebral fractures was based entirely on spine radiographs, following the method of McCloskey et al. (51), with a 3 SD cut-off value for each vertebral level. Radiographs of the lumbar spine were further evaluated for the presence of osteophytosis and facet joint osteoarthritis according to the methods of Orwoll et al. (52) and Masud et al. (53), respectively.
Genotyping
Genomic DNA was extracted from EDTA blood samples by a standard phenol–chloroform extraction procedure. To analyze polymorphisms at intron 1 of the human ER gene, 0.1 µg of DNA was amplified in 50 µl of buffer solution (10 mM Tris–HCl, 50 mM KCl, 5 mM MgCl2, 1% Triton X-100 and 200 µM each of the four deoxyribonucleotides) with 1 U of Taq polymerase (Promega, Madison, WI) and 0.4 µM oligonucleotide primer (forward, 5'-CTGCCACCCTATCTGTATCTTTTCCTATTCTCC-3'; reverse, 5'-TCTTTCTCTGCCACCCTGGCGTCGATTATCTGA-3'), according to Kobayashi et al. (19). Polymerase chain reaction (PCR) was performed for 30 cycles using the following steps: denaturation at 94°C for 30 s, annealing at 60°C for 1 min and extension at 72°C for 90 s. The product contains a part of intron 1 and exon 2 of the ER gene. After amplification the PCR product was digested with 10 U of either PvuII or XbaI restriction endonucleases (Roche Diagnostics, Monza, Italy) and electrophoresed in a 1.0% agarose gel. The presence of the restriction site for each endonuclease was conventionally indicated with a lower case letter (p or x, respectively, for PvuII and XbaI endonucleases), whereas upper case letters (P or X) indicated the absence of the restriction site. Subjects were scored as pp or xx homozygotes, Pp or Xx heterozygotes and PP or XX homozygotes according to the digestion pattern.
The DNA region containing the polymorphic (TA)n repeat at 1174 bp upstream of the human ER gene was amplified by PCR according to Sano et al. (18). The reaction was carried out in 10 µl volumes containing 100 ng of genomic DNA, buffer solution (10 mM Tris–HCl pH 9, 50 mM KCl, 5 mM MgCl2, 1% Triton X-100), 200 µM each of dTTP, dGTP, dATP and 10 µM dCTP plus 1.0 µCi of [-32P]dCTP, 1 U of Taq polymerase and 0.4 µM oligonucleotide primers (forward, 5'-GACGCATGATATACTTACC-3'; reverse, 5'-GCAGAATCAAATATCCAGATG-3') (7). PCR was performed for 30 cycles at 94°C for 30 s, 58°C for 45 s and 72°C for 1 min. Products were detected on 6% denaturing polyacrylamide gel (19). The PCR products ranged in length from 160 bp (10 TA repeats) to 194 bp (27 TA repeats). In addition PCR products from the DNA of four cases (homozygous for 14, 15, 20 and 21 repeats, respectively) were cloned and sequenced using the ABI Prism 310 (Perkin Elmer, Monza, Italy). A large sequence 5' upstream of the coding region from the most common homozygous genotype, bearing 14 TA repeats, was sequenced and is shown in Figure 7.
Statistical methods
Data were evaluated by ANOVA and ANCOVA, with Fisher’s protected least significant difference post hoc test, and presented as means ± SEM, with P < 0.05 accepted as the value of significance. The following covariates were considered for the ANCOVA analysis: age, weight, YSM, calcium intake and smoking status. The frequency distribution of genotypes in osteoporotic, osteopenic and normal groups were compared using cross-tabulation and standard 2 tests. In order to test for linkage disequilibrium between the alleles of the different polymorphisms, contingency tables were used, with standard 2 tests. The latter was also used to compare observed genotype frequencies with those expected under the Hardy–Weinberg equilibrium (54). Odds ratios (with 95% confidence intervals) were calculated by logistic regression analysis to estimate the relative risk of osteoporotic vertebral fracture. All statistical analyses were performed by using Statgraphics (Manugistic, Rockville, MA) and Statistica 5.1 (Statsoft, Tulsa, OK).
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AKNOWLEDGEMENTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSAKNOWLEDGEMENTSREFERENCES |
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The authors thank Dr Carlo Gennari for critical discussion and Pasquale Imperiale for expert technical assistance.
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +39 55 4271404; Fax: +39 55 2337867; Email: m.brandi@dfc.unifi.it
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REFERENCES |
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