help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-1153
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
90/12/6575    most recent
Author Manuscript (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Nguyen, T. V.
Right arrow Articles by Eisman, J. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Nguyen, T. V.
Right arrow Articles by Eisman, J. A.
Related Collections
Right arrow Calcium and Bone Metabolism
The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 12 6575-6579
Copyright © 2005 by The Endocrine Society

Contribution of the Collagen I {alpha}1 and Vitamin D Receptor Genes to the Risk of Hip Fracture in Elderly Women

Tuan V. Nguyen, Luis M. Esteban, Christopher P. White, Struan F. Grant, Jacqueline R. Center, Edith M. Gardiner and John A. Eisman

Bone and Mineral Research Program, Garvan Institute of Medical Research, St. Vincent’s Hospital, Sydney, New South Wales 2010, Australia

Address all correspondence and requests for reprints to: Dr. Tuan V. Nguyen, Bone and Mineral Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia. E-mail: t.nguyen{at}garvan.org.au.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context and Objective: Hip fracture is partially genetically determined. The present study was designed to examine the contributions of vitamin D receptor (VDR) and collagen I {alpha}1 (COLIA1) genotypes to the liability to hip fracture in postmenopausal women.

Design: The study was designed as a prospective population-based cohort investigation.

Subjects: Six hundred seventy-seven postmenopausal women of Caucasian background, aged 70 ± 7 yr (mean ± SD), have been followed for up to 14 yr. Sixty-nine women had sustained a hip fracture during the period.

Main Outcome: Atraumatic hip fractures were prospectively identified through radiologists’ reports. Bone mineral density (BMD) at the hip and lumbar spine was measured by dual-energy x-ray absorptiometry.

Genotypes: The TaqI and SpI COLIA1 polymorphisms of the VDR and COLIA1 genes were determined. Using the Single Nucleotide Polymorphism database, VDR TT, Tt, and tt genotypes were coded as TT, TC, and CC, whereas COLIA1 SS, Ss, and ss were coded as GG, GT, and TT.

Results: Women with VDR CC genotype (16% prevalence) and COLIA1 TT genotype (5% prevalence) had an increased risk of hip fracture [odds ratio (OR) associated with CC, 2.6; 95% confidence interval (CI), 1.2–5.3; OR associated with TT, 3.8; 95% CI, 1.3–10.8] after adjustment for femoral neck BMD (OR, 3.4 per SD; 95% CI, 2.3–5.0) and age (OR, 1.4 per 5 yr; 95% CI, 1.1–1.7). Approximately 20 and 12% of the liability to hip fracture was attributable to the presence of the CC genotype and TT genotype, respectively.

Conclusion: The VDR CC genotype and COLIA1 TT genotype were associated with increased hip fracture risk in Caucasian women, and this association was independent of BMD and age.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
OSTEOPOROTIC FRACTURE, INCLUDING hip fracture, commonly results from low bone mineral density (BMD) and a fall (1). The liability to osteoporotic fracture is partially determined by genetic factors (2). Women with a family history of hip fracture have a 2-fold increase in the risk of hip fracture (3), consistent with a deficit in BMD among daughters of mothers with a history of hip fracture (4). However, it is not clear which genes are involved in the genetic regulation of hip fracture risk.

Polymorphic variations in the vitamin D receptor (VDR) (5) and collagen 1 {alpha}1 (COLIA1) genes are associated with BMD (6) and fracture risk in some (7, 8, 9) but not all (10, 11, 12, 13) studies. Additional data are required to elucidate the possible role of the VDR and COLIA1 genes in the pathogenesis of osteoporosis. The present study was designed to examine the association between VDR and COLIA1 polymorphisms and hip fracture in a sample of elderly Caucasian women.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
The Dubbo Osteoporosis Epidemiology Study, which has been ongoing since June 1989, is a prospective epidemiological study of incidence and risk factors of osteoporotic fractures (1, 14, 15). To date, more than 1200 women have participated in the study, representing 70% of the target population of the Dubbo city (New South Wales, Australia). All women are of Caucasian background and were born before 1929.

After signing a written informed consent, subjects were assisted to complete a structured questionnaire including age, anthropometric variables, lifestyle, and clinical data. BMD (grams per square centimeter) at the femoral neck and lumbar spine was measured by dual-energy x-ray absorptiometry using a LUNAR DPX-L densitometer (GE Lunar Corporation, Madison, WI). The intrasubject coefficient of variation at our institution for repeated measures of normal subjects is 1.5% for the lumbar spine and 1.3% for the femoral neck (16).

Hip fractures during the study period were identified through radiological reports from all sources providing x-ray services in Dubbo (14). Fractures were only included if the report of fracture was definite and, on interview, had occurred with minimum or no trauma, including a fall from standing height or less.

After the collection of a blood sample, DNA was extracted from blood leukocytes with proteinase K and phenol chloroform. A 265-bp region of intron 1 of the COLIA1 gene was amplified (6) in a 96-well plate on an Omnigene Thermal cycler (Hybaid, Middlesex, UK). After PCR, DNA was digested overnight with MscI (New England Biolabs, Beverly, MA), an isochizomer of BalI, and analyzed by agarose gel electrophoresis (3%). The presence and absence of this restriction site are denoted by s and S, respectively. Polymorphisms of the VDR gene were determined by cleavage of amplified DNA with the TaqI restriction endonuclease and separated on a 2% agarose gel as described previously (17). Homozygous absence of the TaqI polymorphism (TT) results in two fragments of 245 and 495 bp due to the invariant TaqI site in exon 9. Homozygous presence of the site (tt) results in three fragments of 290, 245, and 205 bp, whereas heterozygotes (Tt) have four fragments, i.e. 495, 290, 245, and 205 bp. To ensure the accuracy of genotyping, recollected blood samples of 30 subjects were randomly selected and regenotyped. Polymorphisms of the VDR and COLIA1 genes were found to be 100% consistent. However, to be consistent with the single nucleotide polymorphism nomenclature, the VDR and COLIA1 genotypes are referred to the actual nucleotide that is changed. According to the Single Nucleotide Polymorphism database, TT, Tt, and tt are referred to as TT, TC, and CC, respectively, whereas SS, Ss, and ss are GG, GT, and TT, respectively.

Based on a previous study (6, 7, 8, 18), it was estimated that a sample size of at least 212 subjects was required to detect an association between either VDR or COLIA1 genotypes and hip fracture with an odds ratio (OR) of 2. However, because hip fracture is a relatively rare event, it was decided to increase the sample size to at least 600. Both univariate and multivariable logistic regression models with the SAS statistical analysis system (SAS Institute, Cary, NC) (19) were used to analyze the association between COLIA1 polymorphisms and hip fracture risk, taking into account potential covariates such as BMD, age, and demographic parameters. The strength of association between each of the risk factors and hip fracture risk was expressed as OR and 95% confidence interval (CI).

As part of the estimation of the risk of fracture associated with the VDR and COLIA1 genotypes, attributable risk fraction was calculated as p(RR – 1)/[p(RR – 1) + 1], where p is the proportion of women carrying a genotype, and RR is the relative risk associated with the genotype (estimated from the logistic regression model). In this formulation, attributable risk is the proportion by which the incidence rate of hip fracture in the population would change if the genotype did not exist in the population.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
VDR and COLIA1 polymorphisms were determined from 677 women (69 hip fracture and 608 nonfracture), aged 70 ± 7 yr (mean ± SD). For the VDR TaqI polymorphisms, the frequency (± SE) of the C allele was 0.40 ± 0.03; for COLIA1, the average frequency of the T allele was 0.20 ± 0.02. The distribution of both VDR and COLIA1 genotypes was consistent with the expected frequencies by the Hardy-Weinberg Equilibrium law.

There was no statistically significant difference in age, weight, or BMD among the VDR and COLIA1 genotypes (Table 1Go). However, there was a statistically significant association between COLIA1 genotype and height: greater height in subjects with TT genotype compared with those with GG or TG genotype (P = 0.03). There was also differences between body mass index in GG, GT, and TT genotypes, consistent with an additive gene dose effect.


View this table:
[in this window]
[in a new window]
  		TABLE 1. Baseline demographic and clinical characteristics of subjects by genotype

 
Women with hip fracture were significantly older, lighter, shorter in stature, and had lower spinal and femoral neck BMD than women without fracture (Table 2Go). The VDR CC genotype was significantly more common in the hip fracture group (26%) than the non-hip fracture group (14.4%; P = 0.03). Furthermore, women with the COLIA1 TT genotype were overrepresented in the hip fracture (10%) compared with the nonfracture group (4.4%; P = 0.07). However, analysis of difference based on allelic frequency revealed a significantly higher prevalence of the COLIA1 T allele in the fracture group compared with nonfracture group (0.275 vs. 0.197; P = 0.032). Although the C allele was more prevalent in fracture group (0.456) than in the control group (0.393), the difference did not reach a statistical significance (P = 0.147).


View this table:
[in this window]
[in a new window]
  		TABLE 2. Demographic and clinical characteristics of subjects at baseline by fracture status

 
Advancing age, lower weight, shorter stature, and lower BMD were each associated with increased hip fracture risk (Table 3Go). In univariate analysis, VDR CC carriers had with an increased risk of hip fracture (OR, 2.1-fold; 95% CI, 1.2–3.7) compared with those with the TT and TC genotypes. The odds of hip fracture in carriers of the COLIA1 TT genotype was 2.4 (95% CI, 1.0–5.8) higher than those with the GG and GT genotypes.


View this table:
[in this window]
[in a new window]
  		TABLE 3. Predictors of risk of hip fracture: univariate analysis

 
When all the factors were considered simultaneously in a multivariable logistic regression model, COLIA1 genotype (OR for TT vs. GG and GT, 3.8; 95% CI, 1.4–10.8) and VDR polymorphism (OR for CC vs. TT and TC, 2.6; 95% CI, 1.2–5.3) remained independent predictors of fracture risk, independent of femoral neck BMD (OR for 1 SD, 3.4; 95% CI, 2.3–5.3) and age (OR per 5 yr, 1.4; 95% CI, 1.1–1.8) (Table 4Go). When current height was included in the model, it did not significantly improve the fitness of the model (data not shown). Based on the allelic frequency, it was estimated that approximately 20% of the liability to hip fracture was attributed to the VDR polymorphism, and 12% was attributed to COLIA1 gene polymorphisms.


View this table:
[in this window]
[in a new window]
  		TABLE 4. Independent predictors of risk of hip fracture: multivariable analysis

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Although the liability to hip fracture is known to be in part genetically determined, it is not clear which specific gene or genes are involved in the genetic regulation. Variants at the COLIA1 gene among others have been reported to be associated with osteoporotic fracture, albeit with inconsistent findings between studies (20). Results of the present study are, however, consistent with the hypothesis that the VDR and COLIA1 genes are associated with hip fracture risk.

The potential role of VDR genotypes in the prediction of osteoporotic fracture, particularly hip fracture, has not been well characterized; therefore, it is difficult to compare the present finding with previous data. Nevertheless, the present finding of dominant effect of TaqI polymorphism on hip fracture risk is consistent with a recent finding of Garnero et al. (21) in which individuals with the BB genotype of the BsmI polymorphism (in strong linkage disequilibrium with the CC genotype) had increased risk of fracture. In a case-control study of 192 osteoporotic fracture subjects and 207 controls, the VDR BsmI B allele was also associated with increased risk of all osteoporotic fractures in a dominant relationship (22), with similar results in a smaller study in Japanese women (23). In the Nurses Health Study, the BB genotype was associated with a 2-fold higher risk of hip fracture (24). Because the BsmI B allele is in strong linkage disequilibrium with the Taq1 C allele, these findings are broadly consistent with our data.

However, other studies have found a statistically nonsignificant association between VDR genotypes and fracture or BMD (10, 25, 26). Although allelic heterogeneity (e.g. different mutations within a gene may have different effects on fracture risk) can be a potential explanation for the discrepancy in findings, sample size issues (18), data analysis (27), and population characteristics could be contributory, as well as interaction between genes and environmental factors. In the case of BMD, an effect of VDR genotypes was more pronounced in younger women than older women (28). These facts, taken together, suggest that the VDR genotypes–hip fracture risk relationship could vary between populations.

The association between COLIA1 polymorphisms and hip fracture risk, the most serious consequence of osteoporosis, has been examined. In a cohort of 1778 Dutch women, the OR of hip fracture associated with each s allele was 3.1 (95% CI, 1.2 to 7.6) with a small number of hip fracture cases (n = 10) (7). In the present study, the presence of two s alleles was associated with a relative risk of 2.4 (95% CI, 1.0–5.8), comparable with previous findings for nonvertebral fracture (7, 8, 29). Given the consistency across several studies, it seems that the COLIA1–hip fracture risk relationship is not due to stochastic fluctuation but to a biological basis.

However, the present finding differs from previous studies in which no significant association between COLIA1 genotypes and fracture risk was found (9, 11, 12). Like the VDR case, although the discrepancy in findings could be due to study design (e.g. study population characteristics, sample size issues, and data analysis), the interaction between genes and environmental factors could also be a contributory factor. Recently, an interaction between the effects of COLIA1 and VDR genotypes on fracture risk has been reported (10). However, in the present study, the effects of VDR and COLIA1 genotypes on hip fracture risk were additive rather than interactive. This is probably expected because the two genes are located in different chromosomes and the chance of linkage disequilibrium between them is highly unlikely.

At present, the mechanism by which VDR and COLIA1 genotype could affect hip fracture risk is not clear. It could be hypothesized that the relationship is mediated via BMD, because the VDR CC (formerly tt) and COLIA1 TT (formerly ss) genotypes were correlated with a low BMD (5, 6), and low BMD is a primary predictor of hip fracture (1). However, this conjecture is not supported by the present data as well as other data (7, 8, 9, 10). Indeed, the present results suggest that the VDR and COLIA1 effects (on fracture) were independent of BMD, consistent with the influence of family history of fracture being independent of BMD. For example, even after adjusting for BMD, the risk of hip fracture remains increased in those with a family history of hip fracture (3). This apparent contradiction may relate to the fact that BMD is a composite measure that includes elements of bone size and incompletely accounts for geometry and mass distribution in the bones measured. Thus, it seems that there is a genetic component in fracture risk independent of those that determine what is measured as BMD.

Although BMD is the key predictor of fracture risk, other factors such as bone structure and bone quality are also likely to be important determinants. The association between fracture risk and VDR or COLIA1 genotypes could be mediated through these intermediate phenotypes. Indeed, it has been suggested that individuals with the COLIA1 SpI s (or T) allele were associated with reduced bone strength (30) and impaired bone mineralization (31). These observations may potentially explain the BMD-independent association between COLIA1 genotypes and fracture risk that has been consistently observed in the present as well as previous studies (7, 8, 9, 10).

A number of considerations should be taken into account in extrapolating the present findings to other populations. The present finding was based on an association (not linkage) analysis and, as such, does not necessarily show that the VDR or COLIA1 genes are directly involved rather than being markers for nearby genes, which are linked to hip fracture liability. Although the study sample size was relatively large with a long duration of follow up, the number of hip fracture cases was relatively small for a genetic association study. The small number of fracture cases relative to the nonfracture controls could result in an overestimate or underestimate of the magnitude of association and a less precise estimate of effect as reflected by the wide CIs. The estimated impact of COLIA1 and VDR polymorphisms on hip fracture (i.e. attributable risk fraction of 20% for VDR and 12% for COLIA1 gene) is likely to be an overestimate, because the estimation assumes that the genes do not interact with other risk factors, which is a rather strong assumption and should be taken into account in the interpretation. Finally, the data are based on a sample of Caucasian women, whose lifestyle and environmental living conditions are relatively homogeneous; hence, they may not apply to other populations and to men.

In summary, in the present study, polymorphisms of the VDR and COLIA1 genes are associated with hip fracture risk in elderly Caucasian women, and this association is independent of BMD. Although the contribution of these genetic polymorphisms to the liability to hip fracture is moderate and not explained mechanistically, these findings, together with previous data, provide evidence for genetic associations with osteoporotic fractures, particularly hip fracture, and indicate the need to delineate the underlying mechanisms.


   Acknowledgments
 
We gratefully acknowledge the expert assistance of Janet Watters and Donna Reeves in the interview, data collection, and measurement of bone densitometry and the invaluable help of the Dubbo community. We gratefully acknowledge Mr. J. McBride for the development and Mrs. N. Ivankovic for the management and maintenance of the database. We also thank Chehani Alles for her expert assistance in the genotyping.


   Footnotes
 
This work has been supported by the National Health and Medical Research Council of Australia.

Present address for S.F.G.: deCode Genetics, Sturlugata 8, IS-101 Reykjavik, Iceland.

First Published Online September 13, 2005

Abbreviations: BMD, Bone mineral density; CI, confidence interval; COLIA1, collagen I {alpha}1; OR, odds ratio; VDR, vitamin D receptor.

Received May 24, 2005.

Accepted September 1, 2005.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Nguyen TV, Sambrook PN, Kelly PJ, Jones G, Gilbert C, Lord S, Freund J, Eisman JA 1993 Prediction of osteoporotic fractures by postural instability and bone density. Br Med J 307:1111–1115
  2. Kannus P, Palvanen M, Kaprio J, Parkkari J, Koskenvuo M 1999 Genetic factors and osteoporotic fractures in elderly people: prospective 25 year follow up of a nationwide cohort of elderly Finnish twins. BMJ 319:1334–1337[Abstract/Free Full Text]
  3. Fox KM, Cummings SR, Powell-Threets K, Stone K 1998 Family history and risk of osteoporotic fracture. Study of Osteoporotic Fractures Research Group. Osteoporos Int 8:557–562[CrossRef][Medline]
  4. Seeman E, Tsalamandris C, Formica C, Hopper JL, McKay J 1994 Reduced femoral neck bone density in the daughters of women with hip fractures: the roles of low peak bone density in the pathogenesis of osteoporosis. J Bone Miner Res 9:739–743[Medline]
  5. Cooper GS, Umbach DM 1996 Are vitamin D receptor polymorphisms associated with bone mineral density? A meta-analysis. J Bone Miner Res 11:1841–1849[Medline]
  6. Grant SFA, Reid DM, Blake G, Herd R, Fogelman I, Ralston SH 1996 Reduced bone density and osteoporotic fracture associated with a polymorphic Sp1 binding site in the collagen type I {alpha} 1 gene. Nat Genet 14:203–205[CrossRef][Medline]
  7. Uitterlinden AG, Burger H, Huang Q, Yue F, McGuigan FE, Grant SF, Hofman A, van Leeuwen JP, Pols HA, Ralston SH 1998 Relation of alleles of the collagen type I {alpha}1 gene to bone density and the risk of osteoporotic fractures in postmenopausal women. N Engl J Med 338:1016–1021[Abstract/Free Full Text]
  8. Uitterlinden AG, Weel AE, Burger H, Fang Y, van Duijn CM, Hofman A, van Leeuwen JP, Pols HA 2001 Interaction between the vitamin D receptor gene and collagen type I {alpha}1 gene in susceptibility for fracture. J Bone Miner Res 16:379–385[CrossRef][Medline]
  9. Langdahl BL, Ralston SH, Grant SF, Eriksen EF 1998 An Sp1 binding site polymorphism in the COLIA1 gene predicts osteoporotic fractures in both men and women. J Bone Miner Res 13:1384–1389[CrossRef][Medline]
  10. Aerssens J, Dequeker J, Peeters J, Breemans S, Broos P, Boonen S 2000 Polymorphisms of the VDR, ER and COLIA1 genes and osteoporotic hip fracture in elderly postmenopausal women. Osteoporos Int 11:583–591[CrossRef][Medline]
  11. Valimaki S, Tahtela R, Kainulainen K, Laitinen K, Loyttyniemi E, Sulkava R, Valimaki M, Kontula K 2001 Relation of collagen type I {alpha}1 (COLIA 1) and vitamin D receptor genotypes to bone mass, turnover, and fractures in early postmenopausal women and to hip fractures in elderly people. Eur J Int Med 12:48–56
  12. Hustmyer FG, Liu G, Johnston CC, Christian J, Peacock M 1999 Polymorphism at an Sp1 binding site of COL1A1 and bone mineral density in premenopausal female twins and elderly fracture patients. Osteoporos Int 9:346–350[CrossRef][Medline]
  13. Ensrud KE, Stone K, Cauley JA, White C, Zmuda JM, Nguyen TV, Eisman JA, Cummings SR 1999 Vitamin D receptor gene polymorphisms and the risk of fractures in older women. For the Study of Osteoporotic Fractures Research Group. J Bone Miner Res 14:1637–1645[CrossRef][Medline]
  14. Jones G, White C, Nguyen TV, Sambrook PN, Kelly PJ, Eisman JA 1996 Prevalent vertebral deformities: relationship to bone mineral density and spinal osteophytosis in elderly men and women. Osteoporos Int 6:399–406[CrossRef][Medline]
  15. Nguyen TV, Center JR, Eisman JA 2000 Osteoporosis in elderly men and women: effects of dietary calcium, physical activity, and body mass index. J Bone Miner Res 15:322–331[CrossRef][Medline]
  16. Nguyen TV, Sambrook PN, Eisman JA 1997 Source of variability in bone density: implication for study design and analysis. J Bone Miner Res 12:124–135[CrossRef][Medline]
  17. Morrison NA, Qi JC, Tokita A, Kelly PJ, Crofts L, Nguyen TV, Sambrook PN, Eisman JA 1994 Prediction of bone density from vitamin D receptor alleles. Nature 367:284–287[CrossRef][Medline]
  18. Nguyen TV, Kelly PJ, Morrison NA, Sambrook PN, Eisman JA 1994 Vitamin D receptor genotypes in osteoporosis. Lancet 344:1580–1581[Medline]
  19. SAS Institute 1992 SAS Technical Report P-229, SAS/STAT software: changes and enhancements, release 6.07. Cary, NC: SAS Institute; 443–480
  20. Ralston SH 2002 Genetic control of susceptibility to osteoporosis. J Clin Endocrinol Metab 87:2460–2466[Abstract/Free Full Text]
  21. Garnero P, Munoz F, Borel O, Sornay-Rendu E, Delmas PD 2005 Vitamin D receptor gene polymorphisms are associated with the risk of fractures in postmenopausal women, independently of bone mineral density. J Clin Endocrinol Metab 90:4829–4835[Abstract/Free Full Text]
  22. Langdahl BL, Gravholt CH, Brixen K, Eriksen EF 2000 Polymorphisms in the vitamin D receptor gene and bone mass, bone turnover and osteoporotic fractures. Eur J Clin Invest 30:608–617[CrossRef][Medline]
  23. Yanagi H, Tomura S, Kawanami K, Hosokawa M, Tanaka M, Kobayashi K, Tsuchiya S, Amagai H, Hayashi K, Hamaguchi H 1996 Vitamin D receptor gene polymorphisms are associated with osteoporosis in Japanese women. J Clin Endocrinol Metab 81:4179–4181
  24. Feskanich D, Hunter DJ, Willett WC, Hankinson SE, Hollis BW, Hough HL, Kelsey KT, Colditz GA 1998 Vitamin D receptor genotype and the risk of bone fractures in women. Epidemiology 9:535–539[Medline]
  25. Houston LA, Grant SF, Reid DM, Ralston SH 1996 Vitamin D receptor polymorphism, bone mineral density, and osteoporotic vertebral fracture: studies in a UK population. Bone 18:249–252[Medline]
  26. Uitterlinden AG, Pols HA, Burger H, Huang Q, Van Daele PL, Van Duijn CM, Hofman A, Birkenhager JC, Van Leeuwen JP 1996 A large-scale population-based study of the association of vitamin D receptor gene polymorphisms with bone mineral density. J Bone Miner Res 11:1241–1248[Medline]
  27. Deng HW, Li J, Li JL, Johnson M, Gong G, Recker RR 1999 Association of VDR and estrogen receptor genotypes with bone mass in postmenopausal Caucasian women: different conclusions with different analyses and the implications. Osteoporos Int 9:499–507[Medline]
  28. Riggs BL, Nguyen TV, Melton III LJ, Morrison NA, O’Fallon WM, Kelly PJ, Egan KS, Sambrook PN, Muhs JM, Eisman JA 1995 The contribution of vitamin D receptor gene alleles to bone mineral density in normal and osteoporotic women. J Bone Miner Res 10:991–996[Medline]
  29. McGuigan FE, Armbrecht G, Smith R, Felsenberg D, Reid DM, Ralston SH 2001 Prediction of osteoporotic fractures by bone densitometry and COLIA1 genotyping: a prospective, population-based study in men and women. Osteoporos Int 12:91–96[CrossRef][Medline]
  30. Mann V, Hobson EE, Li B, Stewart TL, Grant SFA, Robins SP, Aspden RM, Ralston SH 2001 A COLIA1 Sp1 binding site polymorphism predisposes to osteoporotic fracture by affecting bone density and bone quality. J Clin Invest 107:899–907[Medline]
  31. Stewart TL, Roschger P, Misof BM, Mann V, Fratzl P, Klaushofer K, Aspden R, Ralston SH 19 May 2005 Association of COLIA1 Sp1 alleles with defective bone nodule formation in vitro and abnormal bone mineralization in vivo. Calcif Tissue Int 10.1007/s00223-004-0188-8



This article has been cited by other articles:


Home page
 J. Clin. Endocrinol. Metab.Home page
Y. Fang, J. B. J. van Meurs, F. Rivadeneira, N. M. van Schoor, J. P. T. van Leeuwen, P. Lips, H. A. P. Pols, and A. G. Uitterlinden
Vitamin D Receptor Gene Haplotype Is Associated with Body Height and Bone Size
J. Clin. Endocrinol. Metab., April 1, 2007; 92(4): 1491 - 1501.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Clin. Nutr.Home page
M. Rao Vupputuri, R. Goswami, N. Gupta, D. Ray, N. Tandon, and N. Kumar
Prevalence and functional significance of 25-hydroxyvitamin D deficiency and vitamin D receptor gene polymorphisms in Asian Indians
Am. J. Clinical Nutrition, June 1, 2006; 83(6): 1411 - 1419.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
90/12/6575    most recent
Author Manuscript (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Nguyen, T. V.
Right arrow Articles by Eisman, J. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Nguyen, T. V.
Right arrow Articles by Eisman, J. A.
Related Collections
Right arrow Calcium and Bone Metabolism

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals