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Physical activity, Cdx-2 genotype, and BMD
Abstract
The present study investigated the interaction between Cdx-2 polymorphism and physical activity level over bone mineral density (BMD) variation in Brazilian postmenopausal women. One hundred and ninety women volunteered to participate in the study (66.6 +/- 5.3 years, 64.58 +/- 11.74 kg and 151.94 +/- 6.36 cm). Physical activity level (PAL) was assessed using the international physical activity questionnaire (IPAQ). Lumbar spine (L2 - L4), femoral neck, great trochanter and Wards' triangle bone mineral density (BMD) were measured by dual-energy X-ray absorptiometry (DXA). The Cdx-2 polymorphism was genotyped by minisequencing, using the SNaPshottrade mark Multiplex System (Applied Biosystems, Foster City, CA, USA). Overall, no significant association was found between Cdx-2 polymorphism and adjusted BMD at any site. However, the results revealed a significant interaction between PAL and Cdx-2 genotype on adjusted femoral neck and Wards' triangle BMD. Active women carrying the Cdx-G/G genotype showed higher adjusted femoral neck and Wards' triangle BMD than inactive women carrying the same genotype, thus suggesting a larger chronic response to physical activity. These results suggest that, in postmenopausal women, the Cdx-2 polymorphism does not influence BMD by itself; however, it seems to affect the BMD response to physical activity since only the Cdx-G/G genotype carriers presented significant differences between active and inactive.
... (Gentil et al., 2007; Moreno Lima et al., 2007; Bray et al., 2009; Rankinen et al., 2010). E para que os resultados das pesquisas sejam mais precisos, as buscas são baseadas nos efeitos biológicos dos genes, de modo a selecionar fatores associados diretamente aos fenótipos estudados. ...
... A região genômica onde está localizado o sítio polimórfico a ser estudado foi amplificada por meio da técnica da reação em cadeia da polimerase (PCR, do inglês polymerase chain reaction) em procedimentos similares aos usados anteriormente (Gentil et al., 2007; Lins et al., 2007) Após o preparo, a reação foi colocada em um termociclador (GeneAmp PCR System 9700, Applied Biosystems, Foster City, CA, EUA), alternando temperaturas variadas, descritas detalhadamente a seguir, com o intuito de promover a desnaturação do DNA (separação das fitas devido ao rompimento das pontes de hidrogênio), anelamento dos iniciadores às fitas simples de DNA e a síntese de uma nova fita de DNA pela incorporação de dNTPs. ...
... It is a skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and fracture susceptibility. There are multiple factors affecting bone density, including nutrition, environment, hormone, genetic factors, and the interactions between these factors [1]. Furthermore, aging is an important risk factor for osteoporosis [2]. ...
Age-related degenerative changes lead to a gradual decrease in bone mineral density (BMD) and muscle mass. We aimed to assess the effects of decreased BMD and lumbar denervation on lumbar spinal muscle morphometry and the relationship between BMD and lumbar spinal muscular morphometry, respectively. Eighty-one patients, aged 50–85 years, diagnosed with unilateral lumbosacral radiculopathy based on electrodiagnostic studies between January 2016 and April 2021 were enrolled. BMD T scores in the lumbar spine and hip were measured using dual-energy X-ray absorptiometry. The cross-sectional area (CSA) of the psoas, multifidus, and erector spinae located in the middle of the lumbar spine, between the L3 and L4 and between the L4 and L5 levels, respectively, was measured using axial MRI. Functional CSA (FCSA) was defined as the CSA of lean muscle mass. Pearson correlation analyses were performed to evaluate the association between BMD T scores and the CSA, FCSA, and the ratio of the FCSA to the CSA (functional ratio) for each side. The CSA of lumbar spinal muscles showed no significant correlation with lumbar BMD. The FCSA and functional ratio of lumbar spinal muscles were significantly correlated with lumbar BMD. There was no correlation between femur BMD and lumbar spinal muscle morphometry.
... The genotype frequency in this study was in accordance with those of the Hardy-Weinberg equilibrium and previous studies involving Japanese participants [13,17]. While many studies have not demonstrated a relationship between the Cdx2 polymorphism and bone mineral density [13,14,16,17,[28][29][30][31][32][33][34][35], some have identified relationships [36,37]. This inconsistency might be due to relatively small study sample sizes or a wide range of age. ...
Studies investigating the effect of the caudal-type homeobox protein 2 (Cdx2) polymorphism in the vitamin D receptor gene and calcium intake on bone mass have shown inconsistent results. This study investigated whether the effect of calcium intake on peak bone mass is affected by Cdx2 polymorphism in young Japanese women. A cross-sectional study of 500 young women was conducted. Dietary intake was assessed by the Food Frequency Questionnaire. The osteo sono-assessment index (OSI), assessed by the qualitative ultrasound method, was used as a bone mass index. The subjects were divided into two groups by the median calcium intake. The OSI was not different among Cdx2 genotypes and between calcium groups (p = 0.960, p = 0.191, respectively). The interaction between calcium and Cdx2 genotypes on the OSI approached significance (GG versus GA and AA genotypes, p = 0.092). The difference in the OSI between calcium groups was significant in the GG genotype (p = 0.028), but not in the GA or AA genotypes (p = 0.501, p = 0.306, respectively). Adjustment for covariates (body mass index and physical activity) did not change the results. In conclusion, the relationship between dietary calcium intake and peak bone mass may vary according to Cdx2 polymorphism.
... Specifically, Cdx2 polymorphism was associated with femoral neck BMD in a study of 239 osteoporotic postmenopausal women carried out by Mencej-Bedrac et al. (29). In another recent report by Gentil et al. (30), Cdx2 polymorphism did not influence BMD in osteoporotic women by itself, but actually affected the BMD response to physical activity. ...
... Several studies agree that the A allele of the Cdx-2 SNP is associated with increased bone mineral density and decreased fracture risk, which depends on intestinal calcium absorption (Arai et al. 2001;Casado-Díaz et al. 2013;Fang et al. 2003Fang et al. , 2005Morita et al. 2005). However, some inconsistencies exist with at least three studies reporting no association between Cdx-2 genotypes and bone mineral density (Kocabaş et al. 2010;Macdonald et al. 2006;Tantawy et al. 2016) and at least three others reporting the risk allele as A (Gentil et al. 2007;Ling et al. 2016;Stathopoulou et al. 2011). In contrast, the A allele appears to be commonly associated with perturbation of immune function like spontaneous preterm birth due to infection or inflammation (Javorski et al. 2018) and tuberculosis (Harishankar and Selvaraj 2016;Selvaraj et al. 2008). ...
Caudal-type homeobox protein 2 (CDX-2) is an intestine-specific transcription factor (TF), with a polymorphic binding site (Cdx-2, rs11568820, A/G) in the vitamin D receptor gene (VDR). The molecular mechanism underlying Cdx-2 association with conditions like osteoporosis, which depends on intestinal VDR expression and calcium absorption, is believed to be due to higher affinity of CDX-2 for the ancestral A allele compared to the G allele. However, it is unclear why the polymorphism is associated with diseases like tuberculosis, which is dependent on VDR expression in immune cells that do not express CDX-2. This study aimed to explain Cdx-2 variant association with immune-related conditions. We hypothesised that the effect of Cdx-2 polymorphism on VDR expression in monocytes/macrophages, devoid of the CDX-2 TF, is indirect and dependent on circulating 25(OH)D3 and VDR methylation. Primary monocyte/macrophages from healthy donors (n = 100) were activated though TLR2/1 elicitation. VDR mRNA and 25(OH)D3 were quantified by RT-qPCR and LC-MS/MS, respectively. Genotyping and methylation analysis were done by pyrosequencing. AA vs. AG/GG showed reduced levels of 25(OH)D3 (P < 0.010), higher VDR promoter methylation (P < 0.050) and lower VDR mRNA induction (P < 0.050). Analysis of covariance confirmed that the effect of Cdx-2 variants depends primarily on VDR methylation. Thus, VDR methylation may confound association studies linking VDR polymorphisms to disease.
The vitamin D receptor (VDR) regulates bone development and calcium homeostasis, suggesting a central role in musculoskeletal diseases such as osteoporosis (OP). Several studies have examined the contribution of VDR polymorphisms and epigenetic signatures in bone metabolism and OP risk, with sometimes inconclusive results. Our study aimed to explore the association between genetic variability, expression and the methylation pattern of VDR with the risk of OP in a cohort of Caucasian patients. Genomic DNA from 139 OP, 54 osteopenic (Ope) and 73 healthy (CTR) subjects were used for genotyping the rs731236 (TaqI), rs2228570 (FokI) and rs11568820 (Cdx2) poly-morphisms of the VDR gene by an allelic discrimination assay. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis of VDR expression levels and pyrosequencing analysis of a VDR promoter CpG island were carried out in a subcohort (25 OP and 25 CTR) of subjects. Data obtained showed a significantly higher OP risk for rs11568820 G/A and A/A genotypes (p = 0.05). qRT-PCR revealed lower VDR gene expression levels in the OP group compared to CTR subjects (p = 0.0009), also associated with both the rs11568820 A/A genotype (p = 0.03) and femoral fragility fractures (p = 0.05). No association was found between the methylation pattern of the region analyzed of the VDR promoter and its expression levels. Our results identify a significative association between Cdx2 rs11568820 polymorphism and OP risk. In addition, the VDR transcriptomic profile suggests a putative interconnection with OP progression, providing a useful tool to stratify OP phenotype and fragility fracture risk.
Trabecular bone structure has an important influence on bone strength, but little is known about its genetic regulation. To elucidate the genetic factor(s) regulating trabecular bone structure, we compared the trabecular bone structure of two genetically remote mouse strains, C57BL/6J and Japanese wild mouse-derived MSM/Ms. Phenotyping by X-ray micro-CT revealed that MSM/Ms has structurally more fragile trabecular bone than C57BL/6J. Toward identification of genetic determinants for the difference in fragility of trabecular bone between the two mouse strains, we employed phenotype screening of consomic mouse strains in which each C57BL/6J chromosome is substituted by its counterpart from MSM/Ms. The results showed that many chromosomes affect trabecular bone structure, and that the consomic strain B6-Chr15(MSM), carrying MSM/Ms-derived Chromosome 15, has the lowest values for the parameters BV/TV, Tb.N and Conn.D and the highest values for the parameters Tb.Sp and SMI. Subsequent phenotyping of sub-consomic strains for Chromosome 15 (Chr15) mapped four novel trabecular bone structure-related QTLs (Tbsq1-4) on mouse Chr15. These results collectively indicate that genetic regulation of trabecular bone structure is highly complex, and that even in the single Chr15, the combined action of the four Tbsqs controls the fragility of trabecular bone. Given that Tbsq4 is syntenic to Human Chr 12q12-13.3, where several bone-related SNPs are assigned, further study of Tbsq4 should facilitate our understanding of the genetic regulation of bone formation in human.
The aim of this study was to identify the association between ACTN3 (R577X) and ACE (I/D) gene polymorphisms and athletic performance type (endurance, speed/power and mixed). The sample consisted of 176 athletes (100 men and 76 women) with mean age of 16.75 years ± 3.50. We studied 22 sports; all athletes were chosen from the best in their respective Federations of the State of Paraná. DNA samples were withdrawn from 4ml of blood from the median cubital vein. Genotyping of the ACTN3 - R577X gene polymorphism were performed using a TaqMan probe ID rs1815739 (Applied Biosystems, Foster City, CA, USA ). Genotyping of the ACE I / D polymorphism were performed by polymerase chain reaction (PCR), followed by visualization by electrophoresis. The physical tests were vertical jumps (Squat Jump, Jump and Countermovement Jump with help of the arms), speed in the 30m sprint (in seconds) and maximum oxygen consumption (VO2max). Statistical analysis was done with the chi-square test and One Way ANOVA , with significance at p < 0.05. Genotypes were not statistically significant with the duration of effort (ACTN3 vs Duration of Effort, p = 0.709 ; ACE VS Length of Effort, p = 0.140). The prevalence of RX and DI genes were more prevalent in the duration of effort (resistance : RX = 60.6 % , DI = 4.87 %, Power / Speed : . RX = 54.1 % , DI = 50 % ; Mixed: RX = 45 % , DI = 41.98 % ). We therefore conclude that genetic variables show a prevalence that can help in determining the choice of a sport / event that requires a specific type of metabolism to exercise in young athletes, although there was no association between polymorphisms ACTN3 and ACE in relation to exercise duration and physical performance. Key Words: polymorphisms, genotypes, physical performance.
Background: Osteoporosis is a bone fragility disorder with a strong genetic predisposition. The vitamin D receptor gene was one of the main candidate ones. Objective: To investigate whether the gene polymorphism in Cdx-2 binding sites of vitamin D receptor has related to the bone mineral density (BMD) and bone loss in older adults. Design, Time and Setting: Prospective Longitudinal study was performed in the Department of Nutrition and Food Hygiene, Shenyang Medical College form March 2003 to March 2005 Participants: A total of 100 healthy unrelated individuals, over 60 years old, in Han of Shenyang were selected. They all had no history of taking vitamin D and calcium supplement. Methods: The gene polymorphism of Cdx-2 binding sites of vitamin D receptor was measured by polymerase chain reaction-restriction fragment length polymorphism (PCR-RELP). BMD at hip was measured using dual-energy X-ray (DPX-L) absorption apparatus (Lunar,USA) at baseline and after 5 years, respectively. Main Outcome Measures: The distribution of genotypes in Cdx-2 binding sites was measured. The association between the gene polymorphism of Cdx-2 combine sites of vitamin D receptor and BMD in hip were analyzed by covariance analysis. Results: The frequencies of AG, GG and AA genotypes in Cdx-2 binding sites were 57 %, 26 %, and 17 %, repectively. There was no significant difference in alleles between males and females. The frequencies distribution in the population accorded with the Hardy-Weinberg equilibrium. There was no significant difference in age, height, body mass among the genotypes both in males and females. After adjusting for height, weight and age, there was no significant difference in BMD in the femoral neck and trochanter among the different genotypes, as well as the Annualized bone loss rate. Conclusion: The genotype in Cdx-2 binding site of vitamin D receptor did not have obviously related to BMD and bone loss at hip.
The purpose of this study was to investigate the association between the GHR exon 3 fl/d3 polymorphism and body composition traits in Brazilian cohorts of normal post-menarche adolescent girls and in post-menopausal women with and without osteoporosis. First, multiplex PCR and quantitative PCR (TaqMan) were used with 105 DNA samples from the general Brazilian population to validate the SNP rs6873545 as a surrogate marker for the GHR polymorphism. Subsequently, genotyping was carried out to evaluate associations for this polymorphism in 136 post-menarche adolescents and 175 post-menopausal women, who were evaluated for body composition traits such as bone mineral density and fat-free mass. Statistical analysis used an independent sample t test, one-way ANOVA test and post hoc Tukey HSD test. Significant values were assumed by p < 0.05. Genotyping indicated complete linkage disequilibrium between the GHR polymorphism and the SNP alleles (r (2) = 1.0). Adolescents and healthy post-menopausal women showed no genotype associations for body composition traits or osteoporosis. However, a lower total body bone mineral density was observed in fl/fl post-menopausal women with osteoporosis (p = 0.0004). These results suggest that the SNP rs6873545 can be used as a surrogate for the GHR fl/d3 polymorphism due to linkage disequilibrium in the Brazilian population and that the fl/fl genotype is a severity-related risk factor for osteoporosis, but did not appear to be associated with disease status.
The actions of 1,25-dihydroxyvitamin D3 (1,25(OH)2 D3) are mediated through the nuclear vitamin D receptor (VDR). The regulation of VDR abundance plays an important role in determining the magnitude of the target cell response to 1,25(OH)2D3. The major physiological activity of 1,25(OH)2D3 is the regulation of calcium absorption in the small intestine, and the level of VDR is an important factor in this regulation. However, the characterization of VDR gene expression in the small intestine remains unknown. In the present study, we investigated the regulation of the human VDR (hVDR) gene expression in the small intestine. The 4.0 kb of the 5′-flanking region of the hVDR gene promoter was cloned and characterized by the measurement of luciferase activity and an electrophoretic mobility-shift assay (EMSA). With the EMSA, we found that Cdx-2 (a homeodomain protein-related caudal) binds to the sequence 5′-ATAAAAACTTAT-3′ at −3731 to −3720 bp (hVD-SIF1) relative to the transcription start site of the hVDR promoter. This sequence is very similar to the human sucrase-isomaltase footprint 1 (SIF1) element. With a competition analysis and specific antibodies for Cdx-2, we demonstrated that Cdx-2 is able to activate VDR gene transcription by binding to this element. The mutation of the hVD-SIF1 sequence in the hVDR gene promoter markedly suppressed the transactivation of the reporter gene in Caco-2 cells. In addition, the DNA fragment (−3996 to −3286) containing the hVD-SIF1 binding site increased transcription when placed upstream of the herpes simplex virus thymidine kinase promoter. These findings suggest that Cdx-2 plays an important role in the intestine-specific transcription of the hVDR gene.
OBJECTIVE--To encourage increased participation in physical activity among Americans of all ages by issuing a public health recommendation on the types and amounts of physical activity needed for health promotion and disease prevention. PARTICIPANTS--A planning committee of five scientists was established by the Centers for Disease Control and Prevention and the American College of Sports Medicine to organize a workshop. This committee selected 15 other workshop discussants on the basis of their research expertise in issues related to the health implications of physical activity. Several relevant professional or scientific organizations and federal agencies also were represented. EVIDENCE--The panel of experts reviewed the pertinent physiological, epidemiologic, and clinical evidence, including primary research articles and recent review articles. CONSENSUS PROCESS--Major issues related to physical activity and health were outlined, and selected members of the expert panel drafted sections of the paper from this outline. A draft manuscript was prepared by the planning committee and circulated to the full panel in advance of the 2-day workshop. During the workshop, each section of the manuscript was reviewed by the expert panel. Primary attention was given to achieving group consensus concerning the recommended types and amounts of physical activity. A concise \"public health message was developed to express the recommendations of the panel. During the ensuing months, the consensus statement was further reviewed and revised and was formally endorsed by both the Centers for Disease Control and Prevention and the American College of Sports Medicine. CONCLUSION--Every US adult should accumulate 30 minutes or more of moderate-intensity physical activity on most, preferably all, days of the weekType: CONSENSUS DEVELOPMENT CONFERENCEType: JOURNAL ARTICLEType: REVIEWLanguage: Eng
Reduced levels of physical activity have been found to be associated with an increased risk of osteoporotic fracture in a number of epidemiological studies, and intervention studies have shown beneficial effects of exercise regimes on bone mineral density. It is not yet established, however, which specific forms of customary physical activity are most strongly associated with bone mineral density in postmenopausal women.
A cross-sectional study was conducted in 580 postmenopausal women, aged 45-61 years, resident in Nottingham, England. The participants completed a detailed interviewer-administered activity questionnaire. Physical activity was assessed as total hours of participation per week in activities including housework, walking, gardening and sports. Stair-climbing and self-reported walking pace were also reported. Bone mineral density measurements were made using dual energy x-ray absorptiometry, measurements at five sites were used in analysis.
The strongest associations between the activity measures and bone mineral density were for stair-climbing and walking pace, which both gave statistically significant positive associations at the trochanter hip site and the whole body. In women reporting a fairly brisk or fast walking pace, bone mineral density at the proximal femur was also significantly and positively associated with the frequency of walking at least a mile. There were no significant associations with aggregate measures of total customary physical activity.
This study has identified two forms of physical activity, namely stair-climbing and brisk walking which are associated with increased bone mineral density at the hip and whole body in postmenopausal women. Both are feasible forms of activity for promoting to middle-aged women.
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The possible role of genetic and/or environmental factors in determining bone mass has been investigated in 30 pairs of twins (16 monozygotic and 14 dizygotic) divided in two age groups (below and above 25 years of age). Bone mineral content was evaluated by single- and dual photon absorptiometry at the distol third of the radius for peripheral cortical bone and in the lumbar spine for the axial bone. The "within pair" variance has been used as an index of genetic influence. A significant (p less than 0.01) genetic determinant was found for the bone mass of the radius in adults and for the spinal bone mass in the age group younger than 25 years. The heritability index h2 was 0.75 for cortical BMC and 0.88 for axial BMC. Such a genetic determinant could not conclusively be demonstrated in adult twins for the spine and in youngsters for the cortical bone, suggesting that environmental factors may play a more dominant role in growth of cortical bone during adolescence and diminution of axial bone during adult life.
Many risk factors for hip fractures have been suggested but have not been evaluated in a comprehensive prospective study.
We assessed potential risk factors, including bone mass, in 9516 white women 65 years of age or older who had had no previous hip fracture. We then followed these women at 4-month intervals for an average of 4.1 years to determine the frequency of hip fracture. All reports of hip fractures were validated by review of x-ray films.
During the follow-up period, 192 women had first hip fractures not due to motor vehicle accidents. In multivariable age-adjusted analyses, a maternal history of hip fracture doubled the risk of hip fracture (relative risk, 2.0; 95 percent confidence interval, 1.4 to 2.9), and the increase in risk remained significant after adjustment for bone density. Women who had gained weight since the age of 25 had a lower risk. The risk was higher among women who had previous fractures of any type after the age of 50, were tall at the age of 25, rated their own health as fair or poor, had previous hyperthyroidism, had been treated with long-acting benzodiazepines or anticonvulsant drugs, ingested greater amounts of caffeine, or spent four hours a day or less on their feet. Examination findings associated with an increased risk included the inability to rise from a chair without using one's arms, poor depth perception, poor contrast sensitivity, and tachycardia at rest. Low calcaneal bone density was also an independent risk factor. The incidence of hip fracture ranged from 1.1 (95 percent confidence interval, 0.5 to 1.6) per 1,000 woman-years among women with no more than two risk factors and normal calcaneal bone density for their age to 27 (95 percent confidence interval, 20 to 34) per 1,000 woman-years among those with five or more risk factors and bone density in the lowest third for their age.
Women with multiple risk factors and low bone density have an especially high risk of hip fracture. Maintaining body weight, walking for exercise, avoiding long-acting benzodiazepines, minimizing caffeine intake, and treating impaired visual function are among the steps that may decrease the risk.
Osteoporotic fragility fractures are related to bone density and injury, which are both related to muscle strength. The influence of genetic factors, such as the vitamin D receptor (VDR) polymorphism on bone mineral density (BMD), is documented but still controversial, and is not known for muscle strength. In the present study, we investigated the association between the VDR BsmI polymorphism and BMD (femoral neck [FN], lumbar spine [LS], and proximal forearm [FA]) and muscle strength (quadriceps and grip strength) in 501 healthy women older than 70 years. No association was found between the VDR genotypes and BMD in elderly women. However, in nonobese women (body mass index <30 kg/cm2), the BMD in the FN was 5% higher in women with the bb BsmI genotype than in women with the BB genotype (p < 0.05). After correction for muscle strength, no association was found. A significant association between the VDR genotypes and quadriceps and grip strength was observed. In nonobese women, a 23% difference in quadriceps strength (p < 0.01) and 7% in grip strength (NS) was observed between the bb and BB genotype of the VDR. After correction for confounding factors and BMD, this association was significant for quadriceps and grip strength. These results indicate a major association of an allelic variant at the VDR locus with muscle strength in elderly nonobese women, which could explain a small association between VDR polymorphism with BMD in the femoral neck in nonobese women. No such associations were found in obese women, suggesting that factors related to obesity obscure such an association.
Involvement of genetic factors in determining bone mineral density (BMD) is doubtless. However, the exact nature of the genes governing BMD variation and sources for genetic determination of BMD of different parts of bone (compact and cancellous) have not been completely studied. The results of the complex segregation analyses performed in our previous study (Livshits et al. 1996) on a Turkmenian sample strongly support the hypothesis that a single Mendelian locus has a large effect on BMD. The parameter estimates for both types of bone tissue were so similar that we could assume a common gene effect for BMD variation of cancellous and compact bone. The objectives of the present study are to test again the possibility of major gene control of BMD in a different ethnic sample of pedigrees, namely, the Chuvasha. In addition, we report here the results of a bivariate segregation analysis of compact and cancellous BMD performed in both the Turkemenian and the Chuvasha samples of pedigrees. The results of the present study closely resemble the results obtained on the Turkmenian pedigrees. Likewise, the major finding of the present study is that there is a significant major gene effect on both compact and cancellous BMD; polygenic hypotheses were clearly rejected. Moreover, the results of the bivariate segregation analysis in both the Chuvasha and Turkmenian samples were similar. They lead to acceptance of the hypothesis that there is a single major locus with pleiotropy to both compact and cancellous bone.
The vitamin D receptor (VDR) gene has been implicated as one of the major genetic components of osteoporosis. We evaluated the relationship between markers of mineral status and restriction fragment length polymorphisms of the VDR gene in 72 healthy children age 7-12 years. Using stable isotope techniques and dual-energy X-ray absorptiometry, we measured dietary calcium absorption, bone calcium deposition rates, and total body bone mineral density (BMD). The Fok1 polymorphism at the VDR translation initiation site was significantly associated with BMD (p = 0.02) and calcium absorption (p = 0.04). Children who were FF homozygotes had a mean calcium absorption that was 41.5% greater than those who were ff homozygotes and 17% greater absorption than Ff heterozygotes. BMD was 8.2% greater in the FF genotype than the ff genotype and 4.8% higher than the Ff genotype. These results suggest a substantial relationship between the VDR gene and bone metabolism at one or more levels, including dietary absorption of calcium and BMD in growing children.