Dataset Information

High-density association study of 383 candidate genes for volumetric BMD at the femoral neck and lumbar spine among older men.

ABSTRACT: Genetics is a well-established but poorly understood determinant of BMD. Whereas some genetic variants may influence BMD throughout the body, others may be skeletal site specific. We initially screened for associations between 4608 tagging and potentially functional single nucleotide polymorphisms (SNPs) in 383 candidate genes and femoral neck and lumbar spine volumetric BMD (vBMD) measured from QCT scans among 862 community-dwelling white men >or=65 yr of age in the Osteoporotic Fractures in Men Study (MrOS). The most promising SNP associations (p < 0.01) were validated by genotyping an additional 1156 white men from MrOS. This analysis identified 8 SNPs in 6 genes (APC, DMP1, FGFR2, FLT1, HOXA, and PTN) that were associated with femoral neck vBMD and 13 SNPs in 7 genes (APC, BMPR1B, FOXC2, HOXA, IGFBP2, NFATC1, and SOST) that were associated with lumbar spine vBMD in both genotyping samples (p < 0.05). Although most associations were specific to one skeletal site, SNPs in the APC and HOXA gene regions were associated with both femoral neck and lumbar spine BMD. This analysis identifies several novel and robust genetic associations for volumetric BMD, and these findings in combination with other data suggest the presence of genetic loci for volumetric BMD that are at least to some extent skeletal-site specific.

SUBMITTER: Yerges LM

PROVIDER: S-EPMC2791518 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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High-density association study of 383 candidate genes for volumetric BMD at the femoral neck and lumbar spine among older men.

Yerges Laura M LM Klei Lambertus L Cauley Jane A JA Roeder Kathryn K Kammerer Candace M CM Moffett Susan P SP Ensrud Kristine E KE Nestlerode Cara S CS Marshall Lynn M LM Hoffman Andrew R AR Lewis Cora C Lang Thomas F TF Barrett-Connor Elizabeth E Ferrell Robert E RE Orwoll Eric S ES Zmuda Joseph M JM

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 20091201 12

Genetics is a well-established but poorly understood determinant of BMD. Whereas some genetic variants may influence BMD throughout the body, others may be skeletal site specific. We initially screened for associations between 4608 tagging and potentially functional single nucleotide polymorphisms (SNPs) in 383 candidate genes and femoral neck and lumbar spine volumetric BMD (vBMD) measured from QCT scans among 862 community-dwelling white men >or=65 yr of age in the Osteoporotic Fractures in Me ...[more]

PMID: 19453261

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Project description:Abaloparatide is a selective activator of the parathyroid hormone type 1 receptor signaling pathway that favors the stimulation of bone formation. Here, we report a prospective, exploratory analysis of bone mineral density (BMD) response rates comparing sequential abaloparatide/alendronate vs placebo/alendronate across the ACTIVE and ACTIVExtend studies. BMD was measured at the lumbar spine, total hip, and femoral neck from the beginning of ACTIVE to the end of ACTIVExtend (18 months of abaloparatide or placebo followed by about 1 month for re-consent, followed by 24 months of alendronate treatment for a total of 43 months). Responders were defined as those patients who had improvements in BMD at 3 anatomic sites-the lumbar spine, total hip, and femoral neck. Three response thresholds, >0%, >3%, and >6%, were evaluated. Five hundred fifty-eight patients in the abaloparatide/alendronate group and 581 patients in the placebo/alendronate group from ACTIVExtend were included in the analysis. At Month 43, a significantly greater proportion of those in the abaloparatide/alendronate group compared with the placebo/alendronate group responded with BMD changes from ACTIVE baseline of >0%, >3%, and >6% at all 3 anatomic sites (p < 0.001 for each comparison). At the>3% threshold, 60.7% (307/506) vs 24.0% (121/505) of patients experienced BMD increases at all 3 sites in the abaloparatide/alendronate vs placebo/alendronate groups, respectively (p < 0.001). A significantly greater proportion of the abaloparatide/alendronate group experienced BMD increases of>0%, >3%, and >6% at each individual anatomic site compared with the placebo/alendronate group at 43 months (p < 0.001). Additionally, at each visit in ACTIVExtend, there was a significantly greater proportion of patients in the abaloparatide/alendronate group above the 3% threshold at each anatomic site compared with the placebo/alendronate group. Results are consistent with the significant BMD response with abaloparatide vs placebo observed in ACTIVE and with the continued fracture risk reduction with sequential abaloparatide/alendronate compared with placebo/alendronate treatment observed in ACTIVE through ACTIVExtend.

Project description:BackgroundLow bone mineral density (BMD) and subsequent fractures are a major public health problem in postmenopausal women. The purpose of this study was to use the aggregate data meta-analytic approach to examine the effects of ground (for example, walking) and/or joint reaction (for example, strength training) exercise on femoral neck (FN) and lumbar spine (LS) BMD in postmenopausal women.MethodsThe a priori inclusion criteria were: (1) randomized controlled trials, (2) exercise intervention ≥ 24 weeks, (3) comparative control group, (4) postmenopausal women, (5) participants not regularly active, i.e., less than 150 minutes of moderate intensity (3.0 to 5.9 metabolic equivalents) weight bearing endurance activity per week, less than 75 minutes of vigorous intensity (> 6.0 metabolic equivalents) weight bearing endurance activity per week, resistance training < 2 times per week, (6) published and unpublished studies in any language since January 1, 1989, (7) BMD data available at the FN and/or LS. Studies were located by searching six electronic databases, cross-referencing, hand searching and expert review. Dual selection of studies and data abstraction were performed. Hedge's standardized effect size (g) was calculated for each FN and LS BMD result and pooled using random-effects models. Z-score alpha values, 95%confidence intervals (CI) and number-needed-to-treat (NNT) were calculated for pooled results. Heterogeneity was examined using Q and I2. Mixed-effects ANOVA and simple meta-regression were used to examine changes in FN and LS BMD according to selected categorical and continuous variables. Statistical significance was set at an alpha value ≤0.05 and a trend at >0.05 to ≤ 0.10.ResultsSmall, statistically significant exercise minus control group improvements were found for both FN (28 g's, 1632 participants, g = 0.288, 95% CI = 0.102, 0.474, p = 0.002, Q = 90.5, p < 0.0001, I2 = 70.1%, NNT = 6) and LS (28 g's, 1504 participants, g = 0.179, 95% CI = -0.003, 0.361, p = 0.05, Q = 77.7, p < 0.0001, I2 = 65.3%, NNT = 6) BMD. Clinically, it was estimated that the overall changes in FN and LS would reduce the 20-year relative risk of osteoporotic fracture at any site by approximately 11% and 10%, respectively. None of the mixed-effects ANOVA analyses were statistically significant. Statistically significant, or a trend for statistically significant, associations were observed for changes in FN and LS BMD and 20 different predictors.ConclusionsThe overall findings suggest that exercise may result in clinically relevant benefits to FN and LS BMD in postmenopausal women. Several of the observed associations appear worthy of further investigation in well-designed randomized controlled trials.

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Project description:BackgroundCow milk contains more calcium, magnesium, potassium, zinc, and phosphorus minerals. For a long time, people have believed that increasing milk intake is beneficial to increasing bone density. Many confounding factors can affect milk consumption, and thus the association described to date may not be causal. We explored the causal relationship between genetically predicted milk consumption and Bone Mineral Density (BMD) of the femoral neck and lumbar spine based on 53,236 individuals from 27 studies of European ancestry using the Mendelian randomization (MR) study. 32,961 individuals of European and East Asian ancestry were used for sensitivity analysis.MethodsA genetic instrument used for evaluating milk consumption is rs4988235, a locus located at 13,910 base pairs upstream of the LCT gene. A Mendelian randomization (MR) analysis was conducted to study the effect of selected single nucleotide polymorphisms (SNPs) and BMD. The summary-level data for BMD of the femoral neck and lumbar spine were obtained from two GWAS meta-analyses ['Data Release 2012' and 'Data Release 2015' in the GEnetic Factors for OSteoporosis Consortium (GEFOS)].Resultswe found that genetically predicted milk consumption was not associated with FN-BMD(OR 1.007; 95% CI 0.991-1.023; P = 0.385), LS-BMD(OR 1.003; 95% CI 0.983-1.024; P = 0.743) by performing a meta-analysis of several different cohort studies. High levels of genetically predicted milk intake were positively associated with increased FN-BMD in Women. The OR for each additional milk intake increasing allele was 1.032 (95%CI 1.005-1.059; P = 0.014). However, no causal relationship was found between milk consumption and FN-BMD in men (OR 0.996; 95% CI 0.964-1.029; P = 0.839). Genetically predicted milk consumption was not significantly associated with LS-BMD in women (OR 1.017; 95% CI 0.991-1.043; P = 0.198) and men (OR 1.011; 95% CI 0.978-1.045; P = 0.523).ConclusionOur study found that women who consume more milk have a higher FN-BMD. When studying the effect of milk consumption on bone density in further studies, we need to pay more attention to women.

Dataset Information

High-density association study of 383 candidate genes for volumetric BMD at the femoral neck and lumbar spine among older men.

Publications

High-density association study of 383 candidate genes for volumetric BMD at the femoral neck and lumbar spine among older men.

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