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Abstract Context Estradiol is the primary female sex hormone and plays an important role for skeletal health in both sexes. Several enzymes are involved in estradiol metabolism, but few genome-wide association studies (GWAS) have been performed to characterize the genetic contribution to variation in estrogen levels. Objective Identify genetic loci affecting estradiol levels and estimate causal effect of estradiol on bone mineral density (BMD). Design We performed GWAS for estradiol in males (n = 147 690) and females (n = 163 985) from UK Biobank. Estradiol was analyzed as a binary phenotype above/below detection limit (175 pmol/L). We further estimated the causal effect of estradiol on BMD using Mendelian randomization. Results We identified 14 independent loci associated (P < 5 × 10−8) with estradiol levels in males, of which 1 (CYP3A7) was genome-wide and 7 nominally (P < 0.05) significant in females. In addition, 1 female-specific locus was identified. Most loci contain functionally relevant genes that have not been discussed in relation to estradiol levels in previous GWAS (eg, SRD5A2, which encodes a steroid 5-alpha reductase that is involved in processing androgens, and UGT3A1 and UGT2B7, which encode enzymes likely to be involved in estradiol elimination). The allele that tags the O blood group at the ABO locus was associated with higher estradiol levels. We identified a causal effect of high estradiol levels on increased BMD in both males (P = 1.58 × 10−11) and females (P = 7.48 × 10−6). Conclusion Our findings further support the importance of the body’s own estrogen to maintain skeletal health in males and in females.

Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in ≤ 21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis.

SummaryBy adopting the extension approaches of Mendelian randomization, we successfully detected and prioritized the potential causal risk factors for BMD traits, which might provide us novel insights for treatment and intervention into bone-related complex traits and diseases.IntroductionOsteoporosis (OP) is a common metabolic skeletal disease characterized by reduced bone mineral density (BMD). The identified SNPs for BMD can only explain approximately 10% of the variability, and very few causal factors have been identified so far.MethodsThe Mendelian randomization (MR) approach enables us to assess the potential causal effect of a risk factor on the outcome by using genetic IVs. By using extension methods of MR—multivariable MR (mvMR) and MR based on Bayesian model averaging (MR-BMA)—we intend to estimate the causal relationship between fifteen metabolic risk factors for BMD and try to prioritize the most potential causal risk factors for BMD.ResultsOur analysis identified three risk factors T2D, FG, and HCadjBMI for FN BMD; four risk factors FI, T2D, HCadjBMI, and WCadjBMI for FA BMD; and three risk factors FI, T2D, and HDL cholesterol for LS BMD, and all risk factors were causally associated with heel BMD except for triglycerides and WCadjBMI. Consistent with the mvMR results, MR-BMA confirmed those risk factors as top risk factors for each BMD trait individually.ConclusionsBy combining MR approaches, we identified the potential causal risk factors for FN, FA, LS, and heel BMD individually and we also prioritized and ranked the potential causal risk factors for BMD, which might provide us novel insights for treatment and intervention into bone-related complex traits and diseases.

Introduction. The Fat Mass and Obesity-Associated (FTO) gene encodes a demethylase, which modulates RNA N6-methyladenosine (m6A) and plays a regulatory role in adipocyte differentiation and the pathogenesis of human obesity. Methods. To understand the potential role of FTO in osteoporosis (OP), we investigated five single nucleotide variations (SNVs) in intron 1 (rs8057044, rs8050136, rs9939609, rs62033406, and rs9930506) of the FTO gene, and a missense SNV i.e., rs3736228 (A1330V), located in exon 18 of the LRP5 gene, in a cohort of postmenopausal women (n = 188) from Central Europe. Genotyping was performed with an allele discrimination assay, while haplotypes were reconstructed in the population by PHASE 2.1. Results. The rs9930506 was strongly associated with OP (p < 0.0035), which was supported by Bonferroni correction (p < 0.0175), and all SNVs located in the FTO gene were more strongly associated with severe OP with fragility fractures. Among seventeen haplotypes detected for the FTO gene, two haplotypes (H1 and H9) were frequent (frequency > 10%) and distributed in three main haplotypes pairs (H1/H1, H1/H9 and H9/H9, respectively). The pathogenic pair H1/H9 was associated with a leaner phenotype, increased fracture risk, and a lower bone mineral density (BMD), and carried the heterozygous GA of rs9930506, while the protective pair H9/H9 was associated with an increased obesity risk and carried AA alleles of rs9939609. Conclusions. Concordant associations with OP, an increased fracture risk, and a lower BMD at all skeletal sites indicate that the FTO gene is a promising candidate for OP, explaining the complex relationship with obesity and offering new perspectives for the study of the epigenetic regulation of bone metabolism.

Adjuvant therapy for hormone receptor (HR) positive postmenopausal breast cancer patients includes aromatase inhibitors (AI). While both the non-steroidal AI letrozole and the steroidal AI exemestane decrease serum estrogen concentrations, there is evidence that exemestane may be less detrimental to bone. We hypothesized that single nucleotide polymorphisms (SNP) predict effects of AIs on bone turnover. Early stage HR-positive breast cancer patients were enrolled in a randomized trial of exemestane versus letrozole. Effects of AI on bone mineral density (BMD) and bone turnover markers (BTM), and associations between SNPs in 24 candidate genes and changes in BMD or BTM were determined. Of the 503 enrolled patients, paired BMD data were available for 123 and 101 patients treated with letrozole and exemestane, respectively, and paired BTM data were available for 175 and 173 patients, respectively. The mean change in lumbar spine BMD was significantly greater for letrozole-treated (−3.2 %) compared to exemestane-treated patients (−1.0 %) ( p  = 0.0016). Urine N-telopeptide was significantly increased in patients treated with exemestane ( p  = 0.001) but not letrozole. Two SNPs (rs4870061 and rs9322335) in ESR1 and one SNP (rs10140457) in ESR2 were associated with decreased BMD in letrozole-treated patients. In the exemestane-treated patients, SNPs in ESR1 (Rs2813543) and CYP19A1 (Rs6493497) were associated with decreased bone density. Exemestane had a less negative impact on bone density compared to letrozole, and the effects of AI therapy on bone may be impacted by genetic variants in the ER pathway.

Background/Objectives: To investigate associations between Follistatin (FST) gene polymorphisms (SNPs) and baseline musculoskeletal traits, and their interactions with 16-week exercise interventions. Methods: A cohort of 470 untrained Northern Han Chinese adults (208 males, 262 females), sourced from the “Research on Key Technologies for an Exercise and Fitness Expert Guidance System” project, was analyzed. These participants were previously randomly assigned to one of four exercise groups (Hill, Running, Cycling, Combined) or a non-exercising Control group, and completed their respective 16-week protocols. Body composition, bone mineral content (BMC), bone mineral density (BMD), and serum follistatin levels were all assessed pre- and post-intervention. Dual-energy X-ray absorptiometry (DXA) was utilized for the body composition, BMC, and BMD measurements. FST SNPs (rs3797296, rs3797297) were genotyped using matrix assisted laser desorption/ionization time-of-flight mass spectrometer (MALDI-TOF MS) or microarrays. To elucidate the biological mechanisms, we performed in silico functional analyses for rs3797296 and rs3797297. Results: Baseline: In females only, the rs3797297 T allele was associated with higher muscle mass (β = 1.159, 95% confidence interval (CI): 0.202–2.116, P_adj = 0.034) and BMC (β = 0.127, 95% CI: 0.039–0.215, P_adj = 0.009), with the BMC effect significantly mediated by muscle mass. Exercise Response: Interventions improved body composition, particularly in females. Gene-Exercise Interaction: A significant interaction occurred exclusively in women undertaking hill climbing: the rs3797296 G allele was associated with attenuated muscle mass gains (β = −1.126 kg, 95% CI: −1.767 to −0.485, P_adj = 0.034). Baseline follistatin correlated with body composition (stronger in males) and increased post-exercise (primarily in males, Hill/Running groups) but did not mediate SNP effects on exercise adaptation. Functional annotation revealed that rs3797297 is a likely causal variant, acting as a skeletal muscle eQTL for the mitochondrial gene NDUFS4, suggesting a mechanism involving muscle bioenergetics. Conclusions: Findings indicate that FST polymorphisms associate with musculoskeletal traits in Northern Han Chinese. Mechanistic insights from functional annotation reveal potential pathways for these associations, highlighting the potential utility of these genetic markers for optimizing training program design.

We investigated whether calcium plus vitamin D supplementation interacts with polymorphisms in the VDR gene promoter region to affect changes on maternal bone mass from 5 to 20 wk postpartum in Brazilian adolescent mothers. Pregnant adolescents (14–19 y) randomly received calcium plus cholecalciferol (600 mg/d + 200 IU/d, n = 30) or placebo (n = 26) from 26 wk of pregnancy until parturition. Bone mineral content (BMC), bone area (BA), and bone mineral density (BMD) at total body, lumbar spine, total hip, and femoral neck were evaluated at 5 and 20 wk postpartum. Serum 25-hydroxyvitamin D (25[OH]D) and parathyroid hormone concentrations were measured. Real-time polymerase chain reaction was used for genotyping rs7139166 (1521 pb G > C) and rs4516035 (1012 pb A > G). Interactions between supplementation and polymorphisms were adjusted for significant covariates. Changes in serum 25(OH)D from pregnancy to postpartum differed between supplemented and placebo groups for mothers carrying 1521 GG/1012 AA genotypes (P = 0.004). Only in the placebo group, mothers carrying 1521 GG/1012 AA had greater reduction in total BMD z score, femoral neck BMC, and BMD from 5 to 20 wk postpartum compared with those with 1521 GC/1012 AG (P < 0.05). In the placebo group, total hip BA decreased from 5 to 20 wk postpartum in adolescents with 1521 GG/1012 AA, but increased in those with 1521 GC/1012 AG (P < 0.05), in contrast to the supplemented group. Calcium plus vitamin D supplementation during pregnancy interacted with polymorphisms in the VDR gene promoter region affecting postpartum bone loss. The increased supply of calcium and vitamin D appeared to minimize postpartum bone loss particularly in adolescents with 1521 GG/1012 AA. •Increased calcium (Ca) demand during pregnancy and lactation results in temporary bone loss.•Supplementation with Ca and vitamin D (Ca/D) during pregnancy reduces postpartum bone loss in adolescents.•Ca/D supplementation and vitamin D receptor gene single nucleotide polymorphisms interacted to affect postpartum bone loss.•Increased Ca supply appeared to minimize bone loss for some (but not all) genotypes.

To investigate the association between LRP5 gene polymorphisms and response to alendronate in Chinese osteoporotic women. Six hundred and thirty nine Chinese postmenopausal women with osteopenia or osteoporosis were included and received alendronate treatment. The A1330V polymorphism of LRP5 was investigated. Bone mineral density (BMD) and bone turnover markers (ALP and β-isomerized carboxy-telopeptide of type I collagen [β-CTX]) were measured before and after treatment. The correlation of LRP5 polymorphisms with changes in BMD and bone turnover biomarkers were analyzed after treatment. After 12 months of treatment, participants with CC and CT genotypes had a larger increase in lumbar spine BMD and a larger decrease in serum β-CTX and ALP levels than those with TT genotype (all p < 0.001). No significant genotype-treatment interaction was found in hip BMD. The A1330V polymorphism of LRP5 is possibly correlated with response to alendronate treatment in Chinese women with osteoporosis, and the TT genotype could possibly predict a weak response to alendronate.

Inter-individual response differences to vitamin D and Ca supplementation may be under genetic control through vitamin D and oestrogen receptor genes, which may influence their absorption and/or metabolism. Metabolomic studies on blood and urine from subjects supplemented with Ca and vitamin D reveal different metabolic profiles that segregate with genotype. Genotyping was performed for oestrogen receptor 1 gene (ESR1) and vitamin D receptor gene (VDR) in fifty-six postmenopausal women. Thirty-six women were classified as low bone density as determined by a heel ultrasound scan and twenty women had normal bone density acting as ‘controls’. Those with low bone density (LBD) were supplemented with oral Ca and vitamin D and were classified according to whether they were ‘responders’ or ‘non-responders’ according to biochemical results before and after therapy compared to controls receiving no supplementation. Metabolomic studies on serum and urine were done for the three groups at 0 and 3 months of therapy using NMR spectroscopy with pattern recognition. The ‘non-responder’ group showed a higher frequency of polymorphisms in the ESR1 (codons 10 and 325) and VDR (Bsm1 and Taq1), compared with to the ‘responders’. The wild-type genotype for Fok1 was more frequent in those with LBD (70 %) compared with the control group (10 %). Distinctive patterns of metabolites were displayed by NMR studies at baseline and 3 months of post-treatment, segregating responders from non-responders and controls. Identification of potential ‘non-responders’ to vitamin D and Ca, before therapy, based on a genomic and/or metabolomic profile would allow targeted selection of optimal therapy on an individual basis.

Background Osteoarthritis (OA) involves changes in both bone and cartilage. These processes might be associated under some circumstances. This study investigated correlations between bone and cartilage degradation in patients with OA as a function of sex, Kellgren-Lawrence (KL) score, Body Mass Index (BMI), oral salmon calcitonin (sCT) treatment and diurnal variation. Methods This study was a 2-week, double-blind, double-dummy, randomized study including 37 postmenopausal women and 36 men, aged 57-75 years, with painful knee OA, and a KL-score of I - III. Subjects were allocated to one of three treatment arms: 0.6 mg or 0.8 mg oral sCT, or placebo given twice-daily for 14 days. Correlations between gender, KL score, or BMI and the bone resorption marker, serum C-terminal telopeptide of collagen type I (CTX-I), or the cartilage degradation marker, urine C-terminal telopeptide of collagen type II (CTX-II) were investigated. Results At baseline, biomarkers indicated women with OA experienced higher bone and cartilage degradation than men. CTX-I levels were significantly higher, and CTX-II levels only marginally higher, in women than in men ( p = 0.04 and p = 0.06, respectively). Increasing KL score was not correlated with bone resorption, but was significantly associated with the cartilage degradation CTX-II marker in both men and women ( p = 0.007). BMI was significantly and negatively correlated to the bone resorption marker CTX-I, r = -0.40 ( p = 0.002), but showed only a borderline positive correlation to CTX-II, r = 0.25 ( p = 0.12). Before morning treatments on days 1 and 14, no correlation was seen between CTX-I and CTX-II in either the sCT or placebo group. However, oral sCT and food intake induced a clear correlation between these bone and cartilage degradation markers. Four hours after the first sCT dose on treatment days 1 and 14, a significant correlation (r = 0.71, p < 0.001) between changes in both CTX-I and CTX-II was seen. In the placebo group a weakly significant correlation between changes in both markers was found on day 1 (r = 0.49, p = 0.02), but not on day 14. Conclusion Bone resorption was higher in females than males, while cartilage degradation was correlated with increasing KL-score and only weakly associated with BMI. Bone and cartilage degradation were not correlated in untreated individuals, but dosing with oral sCT with or without food, and a mid-day meal, decreased bone and cartilage degradation and induced a correlation between both markers. Changes in bone and cartilage markers may aid in the identification of potential new treatment opportunities for OA. Trial Registration Clinical trial registration number (EUDRACT2006-005532-24 & NCT00486369)