scholarly journals GWAS META-analysis followed by MENDELIAN randomisation revealed potential control mechanisms for circulating α-klotho levels

2021 ◽  
Author(s):  
Ingrid Gergei ◽  
Jie Zheng ◽  
Till F M Andlauer ◽  
Vincent Brandenburg ◽  
Nazanin Mirza-Schreiber ◽  
...  
Keyword(s):  
Disease Risk ◽  
Meta Analysis ◽  
Fibroblast Growth Factor 23 ◽  
Genetic Correlations ◽  
Mendelian Randomisation ◽  
Control Mechanisms ◽  
Post Translational Modification ◽  
Mineral Density ◽  
Phosphate Homeostasis ◽  
Fgf 23

Abstract Background The protein α-Klotho acts as transmembrane the co-receptor for fibroblast growth factor 23 (FGF-23) and is a key regulator of phosphate homeostasis. However, α-Klotho also exists in a circulating form, with pleiotropic, but incompletely understood functions and regulation. Therefore, we undertook a GWAS meta-analysis followed by Mendelian randomisation (MR) of circulating α-Klotho levels. Methods Plasma α-Klotho levels were measured by ELISA in the LURIC and ALSPAC (mothers) cohorts, followed by a GWAS meta-analysis in 4376 individuals across the two cohorts. Results Six signals at five loci were associated with circulating α-Klotho levels at genome-wide significance (p < 5 × 10−8), namely ABO, KL, FGFR1, and two post-translational modification genes, B4GALNT3 and CHST9. Together, these loci explained > 9% of the variation in circulating α-Klotho levels. MR analyses revealed no causal relationships between α-Klotho and renal function, FGF-23-dependent factors such as vitamin D and phosphate levels, or bone mineral density. The screening for genetic correlations with other phenotypes, followed by targeted MR suggested causal effects of liability of Crohn’s disease risk [IVW beta = 0.059 (95% CI 0.026, 0.093)] and low-density lipoprotein cholesterol (LDL-C) levels [−0.198, (−0.332, −0.063)] on α-Klotho. Conclusions Our GWAS findings suggest that two enzymes involved in post-translational modification, B4GALNT3 and CHST9, contribute to genetic influences on α-Klotho levels, presumably by affecting protein turnover and stability. Subsequent evidence from MR analyses on α-Klotho levels suggest regulation by mechanisms besides phosphate-homeostasis and raise the possibility of cross-talk with FGF19- and FGF21-dependent pathways, respectively.

scholarly journals The Serum Level of Fibroblast Growth Factor-23 and Calcium-Phosphate Homeostasis in Obese Perimenopausal Women

2011 ◽  
Vol 2011 ◽  
pp. 1-5 ◽  
Author(s):  
M. Holecki ◽  
J. Chudek ◽  
A. Więcek ◽  
M. Titz-Bober ◽  
J. Duława
Keyword(s):  
Calcium Phosphate ◽  
Bone Turnover ◽  
Fibroblast Growth Factor 23 ◽  
Elevated Serum ◽  
Serum Phosphorus ◽  
Obese Women ◽  
Mineral Density ◽  
Phosphate Homeostasis ◽  
Hydroxyvitamin D ◽  
Fgf 23

Plasma FGF-23 concentrations and its relationship with calcium-phosphate homeostasis were evaluated in 48 perimenopausal obese women and in 29 nonobese controls. Serum parathyroid hormone, 25-hydroxyvitamin D3, CTX1, osteocalcin, total calcium, phosphorus, creatinine, and plasma intact FGF-23 concentrations were assessed. DXA of lumbar spine and femoral neck was performed to determine bone mineral density (BMD). Plasma iFGF-23 concentration was significantly higher in obese patients (by 42%) and correlated with age and BMD of proximal femur (R=-0.346;R=0.285, resp.) but not with markers of bone turnover. However, serum phosphorus level in obese subjects was significantly lower. iFGF-23 concentration correlated significantly with body mass index (R=0.292) and fat content (R=0.259) in all study subjects. Moreover, a significant correlation between iFGF-23 and iPTH (R=0.254) was found. No correlation between serum phosphorus or eGFR and plasma iFGF-23 and between eGFR and serum phosphorus was found. Elevated serum iFGF-23 concentration may partially explain lower phosphorus levels in the obese and seems not to reflect bone turnover.

scholarly journals Genetic meta-analysis identifies 9 novel loci and functional pathways for Alzheimer’s disease risk

2018 ◽  
Author(s):  
Iris E Jansen ◽  
Jeanne E Savage ◽  
Kyoko Watanabe ◽  
Julien Bryois ◽  
Dylan M Williams ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genome Wide Association Study ◽  
Disease Risk ◽  
Late Onset ◽  
Meta Analysis ◽  
Genetic Correlations ◽  
Cell Types ◽  
Mendelian Randomisation ◽  
Genome Wide

AbstractLate onset Alzheimer’s disease (AD) is the most common form of dementia with more than 35 million people affected worldwide, and no curative treatment available. AD is highly heritable and recent genome-wide meta-analyses have identified over 20 genomic loci associated with AD, yet only explaining a small proportion of the genetic variance indicating that undiscovered loci exist. Here, we performed the largest genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 AD cases, 383,378 controls). AD-by-proxy status is based on parental AD diagnosis, and showed strong genetic correlation with AD (rg=0.81). Genetic meta analysis identified 29 risk loci, of which 9 are novel, and implicating 215 potential causative genes. Independent replication further supports these novel loci in AD. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver and microglia). Furthermore, gene-set analyses indicate the genetic contribution of biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomisation results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying more of the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD to guide new drug development.

scholarly journals Genetic predisposition to increased serum calcium, bone mineral density, and fracture risk in individuals with normal calcium levels: mendelian randomisation study

BMJ ◽  
2019 ◽  
pp. l4410 ◽  
Author(s):  
Agustin Cerani ◽  
Sirui Zhou ◽  
Vincenzo Forgetta ◽  
John A Morris ◽  
Katerina Trajanoska ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Bone Mineral ◽  
Serum Calcium ◽  
Genetic Predisposition ◽  
Calcium Supplementation ◽  
Meta Analysis ◽  
Mendelian Randomisation ◽  
Uk Biobank ◽  
Mineral Density ◽  
The Uk

Abstract Objective To determine if genetically increased serum calcium levels are associated with improved bone mineral density and a reduction in osteoporotic fractures. Design Mendelian randomisation study. Setting Cohorts used included: the UK Biobank cohort, providing genotypic and estimated bone mineral density data; 25 cohorts from UK, USA, Europe, and China, providing genotypic and fracture data; and 17 cohorts from Europe, providing genotypic and serum calcium data (summary level statistics). Participants A genome-wide association meta-analysis of serum calcium levels in up to 61 079 individuals was used to identify genetic determinants of serum calcium levels. The UK Biobank study was used to assess the association of genetic predisposition to increased serum calcium with estimated bone mineral density derived from heel ultrasound in 426 824 individuals who had, on average, calcium levels in the normal range. A fracture genome-wide association meta-analysis comprising 24 cohorts and the UK Biobank including a total of 76 549 cases and 470 164 controls, who, on average, also had calcium levels in the normal range was then performed. Results A standard deviation increase in genetically derived serum calcium (0.13 mmol/L or 0.51 mg/dL) was not associated with increased estimated bone mineral density (0.003 g/cm 2 , 95% confidence interval −0.059 to 0.066; P=0.92) or a reduced risk of fractures (odds ratio 1.01, 95% confidence interval 0.89 to 1.15; P=0.85) in inverse-variance weighted mendelian randomisation analyses. Sensitivity analyses did not provide evidence of pleiotropic effects. Conclusions Genetic predisposition to increased serum calcium levels in individuals with normal calcium levels is not associated with an increase in estimated bone mineral density and does not provide clinically relevant protection against fracture. Whether such predisposition mimics the effect of short term calcium supplementation is not known. Given that the same genetically derived increase in serum calcium is associated with an increased risk of coronary artery disease, widespread calcium supplementation in the general population could provide more risk than benefit.

scholarly journals P0869EXOGENOUS OSTEOGENIC FACTOR 1 ADMINISTRATION ATTENUATED VASCULAR CALCIFICATION AND IMPROVED BONE DISORDERS IN CHRONIC UREMIC RATS

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Chien-Te Lee ◽  
Hwee-Yeong Ng ◽  
Wen-Lin Chen ◽  
Yuai-Ting Lee
Keyword(s):  
Renal Failure ◽  
Vascular Calcification ◽  
Fibroblast Growth Factor 23 ◽  
Mineral Density ◽  
Bone Disorders ◽  
Trabecular Thickness ◽  
Bony Structure ◽  
Significant Difference ◽  
Fgf 23 ◽  
Osteogenic Factor

Abstract Background and Aims Hyperphosphatemia and secondary hyperparathyroidism are frequent complications in chronic kidney disease (CKD) which both contribute to increased morbidity and mortality in CKD. Osteogenic factor-1 (OP-1) is an important member of BMPs subfamily and its effects on CKD-associated mineral and bone disorders (MBD) is controversial. The study examined whether exogenous OP-1 administration can modulate disturbed CKD-MBD in adenine-induced chronic uremic rats Method Chronic renal failure was induced in adult male SD rats by feeding adenine-containing diet. After adenine diet feeding 3 weeks, animals were injected with OP-1 (5μg/kg/day) intraperitoneally for 2 weeks. The serum and urine phosphorus levels and associated mineral parameters, including fibroblast growth factor 23(FGF-23), DKK-1 and sclerostin were measured. Vascular calcification was assessed by immunohistochemistry staining on aortic tissue. Bony structure was evaluated by microCT (Bruker-microCT, Kontich, Belgium). Results A significant decrease of body weight and deteriorated renal function was observed in adenine and OP-1 treatment groups during study period and serum creatinine levels were similar (5.23 ±1.1 mg/dL vs. 5.4 ±1.2 mg/dL, p>0.05). Animals in OP-1 group had lower serum phosphorous (18.7±5.1 vs. 29.0±9.6 mg/dL, p<0.05) and intact parathyroid hormone levels (2906.1±1206.9 vs. 4669.7±2505.9 pg/dL, p<0.05) compared to adenine group. Decreased urine phosphorous excretion was noted in both groups without significant difference. Levels of serum FGF-23, sclerostin and DKK-1 were significantly lower in OP-1 treatment group (all p< 0.05). OP-1 administration diminished the staining of RUNX2 (59.1±3% of adenine-treated group), alkaline-phosphatase (49.4±5.7%), β-caterin (39.3±1.8%), BMP2 (43.2%±6.7%), and BMP7 (51.9±10%, all p <0.05). MicroCT revealed that bone mineral density was increased by OP-1 treatment (0.46±0.1 vs.0.39±0.06 g/cm3). Total volume was increased but bone volume was not changed. OP-1 administration did not affect trabecular thickness and trabecular number. Conclusion Our data indicated administration of exogenous OP-1 improved hyperparathyroidism and attenuated vascular calcification. OP-1 treatment was also associated with beneficial effects on bony structure in animals with renal failure.

scholarly journals Effect of empagliflozin on phosphorus and calcium metabolism in patients with type 2 diabetes mellitus with preserved kidney function

2021 ◽  
Vol 24 (1) ◽  
pp. 4-9
Author(s):  
D. A. Lebedev ◽  
N. V. Timkina ◽  
T. L. Karonova ◽  
A. T. Andreeva ◽  
M. A. Kokina ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Kidney Function ◽  
Trabecular Bone Score ◽  
Fibroblast Growth Factor 23 ◽  
Mineral Density ◽  
Increased Risk ◽  
Fgf 23

Background: Sodium glucose co-transporter type 2 inhibitors (iSGLT2) are antihyperglycemic drugs approved for the treatment of type 2 diabetes mellitus (T2DM). Clinical trials with these drugs have shown evidence of an increased risk of fractures and an effect on phosphorus, vitamin D and parathyroid hormone (PTH) levels.Aim: The aim of this study was to investigate the effect of the most selective iSGLT2 empagliflozin on the calcium and phosphorus metabolism in patients with T2DM and preserved kidney function.Materials and methods: Thirty-nine T2DM patients were received empagliflozin 10 mg in addition to their antihyperglycemic drugs for 12 weeks. Before starting treatment, a dual-energy X-ray absorptiometry (DXA) with an assessment of the trabecular bone score (TBS) was performed. The concentration of phosphorus (P), total (tCa) and ionized calcium (Ca++), fibroblast growth factor 23 (FGF-23), 25(OH)D and PTH were assessed.Results: According to the DXA results, only 2 patients had osteoporosis, 10 (25.6%) patients had bone mineral density (BMD) values below 1.35 g /cm2 on the TCI scale. Treatment with empagliflozin for 12 weeks was lead to significant increase in FGF-23. Compared to the baseline level, there were no statistically significant differences in the concentrations of P, oCa, Ca++, PTH and 25(OH)D after 12 weeks of treatment. The level of FGF-23 did not correlate with the level of glomerular filtration rate either before or after treatment (r = 0.31, p = 0.27 and r = 0.39, p = 0.55, respectively). In addition, baseline BMD adjusted for TBS and baseline 25(OH)D did not correlate with Ca, F, FGF-23, and PTH concentrations (p>0.05).Conclusion: Thus, empagliflozin has increased the level of FGF-23 without significant changes in the concentration of phosphorus, calcium, 25 (OH) D, and PTH after 12 weeks of treatment in patients with T2DM and preserved renal function. The obtained data confirmed the necessity to assess the TBS in patients with T2DM, because it’s provide additional information on the quality of bone tissue.

scholarly journals Tumor-induced osteomalacia with the culprit lesion located in the palm: a case report

2019 ◽  
Vol 47 (5) ◽  
pp. 2240-2247
Author(s):  
Yanying Qian ◽  
Zhijuan Dai ◽  
Cong Zhu ◽  
Luya Ruan ◽  
Saroj Thapa ◽  
...  
Keyword(s):  
Fibroblast Growth Factor 23 ◽  
Elevated Serum ◽  
Serum Phosphorus ◽  
Postoperative Phase ◽  
Phosphorus Level ◽  
Serum Phosphorus Level ◽  
Mineral Density ◽  
Metacarpal Bones ◽  
The Right ◽  
Fgf 23

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome. We herein report a rare case of TIO in a 58-year-old Chinese man who presented with a large lump in the right palm. Clinical, biochemical, and radiological assessments were performed. Laboratory examination showed severe hypophosphatemia, phosphaturia, an elevated serum alkaline phosphatase level, and an elevated serum fibroblast growth factor 23 (FGF-23) level. Dual-energy X-ray absorptiometry showed low bone mineral density. Magnetic resonance imaging revealed an irregular mass located in the right palm and abnormal findings in several metacarpal bones. During the operation, the surgeons found that the tumor had penetrated the surrounding muscles. The tumor had unique characteristics of local tissue invasion. The patient’s symptoms fully resolved and his serum phosphorus level normalized, although his serum FGF-23 level remained slightly high in the postoperative phase. Our findings suggest that in some patients with TIO, the serum phosphorus level might return to the normal range despite a relatively high postoperative serum FGF-23 level. These patients should be kept under close observation and regularly surveyed for any evidence of a residual tumor.

Plasma levels of the anti-coagulation protein C and the risk of ischaemic heart disease

2017 ◽  
Vol 117 (02) ◽  
pp. 262-268 ◽  
Author(s):  
C. Mary Schooling ◽  
Yi Zhong
Keyword(s):  
Cardiovascular Disease ◽  
Heart Disease ◽  
Ischaemic Heart Disease ◽  
Protein C ◽  
Disease Risk ◽  
Meta Analysis ◽  
Cardiovascular Disease Risk ◽  
Mendelian Randomisation ◽  
Instrumental Variable Analysis ◽  
Artery Disease

SummaryProtein C is an environmentally modifiable anticoagulant, which protects against venous thrombosis, whether it also protects against ischaemic heart disease is unclear, based on observational studies and relatively small genetic studies. It was our study aim to clarify the role of protein C in ischaemic heart disease. The risk of coronary artery disease/myocardial infarction (CAD/MI) was assessed according to genetically predicted protein C in very large studies. Associations with lipids and diabetes were similarly assessed to rule out effects via traditional cardiovascular disease risk factors. Separate sample instrumental variable analysis with genetic instruments (Mendelian randomisation) was used to obtain an unconfounded estimate of the association of protein C (based on (rs867186 (PROCR), rs3746429 (EDEM2), rs7580658 (inter/PROC)) with CAD/MI in an extensively genotyped case (n=64374)-control (n=130681) study, CARDIoGRAMplusC4D. Associations with lipids and diabetes were similarly assessed using the Global Lipids Genetics Consortium Results (n=196,475) and the DIAbetes Genetics Replication And Meta-analysis case (n=34,380)-control (n=114,981) study. Genetically predicted protein C was negatively associated with CAD/MI, odds ratio (OR) 0.85 µg/ml, 95 % confidence interval 0.80 to 0.90, but had no such negative association with lipids or diabetes. Results were similar for the SNP rs867186 functionally relevant to protein C, and including additional potentially pleiotropic SNPs (rs1260326 (GCKR), rs17145713 (BAZ1B) and rs4321325 (CYP27C1)). In conclusion, protein C may protect against CAD/MI. Whether environmental or dietary items that raise protein C protect against ischaemic cardiovascular disease by that mechanism should be investigated.Supplementary Material to this article is available online at www.thrombosis-online.com.

scholarly journals Mendelian Randomization analysis reveals a causal influence of circulating sclerostin levels on bone mineral density and fractures

2018 ◽  
Author(s):  
Jie Zheng ◽  
Winfried Maerz ◽  
Ingrid Gergei ◽  
Marcus Kleber ◽  
Christiane Drechsler ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Femoral Neck ◽  
Fracture Risk ◽  
Bone Mineral ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Mendelian Randomisation ◽  
Adaptive Responses ◽  
Mineral Density ◽  
A Genome

ABSTRACTIn bone, sclerostin is mainly osteocyte-derived and plays an important local role in adaptive responses to mechanical loading. Whether circulating levels of sclerostin also play a functional role is currently unclear, which we aimed to examine by two sample Mendelian Randomisation (MR). A genetic instrument for circulating sclerostin, derived from a genome wide association study (GWAS) meta-analysis of serum sclerostin in 10,584 European-descent individuals, was examined in relation to femoral neck bone mineral density (BMD; n= 32,744) in GEFOS, and estimated BMD by heel ultrasound (eBMD; n=426,824), and fracture risk (n=426,795), in UK Biobank. Our GWAS identified two novel serum sclerostin loci, B4GALNT3 (standard deviation (SD)) change in sclerostin per A allele (β=0.20, P=4.6×10−49), and GALNT1 (β=0.11 per G allele, P=4.4×10−11). B4GALNT3 is an N-acetyl-galactosaminyltransferase, adding a terminal LacdiNAc disaccharide to target glycocoproteins, found to be predominantly expressed in kidney, whereas GALNT1 is an enzyme causing mucin-type O-linked glycosylation. Using these two SNPs as genetic instruments, MR revealed an inverse causal relationship between serum sclerostin and femoral neck BMD (β= −0.12, 95%CI= −0.20 to −0.05) and eBMD (β= −0.12, 95%CI= −0.14 to −0.10), and a positive relationship with fracture risk (β= 0.11, 95%CI= 0.01 to 0.21). Colocalization analysis demonstrated common genetic signals within the B4GALNT3 locus for higher sclerostin, lower eBMD, and greater B4GALNT3 expression in arterial tissue (Probability>99%). Our findings suggest that higher sclerostin levels are causally related to lower BMD and greater fracture risk. Hence, strategies for reducing circulating sclerostin, for example by targeting glycosylation enzymes as suggested by our GWAS results, may prove valuable in treating osteoporosis.

scholarly journals Fibroblast Growth Factor-23 and Risks of Cardiovascular and Noncardiovascular Diseases: A Meta-Analysis

2018 ◽  
Vol 29 (7) ◽  
pp. 2015-2027 ◽  
Author(s):  
Amarnath Marthi ◽  
Killian Donovan ◽  
Richard Haynes ◽  
David C. Wheeler ◽  
Colin Baigent ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Disease Risk ◽  
Fibroblast Growth Factor 23 ◽  
Cardiovascular Disease Risk ◽  
Fibroblast Growth ◽  
Adjusted Risk ◽  
Increased Risk ◽  
Fgf 23

Background Fibroblast growth factor-23 (FGF-23) has been hypothesized to play a role in the increased risk of cardiovascular disease in patients with CKD.Methods We identified prospective studies reporting associations between FGF-23 concentration and risk of cardiovascular events. Maximally adjusted risk ratios (RRs) were extracted for each outcome and scaled to a comparison of the top versus bottom third of the baseline FGF-23 concentration, and the results aggregated.Results Depending on the assay used, median FGF-23 concentrations were 43–74 RU/ml and 38–47 pg/ml in 17 general population cohorts; 102–392 RU/ml in nine cohorts of patients with CKD not requiring dialysis; and 79–4212 RU/ml and 2526–5555 pg/ml in eight cohorts of patients on dialysis. Overall, comparing participants in the top and bottom FGF-23 concentration thirds, the summary RRs (95% confidence intervals [95% CIs]) were 1.33 (1.12 to 1.58) for myocardial infarction, 1.26 (1.13 to 1.41) for stroke, 1.48 (1.29 to 1.69) for heart failure, 1.42 (1.27 to 1.60) for cardiovascular mortality, and 1.70 (1.52 to 1.91) for all-cause mortality. The summary RR for noncardiovascular mortality, calculated indirectly, was 1.52 (95% CI, 1.28 to 1.79). When studies were ordered by average differences in FGF-23 concentration between the top and bottom thirds, there was no trend in RRs across the studies.Conclusions The similarly-sized associations between increased FGF-23 concentration and cardiovascular (atherosclerotic and nonatherosclerotic) and noncardiovascular outcomes, together with the absence of any exposure–response relationship, suggest that the relationship between FGF-23 and cardiovascular disease risk may be noncausal.

scholarly journals Fasting glucose, bone area and bone mineral density: a Mendelian randomisation study

Diabetologia ◽  
2021 ◽  
Author(s):  
Adam Mitchell ◽  
Susanna C. Larsson ◽  
Tove Fall ◽  
Håkan Melhus ◽  
Karl Michaëlsson ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Bone Mineral ◽  
Fasting Glucose ◽  
Meta Analysis ◽  
Statistical Significance ◽  
Mendelian Randomisation ◽  
Bone Area ◽  
Mineral Density ◽  
Total Hip ◽  
Glucose Levels

Abstract Aims/hypothesis Observational studies indicate that type 2 diabetes mellitus and fasting glucose levels are associated with a greater risk for hip fracture, smaller bone area and higher bone mineral density (BMD). However, these findings may be biased by residual confounding and reverse causation. Mendelian randomisation (MR) utilises genetic variants as instruments for exposures in an attempt to address these biases. Thus, we implemented MR to determine whether fasting glucose levels in individuals without diabetes are causally associated with bone area and BMD at the total hip. Methods We selected 35 SNPs strongly associated with fasting glucose (p < 5 × 10−8) in a non-diabetic European-descent population from the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) (n = 133,010). MR was used to assess the associations of genetically predicted fasting glucose concentrations with total hip bone area and BMD in 4966 men and women without diabetes from the Swedish Mammography Cohort, Prospective Investigation of Vasculature in Uppsala Seniors and Uppsala Longitudinal Study of Adult Men. Results In a meta-analysis of the three cohorts, a genetically predicted 1 mmol/l increment of fasting glucose was associated with a 2% smaller total hip bone area (−0.67 cm2 [95% CI −1.30, −0.03; p = 0.039]), yet was also associated, albeit without reaching statistical significance, with a 4% higher total hip BMD (0.040 g/cm2 [95% CI −0.00, 0.07; p = 0.060]). Conclusions/interpretation Fasting glucose may be a causal risk factor for smaller bone area at the hip, yet possibly for greater BMD. Further MR studies with larger sample sizes are required to corroborate these findings. Graphical abstract

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