Dataset Information

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

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/cm2, 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.

SUBMITTER: Cerani A

PROVIDER: S-EPMC6669416 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Cerani Agustin A Zhou Sirui S Forgetta Vincenzo V Morris John A JA Trajanoska Katerina K Rivadeneira Fernando F Larsson Susanna C SC Michaëlsson Karl K Richards J Brent JB

BMJ (Clinical research ed.) 20190801

<h4>Objective</h4>To determine if genetically increased serum calcium levels are associated with improved bone mineral density and a reduction in osteoporotic fractures.<h4>Design</h4>Mendelian randomisation study.<h4>Setting</h4>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 ...[more]

PMID: 31371314

Similar Datasets

Project description:BackgroundThe associations between visceral adipose tissue (VAT) and bone mineral density (BMD) or fracture have been controversial and the causality of the associations remains to be assessed. This study aimed to explore the associations of VAT^ (predicted value of VAT mass) with BMD and fracture risk in men and women, and to examine their potential causation by two-sample Mendelian randomization (MR) analyses.MethodsUK Biobank is a large, population-based prospective cohort study that recruited more than 500,000 participants aged 40-69 in the United Kingdom from 2006 to 2010. In this study, we used a validated and reliable prediction model to estimate the VAT amount of the participants. On this basis, linear and nonlinear multivariable statistical models were used to explore the association of VAT^ with BMD and fracture risk in different groups of sex and BMI. In observational analyses, the multivariable linear regression model and Cox proportional-hazards model were used to assess VAT^ association with BMD and fracture risk, respectively. Inverse variance weighting was used as the main result of MR analysis.ResultsIn 190,836 men, an inverted U-shaped association was observed between VAT^ and heel BMD (P for nonlinearity < 0.001), with a turning point of VAT^ = 1.25 kg. Per kg increase in VAT^ was associated with a 0.13 standard deviation (SD) increase in heel BMD (P = 1.5 × 10-16) among men with lower amounts of VAT^, and associated with a 0.05 SD decrease in heel BMD (P = 1.3 × 10-15) among men with higher amounts of VAT^. In 193,592 women, per kg increase in VAT^ was monotonically associated with a 0.16 SD increase in heel BMD (P = 1.2 × 10-136, P for VAT^-sex interaction = 8.4 × 10-51). During a median follow-up of 8.2 years, VAT^ was associated with lower risks of hip fractures in the overall men and women (P for VAT^-sex interaction = 1.9 × 10-4 for total fractures; 1.5 × 10-4 for other fractures). There were significant interactions of VAT^ and BMI on heel BMD and fracture risks in men only (P for VAT^-BMI interaction = 5.9 × 10-31 for heel BMD; 2.7 × 10-4 for total fractures; 5.7 × 10-3 for hip fractures; 6.8 × 10-3 for other fractures). In two-sample MR analyses, evidence of causality was not observed between VAT^ and DXA-derived BMD or fractures.ConclusionsThese novel findings demonstrated gender-dependent associations of VAT^ with BMD and fracture risk, with the association in men being modified by adiposity. Evidence of causality was not observed, suggesting that the observational association of VAT^ with BMD and fracture risk could be the result of confounding.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets