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Genetic predisposition to increased serum calcium, bone mineral density, and fracture risk in individuals with normal calcium levels: mendelian randomisation study
McGill Univ, Jewish Gen Hosp, Lady Davis Inst, Montreal, PQ, Canada;McGill Univ, Dept Epidemiol Biostat & Occupat Hlth, 3755 Cote Ste Catherine Rd,Suite H-413, Montreal, PQ H3T 1E2, Canada.
McGill Univ, Jewish Gen Hosp, Lady Davis Inst, Montreal, PQ, Canada;McGill Univ, Dept Epidemiol Biostat & Occupat Hlth, 3755 Cote Ste Catherine Rd,Suite H-413, Montreal, PQ H3T 1E2, Canada.
McGill Univ, Jewish Gen Hosp, Lady Davis Inst, Montreal, PQ, Canada.
McGill Univ, Jewish Gen Hosp, Lady Davis Inst, Montreal, PQ, Canada;McGill Univ, Dept Human Genet, Montreal, PQ, Canada.
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2019 (English)In: BMJ. British Medical Journal, E-ISSN 1756-1833, Vol. 366, article id l4410Article in journal (Refereed) Published
Abstract [en]

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 metaanalysis 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.

Place, publisher, year, edition, pages
BMJ PUBLISHING GROUP , 2019. Vol. 366, article id l4410
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Public Health, Global Health, Social Medicine and Epidemiology
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URN: urn:nbn:se:uu:diva-392134DOI: 10.1136/bmj.l4410ISI: 000479164000001PubMedID: 31371314OAI: oai:DiVA.org:uu-392134DiVA, id: diva2:1347860
Available from: 2019-09-02 Created: 2019-09-02 Last updated: 2019-09-02Bibliographically approved

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