Hyperthyroidism and bone mineral density: Dissecting the causal association with Mendelian randomization analysis

Recent cohort studies indicate a potential role of the antioxidant α-tocopherol in reducing bone loss and risk of fractures, especially hip fractures. We performed a Mendelian randomization investigation of the associations of circulating α-tocopherol with estimated bone mineral density (eBMD) using heel ultrasound and fractures, identified from hospital records or by self-reports and excluding minor fractures. Circulating α-tocopherol was instrumented by three genetic variants associated with α-tocopherol levels at p < 5 × 10−8 in a genome-wide association meta-analysis of 7781 participants of European ancestry. Summary-level data for the genetic associations with eBMD in 426,824 individuals and with fracture (53,184 cases and 373,611 non-cases) were acquired from the UK Biobank. Two of the three genetic variants were strongly associated with eBMD. In inverse-variance weighted analysis, a genetically predicted one-standard-deviation increase of circulating α-tocopherol was associated with 0.07 (95% confidence interval, 0.05 to 0.09) g/cm2 increase in BMD, which corresponds to a >10% higher BMD. Genetically predicted circulating α-tocopherol was not associated with odds of any fracture (odds ratio 0.97, 95% confidence interval, 0.91 to 1.05). In conclusion, our results strongly strengthen a causal link between increased circulating α-tocopherol and greater BMD. Both an intervention study in those with a low dietary intake of α-tocopherol is warranted and a Mendelian randomization study with fragility fractures as an outcome.

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Association of sleep traits and heel bone mineral density: Observational and Mendelian randomization studies

Journal of Bone and Mineral Research ◽

10.1002/jbmr.4406 ◽

2021 ◽

Author(s):

Jie Chen ◽

Jihui Zhang ◽

Hon‐Cheong So ◽

Sizhi Ai ◽

Ningjian Wang ◽

...

Keyword(s):

Bone Mineral Density ◽

Bone Mineral ◽

Mendelian Randomization ◽

Mineral Density ◽

Heel Bone

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The effect of plasma lipids and lipid lowering interventions on bone mineral density: a Mendelian randomization study

10.1101/480426 ◽

2018 ◽

Cited By ~ 3

Author(s):

Jie Zheng ◽

Marie-Jo Brion ◽

John P. Kemp ◽

Nicole M. Warrington ◽

Maria-Carolina Borges ◽

...

Keyword(s):

Bone Mineral Density ◽

Standard Deviation ◽

Bone Mineral ◽

Mendelian Randomization ◽

Causal Effect ◽

Plasma Lipid ◽

Density Lipoprotein ◽

Lipid Lowering ◽

Lipid Levels ◽

Mineral Density

AbstractStatin treatment increases bone mineral density (BMD) and reduces fracture risk, but the underlying mechanism is unclear. We used Mendelian randomization (MR) to assess whether this relation is explained by a specific effect in response to statin use, or by a general effect of lipid-lowering. We utilized 400 single nucleotide polymorphisms (SNPs) robustly associated with plasma lipid levels and results from a heel BMD GWAS (derived from quantitative ultrasound) in 426,824 individuals from the UK Biobank. We performed univariate and multivariable MR analyses of low-density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) and triglyceride levels on BMD. To test whether the effect of statins on BMD was mediated by lowering lipid levels, MR was repeated with and without SNPs in theHMGCRregion, the gene targeted by statins. Univariate MR analyses provided evidence for a causal effect of LDL-C on BMD (β= −0.060; −0.084 to −0.036; P = 4×10-6; standard deviation change in BMD per standard deviation change in LDL-C, with 95% CI), but not HDL or triglycerides. Multivariable MR analysis suggested that the effect of LDL-C on BMD was independent of HDL-C and triglycerides, and sensitivity analyses involving MR Egger and weighted median MR approaches suggested that the LDL-C results were robust to pleiotropy. MR analyses of LDL-C restricted to SNPs in theHMGCRregion showed similar effects on BMD(β= −0.083; −0.132 to −0.034; P = 0.001) to those excluding these SNPs (β= −0.063; −0.090 to −0.036; P = 8×10-6). Bidirectional MR analyses provided some evidence for a causal effect of BMD on plasma LDL-C levels. Our results suggest that effects of statins on BMD are at least partly due to their LDL-C lowering effect. Further studies are required to examine the potential role of modifying plasma lipid levels in treating osteoporosis.

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