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Genetically Low Vitamin D Levels, Bone Mineral Density, and Bone Metabolism Markers: a Mendelian Randomisation Study.

ABSTRACT: Low serum 25-hydroxyvitamin D (25OHD) is associated with osteoporosis and osteoporotic fracture, but it remains uncertain whether these associations are causal. We conducted a Mendelian randomization (MR) study of 1,824 postmenopausal Chinese women to examine whether the detected associations between serum 25OHD and bone mineral density (BMD) and bone metabolism markers were causal. In observational analyses, total serum 25OHD was positively associated with BMD at lumbar spine (P?=?0.003), femoral neck (P?=?0.006) and total hip (P?=?0.005), and was inversely associated with intact parathyroid hormone (PTH) (P?=?8.18E-09) and procollagen type 1 N-terminal propeptide (P1NP) (P?=?0.020). By contract, the associations of bioavailable and free 25OHD with all tested outcomes were negligible (all P?>?0.05). The use of four single nucleotide polymorphisms, GC-rs2282679, NADSYN1-rs12785878, CYP2R1-rs10741657 and CYP24A1-rs6013897, as candidate instrumental variables in MR analyses showed that none of the two stage least squares models provided evidence for associations between serum 25OHD and either BMD or bone metabolism markers (all P?>?0.05). We suggest that after controlling for unidentified confounding factors in MR analyses, the associations between genetically low serum 25OHD and BMD and bone metabolism markers are unlikely to be causal.

SUBMITTER: Li SS

PROVIDER: S-EPMC5021966 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Genetically Low Vitamin D Levels, Bone Mineral Density, and Bone Metabolism Markers: a Mendelian Randomisation Study.

Li Shan-Shan SS Gao Li-Hong LH Zhang Xiao-Ya XY He Jin-We JW Fu Wen-Zhen WZ Liu Yu-Juan YJ Hu Yun-Qiu YQ Zhang Zhen-Lin ZL

Scientific reports 20160914

Low serum 25-hydroxyvitamin D (25OHD) is associated with osteoporosis and osteoporotic fracture, but it remains uncertain whether these associations are causal. We conducted a Mendelian randomization (MR) study of 1,824 postmenopausal Chinese women to examine whether the detected associations between serum 25OHD and bone mineral density (BMD) and bone metabolism markers were causal. In observational analyses, total serum 25OHD was positively associated with BMD at lumbar spine (P = 0.003), femor ...[more]

PMID: 27625044

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Project description:PurposeA Disintegrin and Metalloproteinase (ADAM) and A Disintegrin and Metalloproteinase with Thrombospondin Motif (ADAMTS) have been reported potentially involved in bone metabolism and related to bone mineral density. This Mendelian Randomization (MR) analysis was performed to determine whether there are causal associations of serum ADAM/ADAMTS with BMD in rid of confounders.MethodsThe genome-wide summary statistics of four site-specific BMD measurements were obtained from studies in individuals of European ancestry, including forearm (n = 8,143), femoral neck (n = 32,735), lumbar spine (n = 28,498) and heel (n = 426,824). The genetic instrumental variables for circulating levels of ADAM12, ADAM19, ADAM23, ADAMTS5 and ADAMTS6 were retrieved from the latest genome-wide association study of European ancestry (n = 5336 ~ 5367). The estimated causal effect was given by the Wald ratio for each variant, the inverse-variance weighted model was used as the primary approach to combine estimates from multiple instruments, and sensitivity analyses were conducted to assess the robustness of MR results. The Bonferroni-corrected significance was set at P < 0.0025 to account for multiple testing, and a lenient threshold P < 0.05 was considered to suggest a causal relationship.ResultsThe causal effects of genetically predicted serum ADAM/ADAMTS levels on BMD measurements at forearm, femoral neck and lumbar spine were not statistically supported by MR analyses. Although causal effect of ADAMTS5 on heel BMD given by the primary MR analysis (β = -0.006, -0.010 to 0.002, P = 0.004) failed to reach Bonferroni-corrected significance, additional MR approaches and sensitivity analyses indicated a robust causal relationship.ConclusionOur study provided suggestive evidence for the causal effect of higher serum levels of ADAMTS5 on decreased heel BMD, while there was no supportive evidence for the associations of ADAM12, ADAM19, ADAM23, and ADAMTS6 with BMD at forearm, femoral neck and lumbar spine in Europeans.

Dataset Information

Genetically Low Vitamin D Levels, Bone Mineral Density, and Bone Metabolism Markers: a Mendelian Randomisation Study.

Publications

Genetically Low Vitamin D Levels, Bone Mineral Density, and Bone Metabolism Markers: a Mendelian Randomisation Study.

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