身体的代谢状态可能是骨骼健康的主要决定因素。我们使用孟德尔随机化方法来鉴定与骨量相关的代谢物,以更好地了解骨质疏松症的生物学机制。我们测试了骨表型(股骨颈,全髋关节,和腰椎骨矿物质密度[BMD])与来自TwinsUK队列的6055名女性的280空腹血液代谢产物相关,并进行了全基因组基因分型扫描。在使用遗传标记/评分作为工具变量的双向孟德尔随机研究中进一步评估了代谢物和骨表型之间的因果关系。来自香港骨质疏松研究(HKOS)的624名参与者重复了显着的关联。在调整了协变量和多重测试后,有15种代谢物与骨表型直接相关。利用基因仪器,发现这些代谢物中的四种与髋部或脊柱BMD有因果关系.这些包括硫酸雄酮,硫酸表雄酮,5α-雄性激素-3β-17β-二醇二硫酸盐(由CYP3A5编码),和4-雄蕊-3β-17β-二醇二硫酸盐(由SULT2A1编码)。在HKOS人口中,所有4种代谢物在预期方向均与髋部和脊柱BMD显著相关.未发现BMD与任何代谢物之间的因果反向关联。在人类骨密度的第一个代谢组-全基因组孟德尔随机化研究中,我们确定了四种与BMD相关的新型生物标志物。我们的发现揭示了骨质疏松症发病机制中涉及的新型生物学途径。©2017美国骨骼和矿物质研究协会。
The metabolic state of the body can be a major determinant of bone health. We used a Mendelian randomization approach to identify metabolites causally associated with bone mass to better understand the biological mechanisms of osteoporosis. We tested bone phenotypes (femoral neck, total hip, and lumbar spine bone mineral density [BMD]) for association with 280 fasting blood metabolites in 6055 women from TwinsUK cohort with genomewide genotyping scans. Causal associations between metabolites and bone phenotypes were further assessed in a bidirectional Mendelian randomization study using genetic markers/scores as instrumental variables. Significant associations were replicated in 624 participants from the Hong Kong Osteoporosis Study (HKOS). Fifteen metabolites showed direct associations with bone phenotypes after adjusting for covariates and multiple testing. Using genetic instruments, four of these metabolites were found to be causally associated with hip or spine BMD. These included androsterone sulfate, epiandrosterone sulfate, 5alpha-androstan-3beta17beta-diol disulfate (encoded by CYP3A5), and 4-androsten-3beta17beta-diol disulfate (encoded by SULT2A1). In the HKOS population, all four metabolites showed significant associations with hip and spine BMD in the expected directions. No causal reverse association between BMD and any of the metabolites were found. In the first metabolome-genomewide Mendelian randomization study of human bone mineral density, we identified four novel biomarkers causally associated with BMD. Our findings reveal novel biological pathways involved in the pathogenesis of osteoporosis. © 2017 American Society for Bone and Mineral Research.