Identification and Validation of Novel Lipids Linked to Bone Mineral Density Change and Fracture Risk.

IF 3.3 3区 医学 Q2 ENDOCRINOLOGY & METABOLISM
Canchen Ma, Ziyuan Shen, Jing Tian, Yvette L Schooneveldt, Corey Giles, Flavia Cicuttini, Graeme Jones, Peter J Meikle, Feng Pan
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Abstract

To identify and validate lipid metabolites associated with bone mineral density (BMD) change and fracture risk through integrated Mendelian randomization (MR) and observational analyses. Two-sample MR analysis was first performed to uncover potential causal relationships between 32 lipid classes and 576 lipid species and BMD and fractures. Identified signatures were subsequently validated in an independent cohort (N = 492), where lipids, BMD, and fracture status were measured at two time points, 8 years apart. The false discovery rate method was employed to control multiple testing. Linear and log binomial mixed-effects models were used to analyze lipid associations with hip BMD and fracture risk, respectively. Two-sample MR revealed seven lipid classes causally associated with BMD and/or fractures, including acylcarnitine (AC), cholesteryl ester (CE), sphingomyelin (SM), phosphatidylinositol (PI), GM3 ganglioside (GM3), alkylphosphatidylcholine (PC(O)) and triacylglycerol (TG). Causal associations were found between 18 lipid species across these classes and BMD, and 10 lipid species were associated with fractures. Validation in an independent longitudinal cohort confirmed associations for total SM, SM(d18:1/16:0), SM(d18:2/24:0), and CE(18:3) with hip BMD change (β ranging from - 0.036 to - 0.012 g/cm2, per log µM increase, p < 1.13 × 10-2). Total SM, total GM3, and SM(d18:2/18:1), SM(d18:2/22:0), SM(d18:2/17:0) were associated with an increased risk of fractures (RR ranging from 1.038 to 1.290 g/cm2, per log µM increase, p < 5 × 10-2) over 8 years. Our findings suggest that alterations in lipid metabolism play a causal role in bone remodeling and fracture risk. This warrants further investigation into the mechanisms of lipid-mediated BMD changes and the potential for identifying patients at 'high risk' of osteoporotic fracture.

鉴定和验证与骨密度变化和骨折风险相关的新型脂质。
通过综合孟德尔随机化(MR)和观察性分析,鉴定和验证与骨密度(BMD)变化和骨折风险相关的脂质代谢物。首先进行了双样本MR分析,揭示了32种脂类和576种脂类与骨密度和骨折之间的潜在因果关系。随后在一个独立队列(N = 492)中验证了识别的特征,在间隔8年的两个时间点测量脂质、骨密度和骨折状态。采用错误发现率法对多重测试进行控制。采用线性和对数二项混合效应模型分别分析脂质与髋部骨密度和骨折风险的关系。双样本MR显示了七种脂类与BMD和/或骨折有因果关系,包括酰基肉碱(AC)、胆固醇酯(CE)、鞘磷脂(SM)、磷脂酰肌醇(PI)、GM3神经节苷脂(GM3)、烷基磷脂酰胆碱(PC(O))和三酰基甘油(TG)。在这些类别中发现了18种脂质与骨密度之间的因果关系,其中10种脂质与骨折有关。独立纵向队列验证证实了总SM、SM(d18:1/16:0)、SM(d18:2/24:0)和CE(18:3)与髋部骨密度变化(β范围为- 0.036至- 0.012 g/cm2,每logµM增加,p -2)之间的关联。总SM、总GM3、SM(d18:2/18:1)、SM(d18:2/22:0)、SM(d18:2/17:0)与8年内骨折风险增加相关(RR范围为1.038 ~ 1.290 g/cm2,每logµM增加,p -2)。我们的研究结果表明,脂质代谢的改变在骨重塑和骨折风险中起因果作用。这就需要进一步研究脂质介导的骨密度变化的机制,以及识别骨质疏松性骨折“高风险”患者的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Calcified Tissue International
Calcified Tissue International 医学-内分泌学与代谢
CiteScore
8.00
自引率
2.40%
发文量
112
审稿时长
4-8 weeks
期刊介绍: Calcified Tissue International and Musculoskeletal Research publishes original research and reviews concerning the structure and function of bone, and other musculoskeletal tissues in living organisms and clinical studies of musculoskeletal disease. It includes studies of cell biology, molecular biology, intracellular signalling, and physiology, as well as research into the hormones, cytokines and other mediators that influence the musculoskeletal system. The journal also publishes clinical studies of relevance to bone disease, mineral metabolism, muscle function, and musculoskeletal interactions.
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