Zheng Jie, Brion Marie-Jo, Kemp John P, Warrington Nicole M, Borges Maria-Carolina, Hemani Gibran, Richardson Tom G, Rasheed Humaira, Qiao Zhen, Haycock Philip, Ala-Korpela Mika, Davey Smith George, Tobias Jon H, Evans David M
Medical Research Council (MRC) Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK.
Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
J Bone Miner Res. 2020 Jul;35(7):1224-1235. doi: 10.1002/jbmr.3989. Epub 2020 Mar 12.
Several epidemiological studies have reported a relationship between statin treatment and increased bone mineral density (BMD) and reduced fracture risk, but the mechanism underlying the purported relationship is unclear. We used Mendelian randomization (MR) to assess whether this relationship 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 as exposure. The outcome results were obtained from a heel estimated BMD (eBMD) genomewide association study (GWAS) from the UK Biobank and dual-energy X-ray absorptiometry (DXA) BMD at four body sites and fracture GWAS from the GEFOS consortium. 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 and fracture. Univariate MR analyses suggested a causal effect of LDL-C on eBMD (β = -0.06; standard deviation change in eBMD per standard deviation change in LDL-C, 95% confidence interval [CI] = -0.08 to -0.04; p = 4 × 10 ), total body BMD (β = -0.05, 95% CI = -0.08 to -0.01, p = 6 × 10 ) and potentially on lumbar spine BMD. Multivariable MR suggested that the effects of LDL-C on eBMD and total body BMD were independent of HDL-C and triglycerides. Sensitivity MR analyses suggested that the LDL-C results were robust to pleiotropy. MR analyses of LDL-C restricted to SNPs in the HMGCR region showed similar effects on eBMD (β = -0.083; -0.132 to -0.034; p = .001) to those excluding these SNPs (β = -0.063; -0.090 to -0.036; p = 8 × 10 ). Bidirectional MR analyses provided some evidence for a causal effect of eBMD on plasma LDL-C levels. Our results suggest that effects of statins on eBMD and total body 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. © 2020 American Society for Bone and Mineral Research.
多项流行病学研究报告了他汀类药物治疗与骨矿物质密度（BMD）增加及骨折风险降低之间的关系，但这种所谓关系背后的机制尚不清楚。我们使用孟德尔随机化（MR）来评估这种关系是由对他汀类药物使用的特定反应效应还是由降脂的一般效应所解释。我们利用与血浆脂质水平密切相关的400个单核苷酸多态性（SNP）作为暴露因素。结局结果来自英国生物银行的足跟估计骨矿物质密度（eBMD）全基因组关联研究（GWAS）以及四个身体部位的双能X线吸收法（DXA）骨密度和GEFOS联盟的骨折GWAS。我们对低密度脂蛋白胆固醇（LDL-C）、高密度脂蛋白胆固醇（HDL-C）和甘油三酯水平对骨密度和骨折进行了单变量和多变量MR分析。单变量MR分析表明LDL-C对eBMD有因果效应（β = -0.06；LDL-C每标准差变化时eBMD的标准差变化，95%置信区间[CI] = -0.08至-0.04；p = 4×10）、全身骨密度（β = -0.05，95%CI = -0.08至-0.01，p = 6×10），并且可能对腰椎骨密度有影响。多变量MR表明LDL-C对eBMD和全身骨密度的影响独立于HDL-C和甘油三酯。敏感性MR分析表明LDL-C的结果对多效性具有稳健性。对仅限于HMGCR区域SNP的LDL-C进行MR分析显示，对eBMD的影响（β = -0.083；-0.132至-0.034；p = 0.001）与排除这些SNP的分析结果（β = -0.063；-0.090至-0.036；p = 8×10）相似。双向MR分析为eBMD对血浆LDL-C水平的因果效应提供了一些证据。我们的结果表明，他汀类药物对eBMD和全身骨密度的影响至少部分归因于它们降低LDL-C的作用。需要进一步研究来探讨调节血浆脂质水平在治疗骨质疏松症中的潜在作用。© 2020美国骨与矿物质研究学会。
