BACKGROUND The relationship between lipids and the risk of fracture is currently controversial and whether such association is causal remains elusive. METHODS We performed two-sample inverse variance weighted (IVW) Mendelian randomization (MR) analyses to evaluate causal effects of four lipids (i.e. high-density lipoprotein cholesterol [HDL], low-density lipoprotein cholesterol [LDL], total cholesterol [TC] and triglyceride [TG]) on fracture or bone mineral density (BMD) with summary statistics from large scale genome-wide association studies (up to ~190,000 for lipids, ~66,628 for BMD and ~53,000 for fracture). We validated our MR results with extensive sensitive analyses including MR-PRESSO and MR-Egger regression. Multivariable analyses were implemented to investigate whether other lipids (i.e. LDL and TG) may confound the causal effect of HDL on fracture and mediation analyses were conducted to assess indirect effects of lipids on fracture mediated by BMD. RESULTS The IVW MR showed there existed a statistically significant association between HDL and fracture, with the odd ratio (OR) per standard deviation change of HDL on fracture being 1.12 (95% CI: 1.02-1.22, p = 1.20E-02). HDL was also detected to be causally associated with BMD (beta = -0.116; 95% CI: -0.182 ~ -0.050, p = 5.47E-04). These associations were further confirmed by the weighted median and maximum likelihood methods, with the MR-Egger regression removing the possibility of pleiotropy and the multivariable analysis excluding the confounding effect of other lipids on HDL. Negative associations of HDL with BMD among the elderly and with BMD at the lumbar spine were also discovered. However, no causal associations were detected between other lipids (OR = 0.87, 95% CI: 0.74-1.03, p = .107 for LDL; OR = 1.03; 95% CI: 0.88-1.21, p = .696 for TC and OR = 1.04; 95% CI: 0.90-1.20, p = .610 for TG) and fracture; whereas TG was positively associated BMD (beta = 0.184; 95% CI: 0.048-0.319, p = 7.93E-03). Finally, the mediation effect of BMD was estimated to be -0.116 (95% CI: -0.182 to -0.05, p = 5.47E-04) for HDL or 0.184 (95% CI: 0.048-0.319, p = 7.93E-03) for TG, implying HDL and TG could be indirectly associated with fracture risk via the pathway of BMD. CONCLUSION Our study is supportive of the causal relationship between HDL and fracture but offers little direct evidence for causal associations between other lipids and fracture, and further reveals HDL and TG may have an indirect influence on fracture mediated by BMD.

中文翻译：

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血脂是骨折的危险因素吗？来自工具变量因果推断和使用遗传数据的中介分析的综合证据

背景脂质与骨折风险之间的关系目前存在争议，这种关联是否是因果关系仍然难以捉摸。方法 我们进行了两样本逆方差加权 (IVW) 孟德尔随机化 (MR) 分析，以评估四种脂质（即高密度脂蛋白胆固醇 [HDL]、低密度脂蛋白胆固醇 [LDL]、总胆固醇 [TC]和甘油三酯 [TG]) 对骨折或骨矿物质密度 (BMD) 的影响，以及来自大规模全基因组关联研究的汇总统计数据（脂质最多约 190,000，BMD 约 66,628，骨折约 53,000）。我们通过广泛的敏感分析（包括 MR-PRESSO 和 MR-Egger 回归）验证了我们的 MR 结果。实施多变量分析以研究其他脂质（即 LDL 和 TG）可能会混淆 HDL 对骨折的因果影响，并且进行了中介分析以评估脂质对 BMD 介导的骨折的间接影响。结果 IVW MR 显示 HDL 与骨折之间存在统计学上显着的关联，HDL 对骨折的每个标准差变化的奇数比 (OR) 为 1.12（95% CI：1.02-1.22，p = 1.20E-02）。还检测到 HDL 与 BMD 有因果关系（β = -0.116；95% CI：-0.182 ~ -0.050，p = 5.47E-04）。这些关联通过加权中位数和最大似然方法得到进一步证实，MR-Egger 回归消除了多效性的可能性，多变量分析排除了其他脂质对 HDL 的混杂影响。还发现 HDL 与老年人的 BMD 和腰椎的 BMD 呈负相关。然而，未检测到其他脂质之间的因果关系（OR = 0.87，95% CI：0.74-1.03，LDL 的 p = .107；OR = 1.03；95% CI：0.88-1.21，TC 和 OR 的 p = .696 = 1.04；95% CI：0.90-1.20，TG）和骨折的 p = .610；而 TG 与 BMD 呈正相关（β = 0.184；95% CI：0.048-0.319，p = 7.93E-03）。最后，BMD 对 HDL 的中介效应估计为 -0.116（95% CI：-0.182 至 -0.05，p = 5.47E-04）或 0.184（95% CI：0.048-0.319，p = 7.93E-03） ) 对于 TG，暗示 HDL 和 TG 可能通过 BMD 途径与骨折风险间接相关。