Background

Observational studies have shown a causal association between dyslipidemia and osteoporosis, but the genetic causation and complete mechanism of which are uncertain. The disadvantage of previous observational studies is that they are susceptible to confounding factors and bias, that makes it difficult to infer a causal link between those two diseases. Abnormal epigenetic modifications, represented by DNA methylation, are important causes of many diseases. However, there are no studies showing a bridging role for methylation modifications in blood lipid metabolism and osteoporosis.

Methods

SNPs for lipid profile (Blood VLDL cholesterol (VLDL-C), blood LDL cholesterol (LDL-C), blood HDL cholesterol (HDL-C), blood triglycerides (TG), diagnosed pure hypercholesterolaemia, blood apolipoprotein B (Apo B), blood apolipoprotein A1(Apo A1)), and bone mineral density (BMD) in different body parts (Heel BMD, lumbar BMD, whole-body BMD, femoral neck BMD) were obtained from large meta-analyses of genome-wide association studies as instrumental variables for two-sample Mendelian randomization. Assessment of the genetic effects of lipid profile-associated methylation sites and bone mineral density was carried out using the summary-data-based Mendelian randomization (SMR) method.

Results

Two-sample Mendelian randomization showed that there was a negative causal association between hypercholesterolaemia and heel BMD (p = 0.0103, OR = 0.4590), and total body BMD (p = 0.0002, OR = 0.2826). LDL-C had a negative causal association with heel BMD (p = 8.68E-05, OR = 0.9586). VLDL-C had a negative causal association with heel BMD (p = 0.035, OR = 0.9484), lumbar BMD (p = 0.0316, OR = 0.9356), and total body BMD (p = 0.0035, OR = 0.9484). HDL-C had a negative causal association with heel BMD (p = 1.25E-05, OR = 0.9548), lumbar BMD (p = 0.0129, OR = 0.9358), and total body BMD (p = 0.0399, OR = 0.9644). Apo B had a negative causal association with heel BMD (p = 0.0001, OR = 0.9647). Apo A1 had a negative causal association with heel BMD (p = 0.0132, OR = 0.9746) and lumbar BMD (p = 0.0058, OR = 0.9261). The p-values of all positive results corrected by the FDR method remained significant and sensitivity analysis showed that there was no horizontal pleiotropy in the results despite the heterogeneity in some results. SMR identified 3 methylation sites associated with lipid profiles in the presence of genetic effects on BMD: cg15707428(GREB1), cg16000331(SREBF2), cg14364472(NOTCH1).

Conclusion

Our study provides insights into the potential causal links and co-pathogenesis between dyslipidemia and osteoporosis. The genetic effects of dyslipidaemia on osteoporosis may be related to certain aberrant methylation genetic modifications.

中文翻译：

---

脂质代谢、甲基化异常和骨质疏松症：基于孟德尔随机化的多组学研究

背景

观察性研究表明血脂异常与骨质疏松症之间存在因果关系，但其遗传原因和完整机制尚不确定。以前的观察性研究的缺点是它们容易受到混杂因素和偏见的影响，这使得很难推断这两种疾病之间的因果关系。以DNA甲基化为代表的异常表观遗传修饰是许多疾病的重要原因。然而，尚无研究表明甲基化修饰在血脂代谢和骨质疏松症中具有桥梁作用。

方法

血脂谱 SNP（血液 VLDL 胆固醇 (VLDL-C)、血液 LDL 胆固醇 (LDL-C)、血液 HDL 胆固醇 (HDL-C)、血液甘油三酯 (TG)、诊断的纯高胆固醇血症、血液载脂蛋白 B (Apo B)、血液载脂蛋白 A1(Apo A1)) 和不同身体部位的骨矿物质密度 (BMD)（脚跟 BMD、腰椎 BMD、全身 BMD、股骨颈 BMD）是通过全基因组关联研究的大型荟萃分析获得的：双样本孟德尔随机化的工具变量。使用基于汇总数据的孟德尔随机化（SMR）方法评估脂质谱相关的甲基化位点和骨矿物质密度的遗传效应。

结果

两样本孟德尔随机化显示，高胆固醇血症与足跟 BMD（p  = 0.0103，OR  = 0.4590）和全身 BMD（p  = 0.0002，OR  = 0.2826）之间存在负因果关系。LDL-C 与足跟 BMD 呈负因果关系（p  = 8.68E-05，OR  = 0.9586）。VLDL-C 与足跟 BMD ( p  = 0.035，OR  = 0.9484)、腰椎 BMD ( p  = 0.0316，OR  = 0.9356) 和全身 BMD ( p  = 0.0035，OR = 0.9484)呈负因果关系 。HDL-C 与足跟 BMD（ p  = 1.25E-05，OR  = 0.9548）、腰椎 BMD（p  = 0.0129，OR  = 0.9358）和全身 BMD（p  = 0.0399，OR = 0.9644）呈负因果关系 。Apo B 与足跟 BMD 呈负因果关系（p  = 0.0001，OR  = 0.9647）。Apo A1 与足跟 BMD ( p  = 0.0132，OR  = 0.9746) 和腰椎 BMD ( p  = 0.0058，OR = 0.9261)呈负因果关系 。FDR 方法校正的所有阳性结果的p值仍然显着，敏感性分析表明，尽管某些结果存在异质性，但结果不存在水平多效性。SMR 鉴定出 3 个与 BMD 存在遗传效应的脂质谱相关的甲基化位点：cg15707428(GREB1)、cg16000331(SREBF2)、cg14364472(NOTCH1)。

结论

我们的研究提供了对血脂异常和骨质疏松症之间潜在因果关系和共同发病机制的见解。血脂异常对骨质疏松症的遗传影响可能与某些异常甲基化遗传修饰有关。