背景:大量研究表明,各种细胞因子是影响骨密度(BMD)的重要因素,但是两者之间的因果关系仍然不确定。
方法:来自8,293Finns的全基因组关联研究(GWAS)的与41种循环细胞因子相关的遗传变异被用作两样本孟德尔随机化(MR)分析的工具变量(IVs)。采用逆方差加权(IVW)作为主要方法,以研究41种细胞因子是否与五个不同部位的BMD有因果关系[全身骨矿物质密度(TB-BMD),脚跟骨矿物质密度(HE-BMD),前臂骨矿物质密度(FA-BMD),股骨颈骨密度(FN-BMD),和腰椎骨密度(LS-BMD)]。选择加权中位数和MR-Egger以进一步确认结果的稳健性。我们进行了MR多效性残差和异常值测试(MR-PRESSO),MR-Egger回归,和Cochran的Q测试来检测多效性和灵敏度测试。
结果:Bonferroni校正后,两种循环细胞因子与相应部位的BMD有很强的因果关系.遗传预测的循环肝细胞生长因子(HGF)水平与HE-BMD呈负相关[β(95%CI)-0.035(-0.055,-0.016),P=0.00038]。循环巨噬细胞炎性蛋白-1α(MIP-1α)水平与TB-BMD呈负相关[β(95CI):-0.058(-0.092,-0.024),P=0.00074]。加权中位数和MR-Egger结果与IVW结果一致。我们还发现七种循环细胞因子与相应部位的BMD之间存在暗示性因果关系(IVWP<0.05)。在我们的研究中没有观察到显著的多效性或异质性。
结论:我们的MR分析表明两种循环细胞因子与相应部位的BMD之间存在因果关系(HGF和HE-BMD,MIP-1α和TB-BMD),以及七种细胞因子与相应部位BMD之间潜在因果关系的暗示性证据。这些发现将为骨质疏松症的预防和治疗提供见解,尤其是免疫性骨质疏松症.
BACKGROUND: Numerous studies have shown that various cytokines are important factors affecting bone mineral density (BMD), but the causality between the two remains uncertain.
METHODS: Genetic variants associated with 41 circulating cytokines from a genome-wide association study (GWAS) in 8,293 Finns were used as instrumental variables (IVs) for a two-sample Mendelian randomization (MR) analysis. Inverse variance weighting (IVW) was employed as the primary method to investigate whether the 41 cytokines were causally associated with BMD at five different sites [total body bone mineral density (TB-BMD), heel bone mineral density (HE-BMD), forearm bone mineral density (FA-BMD), femoral neck bone mineral density (FN-BMD), and lumbar spine bone mineral density (LS-BMD)]. Weighted median and MR-Egger were chosen to further confirm the robustness of the results. We performed MR pleiotropy residual sum and outlier test (MR-PRESSO), MR-Egger regression, and Cochran\'s Q test to detect pleiotropy and sensitivity testing.
RESULTS: After Bonferroni correction, two circulating cytokines had a strong causality with BMD at corresponding sites. Genetically predicted circulating hepatocyte growth factor (HGF) levels and HE-BMD were negatively correlated [β (95 % CI) -0.035(-0.055, -0.016), P=0.00038]. Circulating macrophage inflammatory protein-1α (MIP-1α) levels and TB-BMD were negatively correlated [β(95 %CI): -0.058(-0.092, -0.024), P=0.00074]. Weighted median and MR-Egger results were in line with the IVW results. We also found suggestive causal relationship (IVW P<0.05) between seven circulating cytokines and BMD at corresponding sites. No significant pleiotropy or heterogeneity was observed in our study.
CONCLUSIONS: Our MR analyses indicated a causal effect between two circulating cytokines and BMD at corresponding sites (HGF and HE-BMD, MIP-1α and TB-BMD), along with suggestive evidence of a potential causality between seven cytokines and BMD at the corresponding sites. These findings would provide insights into the prevention and treatment of osteoporosis, especially immunoporosis.