■骨质疏松症,一种以骨骼强度降低为特征的普遍骨骼疾病,与IGF系统密切相关,对骨骼代谢至关重要。然而,这种关系的确切性质仍然难以捉摸。在这项研究中,我们采用孟德尔随机化(MR)方法来揭示基因预测的血清IGF系统成员水平与骨质疏松症之间的关联.
■采用双样本MR方法基于两个单独的数据集来研究这些因果关联。在4,301名欧洲血统个体的队列中,使用11,036,163个相关单核苷酸多态性(SNP)对14个IGF系统成员的血清水平进行了预测。骨质疏松症的遗传关联估计来自两个公开的GWAS联盟:来自FinnGen生物库的芬兰联盟,包括212,778名芬兰裔人(3,203例病例和209,575名对照),和英国生物银行的英国财团,包括337159名欧洲血统的人(5266例和331893例对照)。
■根据英国数据集,IGF-1水平与骨质疏松症的风险降低有关,如加权中位数法所示(比值比[OR]=0.998,95%CI=0.997-1.000,P=0.032).此外,使用逆方差加权(IVW)方法(OR=0.999,95%CI=0.998-1.000,P=0.019),较高的IGFBP-3水平与骨质疏松症风险降低有关。CTGF水平与骨质疏松症呈负相关,通过加权中位数法确定(OR=0.998,95%CI=0.996-0.999,P=0.004)。在FinnGen数据集中,未发现IGF-1和IGFBP-3与骨质疏松症相关。同时,IGF-LR1水平与骨质疏松呈负相关,根据MR-Egger法(OR=0.886,95%CI=0.795-0.987,P=0.036),根据加权中位数和IVW方法,CYR61与骨质疏松风险增加相关(OR=1.154,95%CI=1.009-1.319,P=0.037,OR=1.115,95%CI=1.022-1.215,P=0.014).
■这项研究提供了令人信服的证据,表明某些IGF家族成员在不同数据集之间的骨质疏松症发病机制中发挥作用。表明IGF家族与骨质疏松症之间的人群特异性因果效应。尽管来自两个数据集的结果表明IGF家族参与骨质疏松症的发病机理,但是响应的关键分子可能在不同的人群中有所不同。随后的研究有必要评估这些生物标志物作为特定人群中骨质疏松症预防和治疗目标的潜力。
Osteoporosis, a prevalent skeletal disorder characterized by reduced bone strength, is closely linked to the IGF system, crucial for skeletal metabolism. However, the precise nature of this relationship remains elusive. In this
study, we employed Mendelian randomization (MR) to unravel the associations between genetically predicted serum IGF system member levels and osteoporosis.
A two-sample MR approach was employed to investigate these causal associations based on two individual datasets. Predictions of 14 serum levels of IGF system members were made using 11,036,163 relevant Single Nucleotide Polymorphisms (SNPs) within a cohort of 4,301 individuals of European descent. Genetic association estimates for osteoporosis were derived from two publicly available GWAS consortia: the Finnish consortium from the FinnGen biobank, comprising 212,778 individuals of Finnish descent (3,203 cases and 209,575 controls), and the UK consortium from the UK Biobank, including 337,159 individuals of European descent (5,266 cases and 331,893 controls).
According to the UK dataset, IGF-1 levels were associated with a reduced risk of osteoporosis, as indicated by the weighted median method (Odds Ratio [OR] = 0.998, 95% CI = 0.997-1.000, P = 0.032). Additionally, higher levels of IGFBP-3 were linked to a decreased risk of osteoporosis using the Inverse-Variance Weighted (IVW) method (OR = 0.999, 95% CI = 0.998-1.000, P = 0.019), and CTGF levels exhibited a negative association with osteoporosis, as determined by the weighted median method (OR = 0.998, 95% CI = 0.996-0.999, P = 0.004). In the FinnGen dataset, IGF-1 and IGFBP-3 were not identified to be associated with osteoporosis. While, IGF-LR1 levels displayed a negative association with osteoporosis, according to the MR-Egger method (OR = 0.886, 95% CI = 0.795-0.987, P = 0.036), while CYR61 was linked to an increased risk of osteoporosis based on both the weighted median and IVW methods (OR = 1.154, 95% CI = 1.009-1.319, P = 0.037, and OR = 1.115, 95% CI = 1.022-1.215, P = 0.014, respectively).
This
study provides compelling evidence that certain IGF family members play a role in the pathogenesis of osteoporosis between different datasets, indicating population specific causal effects between IGF family and osteoporosis. Although the results from both datasets demonstrated that IGF family involved in the pathogenesis of osteoporosis, but the responding key molecules might be various among different population. Subsequent research is warranted to evaluate the potential of these biomarkers as targets for osteoporosis prevention and treatment in specific population.