Division of Endocrinology, Department of Medicine and Center for Endocrine Tumors Leiden.
Department of Biomedical Data Science, Section Molecular Epidemiology.
Eur J Endocrinol. 2021 Jan;184(1):29-39. doi: 10.1530/EJE-20-0904.
Pathologically high growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels in patients with acromegaly are associated with arthropathy. Several studies highlight the potential role of the GH/IGF-1 axis in primary osteoarthritis (OA). We aimed to disentangle the role of IGF-1 levels in primary OA pathogenesis.
Patients from the Genetics osteoARthritis and Progression (GARP) Study with familial, generalized, symptomatic OA (n = 337, mean age: 59.8 ± 7.4 years, 82% female) were compared to Leiden Longevity Study (LLS) controls (n = 456, mean age: 59.8 ± 6.8 years, 51% female). Subjects were clinically and radiographically assessed, serum IGF-1 levels were measured, and 10 quantitative trait loci (QTL) in the FOXO3, IGFBP3/TNS3, RPA3, SPOCK2 genes, previously related to serum IGF-1 levels, were genotyped. Linear or binary logistic generalized estimating equation models were performed.
Serum IGF-1 levels were increased in OA patients, with male patients exhibiting the strongest effect (males OR = 1.10 (1.04-1.17), P=0.002 vs females OR = 1.04 (1.01-1.07), P = 0.02). Independent of the increased IGF-1 levels, male carriers of the minor allele of FOXO3 QTL rs4946936 had a lower risk to develop hip OA (OR = 0.41 (0.18-0.90), P = 0.026). Additionally, independent of IGF-1 levels, female carriers of the minor alleles of RPA3 QTL rs11769597 had a higher risk to develop knee OA (OR = 1.90 (1.20-2.99), P = 0.006).
Patients with primary OA had significantly higher IGF-1 levels compared to controls. Moreover, SNPs in the FOXO3 and RPA3 genes were associated with an altered risk of OA. Therefore, altered IGF-1 levels affect the development of OA, and are potentially the result of the pathophysiological OA process.
肢端肥大症患者中病理性高生长激素（GH）和胰岛素样生长因子-1（IGF-1）水平与关节病有关。几项研究强调了 GH/IGF-1 轴在原发性骨关节炎（OA）中的潜在作用。我们旨在阐明 IGF-1 水平在原发性 OA 发病机制中的作用。
我们比较了来自遗传骨关节炎和进展（GARP）研究的家族性、全身性、症状性 OA 患者（n=337，平均年龄：59.8±7.4 岁，82%为女性）和莱顿长寿研究（LLS）对照组（n=456，平均年龄：59.8±6.8 岁，51%为女性）。对受试者进行临床和放射学评估，测量血清 IGF-1 水平，并对先前与血清 IGF-1 水平相关的 FOXO3、IGFBP3/TNS3、RPA3、SPOCK2 基因中的 10 个数量性状基因座（QTL）进行基因分型。采用线性或二元逻辑广义估计方程模型进行分析。
OA 患者的血清 IGF-1 水平升高，男性患者的影响最强（男性 OR=1.10（1.04-1.17），P=0.002 与女性 OR=1.04（1.01-1.07），P=0.02）。独立于 IGF-1 水平升高，FOXO3 QTL rs4946936 次要等位基因的男性携带者发生髋关节 OA 的风险较低（OR=0.41（0.18-0.90），P=0.026）。此外，独立于 IGF-1 水平，RPA3 QTL rs11769597 次要等位基因的女性携带者发生膝关节 OA 的风险更高（OR=1.90（1.20-2.99），P=0.006）。
与对照组相比，原发性 OA 患者的 IGF-1 水平显著升高。此外，FOXO3 和 RPA3 基因中的 SNP 与 OA 风险的改变相关。因此，改变的 IGF-1 水平会影响 OA 的发展，并且可能是 OA 病理生理过程的结果。
