Introduction: Increased insulin-like growth factor 1 (IGF-1) levels in patients with acromegaly are associated with clinical and radiological osteoarthritis (OA). We aimed to elucidate whether serum IGF-1 levels differ in patients with primary OA as compared to healthy controls and whether genetic variants known to affect serum IGF-1 levels are also associated with primary OA.
Methods: Patients from the GARP study with familial generalized OA (n=317) were biochemically and clinically assessed, and 10 single nucleotide polymorphisms (SNPs) associated with serum IGF-1 levels were genotyped. Binary logistic regression was performed, stratified for gender, to calculate robust standard errors.
Results: IGF-1 levels correlated with age (r=−0.142, P=0.001) and BMI (r=0.102, P=0.018). Within the GARP study, solely males had higher IGF-1 levels compared to healthy controls (19.8±6.18 nmol/l vs 16.9±4.53 nmol/l, P=0.001). Within healthy controls, IGFBP-3 levels were significantly lower in males (4.29±0.86 mg/l vs 4.50±0.88 mg/l, P=0.0094). The association of the selected SNPs with IGF-1 levels and IGFBP-3 levels were confirmed. Male carriers of the minor allele of rs4946936 had significantly lower risk to develop hip OA specifically (β=−0.860±0.417, P=0.039), but not knee OA. In contrast, female carriers of the minor alleles of rs957755 and rs11769597, which are in high LD, had a significantly higher risk to develop knee OA (β=0.695±0.235, P=0.003). Furthermore, female carriers of the minor allele of rs700753 have significantly less risk to develop knee OA (®=−0.419±0.200, P=0.036).
Conclusion: Since genetic variation could contribute to the occurrence of OA and GH and IGF-1 are involved in the healthy functioning of bone, variants that alter the function of the GH IGF-1 axis influence the (susceptibility to the) development of primary OA. Male carriers of the minor allele of rs4946936 had less risk to develop hip OA, which is most likely due to lower IGF-1 levels. Moreover, female carriers of the minor alleles of rs957755 and rs11769597 had a significantly higher risk to develop knee OA and female carriers of the minor allele of rs700753 have significantly less risk to develop knee OA via the altering of IGFBP-3 levels. In future studies, the exact (patho)physiological mechanisms of (altering) the GH IGF-1 axis in healthy, osteoarthritic and arthritic cartilage, bone and joints needs to be elucidated.
18 - 21 May 2019
European Society of Endocrinology