Variants of FOXO3 and RPA3 genes affecting IGF-1 levels alter the risk of development of primary osteoarthritis

in European Journal of Endocrinology
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  • 1 Division of Endocrinology, Department of Medicine and Center for Endocrine Tumors Leiden
  • 2 Department of Biomedical Data Science, Section Molecular Epidemiology
  • 3 Department of Geriatrics and Gerontology, Leiden University Medical Center, Leiden, the Netherlands
  • 4 Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands
  • 5 Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands
  • 6 Department of Epidemiology, Leiden University Medical Center, Leiden, the Netherlands

Correspondence should be addressed to I C M Pelsma; Email: i.c.m.pelsma@lumc.nl
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Introduction

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.

Methods

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.

Results

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).

Conclusion

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.

 

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