Mendelian randomization provides evidence for a causal effect of higher serum IGF-1 concentration on risk of hip and knee osteoarthritis

April E Hartley*, Eleanor C M Sanderson, Lavinia Paternoster, Alexander Teumer, Robert C Kaplan, Jonathan H Tobias, Celia L Gregson

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)

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Abstract

Objectives: How insulin-like growth factor-1 (IGF-1) is related to osteoarthritis (OA) is not well understood. We determined relationships between IGF-1 and hospital-diagnosed hand, hip and knee OA in UK Biobank, using Mendelian Randomization (MR) to determine causality.

Methods: Serum IGF-1 was assessed by chemiluminescent immunoassay. OA was determined using hospital episode statistics. One-sample MR (1SMR) was performed using two-stage least-squares regression, with an unweighted IGF-1 genetic risk score (GRS) as an instrument. Multivariable MR (MVMR) included BMI as an additional exposure (instrumented by BMI GRS). MR analyses were adjusted for sex, genotyping chip and principal components. We then performed two-sample (2S)MR using summary statistics from CHARGE (IGF-1,N=30,884) and the recent genome-wide association study (GWAS) meta-analysis (N=455,221) of UK Biobank and Arthritis Research UK OA Genetics (arcOGEN).

Results: 332,092 adults in UK Biobank had complete data. Their mean (SD) age was 56.5 (8.0) years and 54% were female. IGF-1 was observationally related to a reduced odds of hand (OR per doubling=0.87[0.82,0.93]), and an increased odds of hip (1.04[1.01,1.07]), OA, but was unrelated to knee OA (0.99[0.96,1.01]). Using 1SMR, we found strong evidence for an increased risk of hip (OR per SD increase=1.57[1.21,2.01]) and knee (1.30[1.07,1.58]) OA with increasing IGF-1 concentration. By contrast we found no evidence for a causal effect of IGF-1 concentration on hand OA (0.98[0.57,1.70]). Results were consistent when estimated using 2SMR and in MVMR analyses accounting for BMI.

Conclusions: We have found evidence that increased serum IGF-1 is causally related to higher risk of hip and knee OA.
Original languageEnglish
Article numberkeaa597
Number of pages13
JournalRheumatology
Early online date7 Oct 2020
DOIs
Publication statusE-pub ahead of print - 7 Oct 2020

Keywords

  • Osteoarthritis
  • UK Biobank
  • BMI
  • Insulin-like Growth Factor-1
  • Mendelian randomization

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