Key messages
- Elevated IGF-1 levels may increase the susceptibility to knee, hip, and hand OA, but not spine OA.
- BMI mediates the increase in OA risk associated with higher IGF-1, including indirect spine OA risk through BMI.
Study information
Details of the study
“The association between IGF-1 levels and four types of osteoarthritis: a bidirectional and two-step mendelian randomization study”1
Methods
Two-sample Mendelian Randomization (MR) approach and its combined forms were conducted to investigate the bidirectional causal relationship between IGF-1 and OA in knee, hip, hand, and spine, while a two-step MR analysis explored the role of BMI in this relationship. Different European sources were used to obtain genome-wide association study (GWAS) data:
- IEU OpenGWAS project provided IGF-1 levels.
- Data of OA was obtained from the musculoskeletal knowledge portal (MSK-KP).
- GWAS BMI data employed the GIANT consortium.
Instrumental variables (IVs) were selected based on stringent criteria including genomewide significance level and exclusion of pairwise linkage disequilibrium. Methods used for the analysis included inverse variance weighted (IVW), MR-Egger regression, and weighted median (WM). Sensitivity analyses, such as the MR-PRESSO test and Egger intercept, ensured robustness by assessing pleiotropy and heterogeneity.
The four-step two-sample MR analysis comprised the following steps:
- Step 1. Mendelian analysis of IGF-1 on four types of OA.
- Step 2. Mendelian analysis of four types of OA on IGF-1.
- Step 3. Mendelian analysis of IGF-1 on BMI.
- Step 4. Mendelian analysis of BMI on the four types of OA.
A bidirectional MR analysis (steps 1 and 2) was conducted to examine both the effect of IGF-1 and OA, and vice versa, while a two-step MR (steps 1, 3 and 4) was employed to evaluate BMI’s mediating role in the relationship between IGF-1 and each type of OA.
Main results
The IVW analysis revealed that elevated IGF-1 levels were significantly associated with an increased risk of knee, hip, and hand OA, but no causal relationship was observed between IGF-1 levels and spine OA. None of the four types of OA had an effect on IGF-1 levels. BMI was also found to play a critical mediating role. Higher BMI significantly increased the risk of all four OA types, particularly for knee and hip OA. The IVW method provided consistent results across different types of OA. Sensitivity analyses showed no evidence of horizontal pleiotropy, and the robustness of the findings was confirmed through heterogeneity tests and leave-one-out analyses.
Overall, the study showed that elevated levels of IGF-1 may increase the risk of OA development in knee, hip, and hand, but not in spine. The risk of all four types of OA studied was particularly increased through the effect of IGF-1 on BMI.
Conclusion
Higher IGF-1 levels are causally linked to an increased risk of knee, hip, and hand OA, but not spine OA. BMI plays a significant mediating role in this relationship, particularly in weight-bearing joints. Although these findings contribute valuable insights into how IGF1 and BMI together influence OA development, the absence of clinical research advises against manipulating blood IGF-1 levels to decrease this potential risk. Authors instead advocate for a holistic approach to managing BMI, including the promotion of physical activity and healthy eating habits.
Bibliography
- Pan X, Cheng M, Li D, Liu Z, Yao Q, Jiang W, et al. The association between IGF-1 levels and four types of osteoarthritis: a bidirectional and two-step mendelian randomization study. Front Genet. 2024;15:1366138.
Link to the full study
This article is a summary based on the following study. For further information and details, please consult the full study. Please do not hesitate to contact us if you have any comments. https://pubmed.ncbi.nlm.nih.gov/39050250/
