The effect of systemic iron status on osteoarthritis: A mendelian randomization study

Guangfeng Ruan; Yi Ying; Shilong Lu; Zhaohua Zhu; Shibo Chen; Muhui Zeng; Ming Lu; Song Xue; Jianwei Zhu; Peihua Cao; Tianyu Chen; Xiaoshuai Wang; Shengfa Li; Jia Li; Yu Liu; Yanqi Liu; Yan Zhang; Changhai Ding

doi:10.3389/fgene.2023.1122955

The effect of systemic iron status on osteoarthritis: A mendelian randomization study

Front Genet. 2023 Mar 16:14:1122955. doi: 10.3389/fgene.2023.1122955. eCollection 2023.

Authors

Guangfeng Ruan¹, Yi Ying², Shilong Lu³, Zhaohua Zhu⁴, Shibo Chen⁴, Muhui Zeng⁴, Ming Lu⁵, Song Xue⁶, Jianwei Zhu⁷, Peihua Cao⁴, Tianyu Chen⁴, Xiaoshuai Wang⁴, Shengfa Li⁴, Jia Li⁴, Yu Liu⁴, Yanqi Liu⁴, Yan Zhang⁴, Changhai Ding^{1

4

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Affiliations

¹ Clinical Research Centre, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China.
² Department of Hematopathology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China.
³ Department of Imaging Diagnosis, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
⁴ Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
⁵ Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China.
⁶ Department of Rheumatology and Immunology, Arthritis Research Institute, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
⁷ Department of Orthopedics, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China.
⁸ Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia.

Abstract

Objective: To assess the causal effect of systemic iron status by using four biomarkers (serum iron; transferrin saturation; ferritin; total iron-binding capacity) on knee osteoarthritis (OA), hip OA, total knee replacement, and total hip replacement using 2-sample Mendelian randomization (MR) design. Methods: Three instrument sets were used to construct the genetic instruments for the iron status: Liberal instruments (variants associated with one of the iron biomarkers), sensitivity instruments (liberal instruments exclude variants associated with potential confounders), and conservative instruments (variants associated with all four iron biomarkers). Summary-level data for four OA phenotypes, including knee OA, hip OA, total knee replacement, and total hip replacement were obtained from the largest genome-wide meta-analysis with 826,690 individuals. Inverse-variance weighted based on the random-effect model as the main approach was conducted. Weighted median, MR-Egger, and Mendelian randomization pleiotropy residual sum and outlier methods were used as sensitivity MR approaches. Results: Based on liberal instruments, genetically predicted serum iron and transferrin saturation were significantly associated with hip OA and total hip replacement, but not with knee OA and total knee replacement. Statistical evidence of heterogeneity across the MR estimates indicated that mutation rs1800562 was the SNP significantly associated with hip OA in serum iron (odds ratio, OR = 1.48), transferrin saturation (OR = 1.57), ferritin (OR = 2.24), and total-iron binding capacity (OR = 0.79), and hip replacement in serum iron (OR = 1.45), transferrin saturation (OR = 1.25), ferritin (OR = 1.37), and total-iron binding capacity (OR = 0.80). Conclusion: Our study suggests that high iron status might be a causal factor of hip OA and total hip replacement where rs1800562 is the main contributor.

Keywords: hip osteoarthritis (hip OA); iron; mendelian randomization (MR); rs1800562; total hip replacement (THR).

Grants and funding

This work has been fully supported by the National Natural Science Foundation of China (82003542 & 82002331) and the Special Program of Chinese Postdoctoral Science Foundation (2022T150301).