Bidirectional two-sample MR analysis of causal relationships between human inflammatory proteins and HS and keloids

Wang Sisi; Xiao Kui; Xiao Hongtao; Han Dawei; Zhang Jian; Wang Lei; Li Yancang

doi:10.3760/cma.j.cn501225-20250117-00025

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Article Navigation > CHINESE JOURNAL OF BURNS AND WOUNDS > > Accepted Manuscript

Wang Sisi,Xiao Kui,Xiao Hongtao,et al.Bidirectional two-sample MR analysis of causal relationships between human inflammatory proteins and HS and keloids[J].Chin J Burns Wounds,2026,42(7):1-10.DOI: 10.3760/cma.j.cn501225-20250117-00025.

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Bidirectional two-sample MR analysis of causal relationships between human inflammatory proteins and HS and keloids

doi: 10.3760/cma.j.cn501225-20250117-00025

1.
Department of Burns, Zhengzhou First People's Hospital, Zhengzhou 450004, China
2.
Basic Medical College, Guangxi Medical University, Nanning 530021, China

Funds:

Henan Provincial Medical Science and Technology Research Initiative Joint Construction Project LHGJ20191002, LHGJ20220809

Zhengzhou City Guidance Program for Scientific and Technological Innovation in the Medical and Health Field 2025YLZDJH086

National Construction Program for Key Clinical Specialties 2023-70

More Information

Corresponding author: Li Yancang, Email: 1841648992@qq.com
Received Date: 2025-01-17
Available Online: 2026-06-29

Abstract

Abstract

Objective To explore the causal relationships between human inflammatory proteins and hypertrophic scars (HS) and keloids. Methods This study was conducted based on bidirectional two-sample Mendelian randomization (MR) analysis. Data of human inflammatory proteins, HS, and keloids were acquired from genome-wide association study database. The inverse variance weighted (IVW) method was adopted to evaluate the causal relationships between 91 kinds of human inflammatory proteins and HS and keloids, i.e., forward MR analysis. For the above associations, Cochran's Q test was used to assess heterogeneity, MR-Egger regression and MR-PRESSO outlier tests were performed to evaluate horizontal pleiotropy, and the leave-one-out method was applied to analyze the robustness of the results. The IVW method was also used to evaluate whether there was a reverse causal relationship between HS, keloids and inflammatory proteins screened out by aforementioned forward MR analysis. Results CD6, leukemia inhibitory factor (LIF), tumor necrosis factor ligand superfamily member 12 (TNFSF12), programmed death-ligand 1 (PD-L1), interleukin-17C (IL-17C), LIF receptor (LIFR), osteoprotegerin (OPG), and fibroblast growth factor 23 (FGF23) had significant causal relationships with HS (with ORs of 1.365, 0.506, 1.567, 1.683, 0.621, 1.375, 0.623, and 0.553, respectively, 95%CIs of 1.100-1.693, 0.289-0.887, 1.081-2.273, 1.090-2.599, 0.408-0.947, 1.025-1.845, 0.402-0.966, and 0.315-0.971, respectively, P<0.05). Among them, CD6, TNFSF12, PD-L1, and LIFR were risk factors for HS, while LIF, IL-17C, OPG, and FGF23 were protective factors for HS. CD5, IL-10 receptor subunit alpha (IL-10RA), IL-5, LIF, and OPG had significant causal relationships with keloids (with ORs of 0.744, 1.303, 0.686, 0.603, and 0.715, respectively, 95%CIs of 0.573-0.965, 1.024-1.660, 0.472-0.996, 0.431-0.842, and 0.553-0.924, respectively, P<0.05). Among them, IL-10RA was a risk factor for keloids, whereas CD5, IL-5, LIF, and OPG were protective factors for keloids. No significant heterogeneity or horizontal pleiotropy was observed in the above associations (P>0.05), and the robustness of the results was not driven by any single nucleotide polymorphism. Significant reverse causal relationships existed between HS and TNFSF12 and LIFR of the 8 inflammatory proteins screened out by aforementioned forward MR analysis (with ORs of 0.972 and 0.968, respectively, 95%CIs of 0.949-0.997 and 0.942-0.994, respectively, P<0.05). No reverse causal relationship was found between keloids and the 5 inflammatory proteins screened out by aforementioned forward MR analysis (P>0.05). Conclusions CD6, TNFSF12, PD-L1, and LIFR may increase the risk of HS, while OPG and FGF23 may decrease the risk of HS. IL-10RA may increase the risk of keloids, while CD5, IL-5, LIF, and OPG may decrease the risk of keloids.
- Keloid,
- Mendelian randomization analysis,
- Hypertrophic scar,
- Inflammatory protein,
- Bidirectional two-sample analysis

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