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Screening Plasma Proteins for the Putative Drug Targets for Carpal Tunnel Syndrome

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Abstract

Carpal tunnel syndrome (CTS) is one of the most common work-related musculoskeletal disorders. The present study sought to identify putative causal proteins for CTS. We conducted a two-sample Mendelian randomization (MR) analysis to evaluate the causal association between 2859 plasma proteins (N = 35,559) and CTS (N = 1,239,680) based on the published GWAS summary statistics. Then we replicated the significant associations using an independent plasma proteome GWAS (N = 10,708). Sensitivity analyses were conducted to validate the robustness of MR results. Multivariate MR and mediation analyses were conducted to evaluate the mediation effects of body mass index (BMI), type 2 diabetes (T2D), and arm tissue composition on the association between putative causal proteins and CTS. Colocalization analysis was used to examine whether the identified proteins and CTS shared causal variant(s). Finally, we evaluated druggability of the identified proteins. Ten plasma proteins were identified as putative causal markers for CTS, including sCD14, PVR, LTOR3, CTSS, SIGIRR, IFNL3, ASPN, TM11D, ASIP, and ITIH1. Sensitivity analyses and reverse MR analysis validated the robustness of their causal effects. Arm tissue composition, BMI, and T2D may play a fully/partial mediating role in the causal relationships of ASIP, TM11D, IFNL3, PVR, and LTOR3 with CTS. The association of ASPN and sCD14 with CTS were supported by colocalization analysis. Druggability assessment demonstrated that sCD14, CTSS, TM11D, and IFNL3 were potential drug therapeutic targets. The present study identified several potential plasma proteins that were causally associated with CTS risk, providing new insights into the pathogenesis of protein-mediated CTS and offering potential targets for new therapies.

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Data Availability

Data generated or analyzed during this study are included in this published article or in the data repositories listed in References. Some datasets generated during and/or analyzed during the current study are not publicly accessible but are available from the corresponding author on reasonable request. Other data or Rscript generated or analyzed in this study are included in the Dropbox (https://www.dropbox.com/scl/fo/yw7ui593d0wj87212uonr/h?rlkey=t13o44u6tcrk94zh8hozyur8d&dl=0).

Abbreviations

ASIP:

Agouti-signaling protein

ASPN:

Asporin

BMI:

Body mass index

CTS:

Carpal tunnel syndrome

CTSS:

Cathepsin S

GIANT:

Genetic investigation of anthropometric traits

GWAS:

Genome-wide association study

IFNL3:

Interferon lambda-3

IRBs:

Institutional review boards

ITIH1:

Inter-alpha-trypsin inhibitor heavy chain H1

IVs:

Instrumental variables

IVW:

Inverse variance weighted

LD:

Linkage disequilibrium

LTOR3:

Ragulator complex protein LAMTOR3

MHC:

Major histocompatibility complex

MR:

Mendelian randomization

MR-PRESSO:

Mendelian randomization pleiotropy residual sum and outlier

MVMR:

Multivariable MR

pQTL:

Protein quantitative trait loci

PVR:

Poliovirus receptor

sCD14:

Monocyte differentiation antigen CD14, soluble

SIGIRR:

Single Ig IL-1-related receptor

SNP:

Single nucleotide polymorphism

T2D:

Type 2 diabetes

TM11D:

Transmembrane protease serine 11D

TTD:

Therapeutic target database

UKBB:

UK Biobank

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Acknowledgements

We are grateful to all studies that released GWAS summary statistics for use in this study.

Funding

YFP was partially supported by the funding from national natural science foundation of China (32170670) and a project funded by the Priority Academic Program Development (PAPD) of Jiangsu higher education institutions.

Author information

Authors and Affiliations

  1. Department of Epidemiology and Biostatistics, School of Public Health, Suzhou Medical College of Soochow University, Suzhou, People’s Republic of China

    Bai-Xue Han, Qi-Gang Zhao, Shan-Shan Yan, Qian Xu, Xin-Ling Ma & Yu-Fang Pei

  2. Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Suzhou, People’s Republic of China

    Bai-Xue Han, Qi-Gang Zhao, Shan-Shan Yan, Qian Xu & Xin-Ling Ma

  3. Department of Orthopedics, Taicang Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China

    Tian-Ye Huang & Yuan Luo

Authors
  1. Bai-Xue Han
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  2. Tian-Ye Huang
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  3. Qi-Gang Zhao
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  4. Shan-Shan Yan
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  5. Qian Xu
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  6. Xin-Ling Ma
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  7. Yuan Luo
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  8. Yu-Fang Pei
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Contributions

YFP and YL designed the study. BXH and TYH collected the data. BXH and TYH analyzed the data. SSY, QX, QGZ, XLM and BXH performed the literature search. BXH drafted the early version of the manuscript. YFP and YL jointly supervised the study. All authors were involved in writing the paper and had final approval of the submitted and published versions.

Corresponding authors

Correspondence to Yuan Luo or Yu-Fang Pei.

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Han, BX., Huang, TY., Zhao, QG. et al. Screening Plasma Proteins for the Putative Drug Targets for Carpal Tunnel Syndrome. Cell Mol Neurobiol 43, 4333–4344 (2023). https://doi.org/10.1007/s10571-023-01428-3

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  • DOI: https://doi.org/10.1007/s10571-023-01428-3

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