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Mendelian randomization of circulating proteome identifies IFN-γ as a druggable target in aplastic anemia

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Abstract

Background

Aplastic anemia (AA) is a kind of bone marrow failure (BMF) characterized by pancytopenia with hypoplasia/aplasia of bone marrow. Immunosuppressive therapy and bone marrow transplantation are effective methods to treat severe aplastic anemia. However, the efficacy is limited by complications and the availability of suitable donors. This study aimed to determine whether any circulating druggable protein levels may have causal effects on AA and provide potential novel drug targets for AA.

Methods

Genetic variants strongly associated with circulating druggable protein levels to perform Mendelian randomization (MR) analyses were used. The effect of these druggable protein levels on AA risk was measured using the summary statistics from a large-scale proteomic genome-wide association study (GWAS) and FinnGen database (https://www.finngen.fi/en/access_results). Multivariable MR analyses were performed to statistically adjust for potential confounders, including platelet counts, reticulocyte counts, neutrophil counts, and proportions of hematopoietic stem cells.

Results

The data showed that higher level of circulating IFN-γ levels was causally associated with AA susceptibility. The causal effects of circulating IFN-γ levels on the AA were broadly consistent, when adjusted for platelet counts, reticulocyte counts, neutrophil counts and proportions of hematopoietic stem cells.

Conclusions

High levels of circulating IFN-γ levels might increase the risk of AA and might provide a potential novel target for AA.

Highlights

Genetic variants associated with circulating proteome to perform Mendelian randomization analyses in aplastic anemia.

A higher level of circulating IFN-γ levels was causally associated with AA susceptibility.

Mendelian randomization of circulating proteome provided large-scale epidemiological evidence and a potential drug target for AA.

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Data availability

All data generated or analyzed during this study are included in this published article [and its supplementary information files].

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Acknowledgments

This study was conducted at the Institute of Clinical Science of Zhongshan Hospital, Fudan University. The study was supported by the Medical Science Data Center of Shanghai Medical College of Fudan University. We sincerely thank all staff and participants for their important contributions.

Funding

This work was supported by grants from the National Natural Science Foundation of China (82370130, 81870098), Program of the Shanghai Academic/Technology Researcher leader (20XD1401000), and Shanghai Engineering Research Center of Tumor Multi-Target Gene Diagnosis (20DZ2254300), and Key Subject Construction Program of Shanghai Health Administrative Authority (ZK2019B30).

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Author notes

  1. Shanshan Qin MD and Yingxin Jiang MD contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China

    Shanshan Qin, Yang Ou, Yanxia Zhan, Lili Ji, Pengcheng Xu, Xia Shao & Yunfeng Cheng

  2. Center for Tumor Diagnosis & Therapy, Jinshan Hospital, Fudan University, Shanghai, 201508, China

    Shanshan Qin, Yang Ou, Xia Shao & Yunfeng Cheng

  3. Centenary Institute, The University of Sydney, Sydney, NSW, 2050, Australia

    Yingxin Jiang

  4. Charles Perkins Centre, The University of Sydney, Sydney, NSW, 2006, Australia

    Yingxin Jiang

  5. Department of Thoracic Surgery, Zhongshan-Xuhui Hospital, Fudan University, Shanghai, 200237, China

    Hao Chen

  6. Department of Hematology, Huashan Hospital, Fudan University, Shanghai, 200040, China

    Tong Chen

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Contributions

Shanshan Qin, Yingxin Jiang, Yang Ou, Yanxia Zhan, and Yunfeng Cheng performed the literature review, drafted and revised the manuscript; Hao Chen, Tong Chen and Yunfeng Cheng contributed to the critical revision of the manuscript; Yanxia Zhan, Lili Ji, Xia Shao, Pengcheng Xu, Shanshan Qin, Hao Chen, and Yunfeng Cheng analyzed data. All authors read and approved the final manuscript.

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Correspondence to Tong Chen or Yunfeng Cheng.

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Qin, S., Jiang, Y., Ou, Y. et al. Mendelian randomization of circulating proteome identifies IFN-γ as a druggable target in aplastic anemia. Ann Hematol (2024). https://doi.org/10.1007/s00277-024-05746-4

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