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

Shanshan Qin; Yingxin Jiang; Yang Ou; Yanxia Zhan; Lili Ji; Pengcheng Xu; Xia Shao; Hao Chen; Tong Chen; Yunfeng Cheng

doi:10.1007/s00277-024-05746-4

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

Ann Hematol. 2024 Apr 22. doi: 10.1007/s00277-024-05746-4. Online ahead of print.

Authors

Shanshan Qin^#^{1

2}, Yingxin Jiang^#^{3

4}, Yang Ou^{1

2}, Yanxia Zhan¹, Lili Ji¹, Pengcheng Xu¹, Xia Shao^{1

2}, Hao Chen⁵, Tong Chen⁶, Yunfeng Cheng^{7

8}

Affiliations

¹ Department of Hematology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
² Center for Tumor Diagnosis & Therapy, Jinshan Hospital, Fudan University, Shanghai, 201508, China.
³ Centenary Institute, The University of Sydney, Sydney, NSW, 2050, Australia.
⁴ Charles Perkins Centre, The University of Sydney, Sydney, NSW, 2006, Australia.
⁵ Department of Thoracic Surgery, Zhongshan-Xuhui Hospital, Fudan University, Shanghai, 200237, China.
⁶ Department of Hematology, Huashan Hospital, Fudan University, Shanghai, 200040, China. chentong@fudan.edu.cn.
⁷ Department of Hematology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. yfcheng@fudan.edu.cn.
⁸ Center for Tumor Diagnosis & Therapy, Jinshan Hospital, Fudan University, Shanghai, 201508, China. yfcheng@fudan.edu.cn.

^# Contributed equally.

PMID: 38644415
DOI: 10.1007/s00277-024-05746-4

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.

Keywords: Aplastic anemia; Cytokine; Genome-wide association study (GWAS); Mendelian randomization (MR).

Abstract

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