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CTLA-4 polymorphisms are associated with treatment outcomes of patients with multiple myeloma receiving bortezomib-based regimens

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Abstract

Single-nucleotide polymorphisms (SNPs) of cytotoxic T lymphocyte antigen-4 (CTLA-4) are important risk factors associated with autoimmune diseases and malignancies. This study explored the association of CTLA-4SNPs with the development of myeloma and evaluated the outcome of patients receiving bortezomib-based regimens in relation to CTLA-4SNPs. Peripheral blood samples from 86 patients with multiple myeloma (MM) and 154 healthy controls were obtained to investigate CTLA4 polymorphisms. Five SNP genotypes of CTLA-4, namely, −1772 (rs733618), −1661 (rs4553808), −318 (rs5742909), CT60 (rs3087243), and +49 (rs231775), were evaluated through TaqMan SNP genotyping assays (Applied Biosystems). Some of the CTLA-4 polymorphisms displayed frequencies that vary among ethnic groups. Kaplan–Meier analysis revealed that patients with rs733618 GG showed a significantly lower disease-free survival (0 vs. 57.4%, P = 0.020) and overall survival (46.3 vs. 83.3%, P = 0.026) than those with GA+AA following bortezomib-based therapy. Multivariate analyses showed that rs733618 GG was a risk factor for OS (HR = 0.012; 95% CI = 0.001–0.199; P = 0.002). The incidence of nonhematologic grade 3/4 adverse events significantly increased in the rs4553808 GG+GA group compared with that in the AA group (P = 0.036). CTLA-4 rs733618 GG reduced the progression-free survival and the overall survival of patients with MM who received bortezomib-based therapy. Information regarding CTLA-4 polymorphisms and haplotypes may be used to improve MM therapy. Future studies must determine the precise effect of CTLA-4 polymorphisms and haplotypes on MM therapy outcomes by using different cohorts with a large number of subjects.

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Acknowledgements

We are grateful to all colleagues for their participation in this research.

Funding

This work was supported by the Key Program of the National Natural Science Foundation of China (81230013, 81530046), the Innovative Research Groups of the National Natural Science Foundation of China (81621001), the National Natural Science Foundation of China (grants 81372535 and 81670192), the Beijing Municipal Science and Technology Commission (no. Z121107002612035), the Scientific Research Foundation for Capital Medicine Development (2011-4022-08), and the China National Science and Technology Major Project during12th Five-Year Plan Period (2012ZX09303019).

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  1. Xiao-Ying Qin and Jin Lu contributed equally to this work.

Authors and Affiliations

  1. Peking University People’s Hospital, Peking University Institute of Hematology, 11 Xizhimen South Street, Beijing, 100044, People’s Republic of China

    Xiao-Ying Qin, Jin Lu, Guo-Xuan Li, Lei Wen, Yang Liu, Lan-Ping Xu, Ying-Jun Chang, Kai-Yan Liu & Xiao-Jun Huang

  2. Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China

    Xiao-Ying Qin, Jin Lu, Guo-Xuan Li, Lei Wen, Yang Liu, Lan-Ping Xu, Ying-Jun Chang, Kai-Yan Liu & Xiao-Jun Huang

  3. State Key Laboratory of Protein and Plant Gene Research, Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing, China

    Zheng-Fan Jiang

  4. Peking University-Tsinghua University Joint Center for Life Sciences, Beijing, China

    Zheng-Fan Jiang

  5. Peking-Tsinghua Center for Life Sciences, Beijing, China

    Xiao-Jun Huang

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Contributions

XYQ conducted molecular genetic studies. XYQ and JL collected and analyzed data and wrote the manuscript. GXL, LW, YL, LPX, YJC, KYL, and ZFJ collected and interpreted the data. XJH designed the study and critically revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Xiao-Jun Huang.

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All patients provided informed consent for treatment, which was performed using a protocol reviewed and approved by the Peking University Institute of Hematology. All healthy individuals also provided written informed consent. The study was conducted in accordance with the principles of the Declaration of Helsinki.

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The authors declare that they have no conflicts of interest.

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Qin, XY., Lu, J., Li, GX. et al. CTLA-4 polymorphisms are associated with treatment outcomes of patients with multiple myeloma receiving bortezomib-based regimens. Ann Hematol 97, 485–495 (2018). https://doi.org/10.1007/s00277-017-3203-7

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