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Identification of 8 Rare Deleterious Variants in ADAMTS13 by Next-generation Sequencing in a Chinese Population with Thrombotic Thrombocytopenic Purpura

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Abstract

Objective

Thrombotic thrombocytopenic purpura (TTP) is a rare and fatal disease caused by a severe deficiency in the metalloprotease ADAMTS13 and is characterized by thrombotic microangiopathy. The present study aimed to investigate the genes and variants associated with TTP in a Chinese population.

Methods

Target sequencing was performed on 220 genes related to complements, coagulation factors, platelets, fibrinolytic, endothelial, inflammatory, and anticoagulation systems in 207 TTP patients and 574 controls. Subsequently, logistic regression analysis was carried out to identify the TTP-associated genes based on the counts of rare deleterious variants in the region of a certain gene. Moreover, the associations between common variants and TTP were also investigated.

Results

ADAMTS13 was the only TTP-associated gene (OR = 3.77; 95% CI: 1.82–7.81; P=3.6×10ȡ4) containing rare deleterious variants in TTP patients. Among these 8 variants, 5 novel rare variants that might contribute to TTP were identified, including rs200594025, rs782492477, c.T1928G (p.I643S), c.3336_3361del (p.Q1114Afs*20), and c.3469_3470del (p.A1158Sfs*17). No common variants associated with TTP were identified under the stringent criteria of correction for multiple testing.

Conclusion

ADAMTS13 is the primary gene related to TTP. The genetic variants associated with the occurrence of TTP were slightly different between the Chinese and European populations.

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References

  1. Sadler JE. Pathophysiology of thrombotic thrombocytopenic purpura. Blood, 2017,130(10):1181–1188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Kremer Hovinga JA, George JN. Hereditary Thrombotic Thrombocytopenic Purpura. N Engl J Med, 2019,381(17):1653–1662

    Article  PubMed  Google Scholar 

  3. Masias C, Cataland SR. The role of ADAMTS13 testing in the diagnosis and management of thrombotic microangiopathies and thrombosis. Blood, 2018,132(9):903–910

    Article  CAS  PubMed  Google Scholar 

  4. Lotta LA, Garagiola I, Palla R, et al. ADAMTS13 mutations and polymorphisms in congenital thrombotic thrombocytopenic purpura. Hum Mutat, 2010,31(1):11–19

    Article  CAS  PubMed  Google Scholar 

  5. Kremer Hovinga JA, Heeb SR, Skowronska M, et al. Pathophysiology of thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. J Thromb Haemost, 2018,16(4):618–629

    Article  CAS  PubMed  Google Scholar 

  6. van Dorland HA, Taleghani MM, Sakai K, et al. The International Hereditary Thrombotic Thrombocytopenic Purpura Registry: key findings at enrollment until 2017. Haematologica, 2019,104(10):2107–2115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. von Krogh AS, Quist-Paulsen P, Waage A, et al. High prevalence of hereditary thrombotic thrombocytopenic purpura in central Norway: from clinical observation to evidence. J Thromb Haemost, 2016,14(1):73–82

    Article  CAS  PubMed  Google Scholar 

  8. de Vries PS, Boender J, Sonneveld MA, et al. Genetic variants in the ADAMTS13 and SUPT3H genes are associated with ADAMTS13 activity. Blood, 2015,125(25):3949–3955

    Article  CAS  PubMed  Google Scholar 

  9. Mancini I, Ricano-Ponce I, Pappalardo E, et al. Immunochip analysis identifies novel susceptibility loci in the human leukocyte antigen region for acquired thrombotic thrombocytopenic purpura. J Thromb Haemost, 2016,14(12):2356–2367

    Article  CAS  PubMed  Google Scholar 

  10. Joly BS, Coppo P, Veyradier A. An update on pathogenesis and diagnosis of thrombotic thrombocytopenic purpura. Expert Rev Hematol, 2019,12(6):383–395

    Article  CAS  PubMed  Google Scholar 

  11. Scully M, Cataland S, Coppo P, et al. Consensus on the standardization of terminology in thrombotic thrombocytopenic purpura and related thrombotic microangiopathies. J Thromb Haemost, 2017,15(2):312–322

    Article  CAS  PubMed  Google Scholar 

  12. Palla R, Valsecchi C, Bajetta M, et al. Evaluation of assay methods to measure plasma ADAMTS13 activity in thrombotic microangiopathies. Thromb Haemost, 2011,105(2):381–385

    Article  CAS  PubMed  Google Scholar 

  13. Mancini I, Valsecchi C, Lotta LA, et al. FRETS-VWF73 rather than CBA assay reflects ADAMTS13 proteolytic activity in acquired thrombotic thrombocytopenic purpura patients. Thromb Haemost, 2014,112(2):297–303

    Article  CAS  PubMed  Google Scholar 

  14. Kremer Hovinga JA, Mottini M, Lämmle B. Measurement of ADAMTS-13 activity in plasma by the FRETS-VWF73 assay: comparison with other assay methods. J Thromb Haemost, 2006,4(5):1146–1148

    Article  CAS  PubMed  Google Scholar 

  15. Chen S, Zhou Y, Chen Y, et al. fastp: an ultra-fast all-in-one FASTQ preprocessor. Bioinformatics, 2018,34(17):i884–i890

    Article  PubMed  PubMed Central  Google Scholar 

  16. McKenna A, Hanna M, Banks E, et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res, 2010,20(9):1297–1303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics, 2009,25(14):1754–1760

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Danecek P, Bonfield JK, Liddle J, et al. Twelve years of SAMtools and BCFtools. Gigascience, 2021,10(2):giab008

    Article  PubMed  PubMed Central  Google Scholar 

  19. Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res, 2010,38(16):e164

    Article  PubMed  PubMed Central  Google Scholar 

  20. Wang XJ, Xu XQ, Sun K, et al. Association of Rare PTGIS Variants With Susceptibility and Pulmonary Vascular Response in Patients With Idiopathic Pulmonary Arterial Hypertension. JAMA Cardiol, 2020,5(6):677–684

    Article  PubMed  Google Scholar 

  21. Povysil G, Petrovski S, Hostyk J, et al. Rare-variant collapsing analyses for complex traits: guidelines and applications. Nat Rev Genet, 2019,20(12):747–759

    Article  CAS  PubMed  Google Scholar 

  22. Camilleri RS, Scully M, Thomas M, et al. A phenotype-genotype correlation of ADAMTS13 mutations in congenital thrombotic thrombocytopenic purpura patients treated in the United Kingdom. J Thromb Haemost, 2012,10(9):1792–1801

    Article  CAS  PubMed  Google Scholar 

  23. Levy GG, Nichols WC, Lian EC, et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature, 2001,413(6855): 488–494

    Article  CAS  PubMed  Google Scholar 

  24. Liu F, Jin J, Dong NZ, et al. Identification of two novel mutations in ADAMTS13 gene in a patient with hereditary thrombotic thrombocytopenic purpura. Zhonghua Xue Ye Xue Za Zhi (Chinese), 2005,26(9):521–524

    CAS  Google Scholar 

  25. Rank CU, Kremer Hovinga J, Taleghani MM, et al. Congenital thrombotic thrombocytopenic purpura caused by new compound heterozygous mutations of the ADAMTS13 gene. Eur J Haematol, 2014,92(2):168–171

    Article  CAS  PubMed  Google Scholar 

  26. Matsumoto M, Kokame K, Soejima K, et al. Molecular characterization of ADAMTS13 gene mutations in Japanese patients with Upshaw-Schulman syndrome. Blood, 2004,103(4):1305–1310

    Article  CAS  PubMed  Google Scholar 

  27. Plaimauer B, Fuhrmann J, Mohr G, et al. Modulation of ADAMTS13 secretion and specific activity by a combination of common amino acid polymorphisms and a missense mutation. Blood, 2006,107(1):118–125

    Article  CAS  PubMed  Google Scholar 

  28. Ma Q, Jacobi PM, Emmer BT, et al. Genetic variants in ADAMTS13 as well as smoking are major determinants of plasma ADAMTS13 levels. Blood Adv, 2017,1(15):1037–1046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kokame K, Matsumoto M, Soejima K, et al. Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity. Proc Natl Acad Sci USA, 2002,99(18):11902–11907

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Fidalgo T, Martinho P, Pinto CS, et al. Combined study of ADAMTS13 and complement genes in the diagnosis of thrombotic microangiopathies using next-generation sequencing. Res Pract Thromb Haemost, 2017,1(1):69–80

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Xiao Wang & Jing-Jing Jiang

  2. Department of Epidemiology and Biostatistics, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Xing-jie Hao & Cheng-guqiu Dai

  3. Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Ya-jie Ding, Lv Xiong & Jun Deng

Authors
  1. Xiao Wang
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  2. Xing-jie Hao
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  3. Cheng-guqiu Dai
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  4. Ya-jie Ding
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  5. Lv Xiong
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  6. Jun Deng
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  7. Jing-Jing Jiang
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Corresponding authors

Correspondence to Jun Deng or Jing-Jing Jiang.

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The authors declare that they have no conflicts of interest.

Additional information

This study was supported by the National Natural Science Foundation of China (No. 82003561).

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Wang, X., Hao, Xj., Dai, Cg. et al. Identification of 8 Rare Deleterious Variants in ADAMTS13 by Next-generation Sequencing in a Chinese Population with Thrombotic Thrombocytopenic Purpura. CURR MED SCI 43, 1043–1050 (2023). https://doi.org/10.1007/s11596-023-2793-7

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  • DOI: https://doi.org/10.1007/s11596-023-2793-7

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