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Massively parallel variant characterization identifies NUDT15 alleles associated with thiopurine toxicity

Suiter, Chase C ; Moriyama, Takaya ; Matreyek, Kenneth A ; Yang, Wentao ; Scaletti, Emma Rose LU ; Nishii, Rina ; Yang, Wenjian ; Hoshitsuki, Keito ; Singh, Minu and Trehan, Amita , et al. (2020) In Proceedings of the National Academy of Sciences of the United States of America 117(10). p.5394-5401
Abstract

As a prototype of genomics-guided precision medicine, individualized thiopurine dosing based on pharmacogenetics is a highly effective way to mitigate hematopoietic toxicity of this class of drugs. Recently, NUDT15 deficiency was identified as a genetic cause of thiopurine toxicity, and NUDT15-informed preemptive dose reduction was quickly adopted in clinical settings. To exhaustively identify pharmacogenetic variants in this gene, we developed massively parallel NUDT15 function assays to determine the variants' effect on protein abundance and thiopurine cytotoxicity. Of the 3,097 possible missense variants, we characterized the abundance of 2,922 variants and found 54 hotspot residues at which variants resulted in complete loss of... (More)

As a prototype of genomics-guided precision medicine, individualized thiopurine dosing based on pharmacogenetics is a highly effective way to mitigate hematopoietic toxicity of this class of drugs. Recently, NUDT15 deficiency was identified as a genetic cause of thiopurine toxicity, and NUDT15-informed preemptive dose reduction was quickly adopted in clinical settings. To exhaustively identify pharmacogenetic variants in this gene, we developed massively parallel NUDT15 function assays to determine the variants' effect on protein abundance and thiopurine cytotoxicity. Of the 3,097 possible missense variants, we characterized the abundance of 2,922 variants and found 54 hotspot residues at which variants resulted in complete loss of protein stability. Analyzing 2,935 variants in the thiopurine cytotoxicity-based assay, we identified 17 additional residues where variants altered NUDT15 activity without affecting protein stability. We identified structural elements key to NUDT15 stability and/or catalytical activity with single amino acid resolution. Functional effects for NUDT15 variants accurately predicted toxicity risk alleles in patients treated with thiopurines with far superior sensitivity and specificity compared to bioinformatic prediction algorithms. In conclusion, our massively parallel variant function assays identified 1,152 deleterious NUDT15 variants, providing a comprehensive reference of variant function and vastly improving the ability to implement pharmacogenetics-guided thiopurine treatment individualization.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Proceedings of the National Academy of Sciences of the United States of America
volume
117
issue
10
pages
8 pages
publisher
National Academy of Sciences
external identifiers
  • pmid:32094176
  • scopus:85081701576
ISSN
1091-6490
DOI
10.1073/pnas.1915680117
language
English
LU publication?
yes
id
c710ee61-be0f-428a-bda8-5601519d2638
date added to LUP
2020-03-06 08:04:26
date last changed
2024-06-13 12:33:00
@article{c710ee61-be0f-428a-bda8-5601519d2638,
  abstract     = {{<p>As a prototype of genomics-guided precision medicine, individualized thiopurine dosing based on pharmacogenetics is a highly effective way to mitigate hematopoietic toxicity of this class of drugs. Recently, NUDT15 deficiency was identified as a genetic cause of thiopurine toxicity, and NUDT15-informed preemptive dose reduction was quickly adopted in clinical settings. To exhaustively identify pharmacogenetic variants in this gene, we developed massively parallel NUDT15 function assays to determine the variants' effect on protein abundance and thiopurine cytotoxicity. Of the 3,097 possible missense variants, we characterized the abundance of 2,922 variants and found 54 hotspot residues at which variants resulted in complete loss of protein stability. Analyzing 2,935 variants in the thiopurine cytotoxicity-based assay, we identified 17 additional residues where variants altered NUDT15 activity without affecting protein stability. We identified structural elements key to NUDT15 stability and/or catalytical activity with single amino acid resolution. Functional effects for NUDT15 variants accurately predicted toxicity risk alleles in patients treated with thiopurines with far superior sensitivity and specificity compared to bioinformatic prediction algorithms. In conclusion, our massively parallel variant function assays identified 1,152 deleterious NUDT15 variants, providing a comprehensive reference of variant function and vastly improving the ability to implement pharmacogenetics-guided thiopurine treatment individualization.</p>}},
  author       = {{Suiter, Chase C and Moriyama, Takaya and Matreyek, Kenneth A and Yang, Wentao and Scaletti, Emma Rose and Nishii, Rina and Yang, Wenjian and Hoshitsuki, Keito and Singh, Minu and Trehan, Amita and Parish, Chris and Smith, Colton and Li, Lie and Bhojwani, Deepa and Yuen, Liz Y P and Li, Chi-Kong and Li, Chak-Ho and Yang, Yung-Li and Walker, Gareth J and Goodhand, James R and Kennedy, Nicholas A and Klussmann, Federico Antillon and Bhatia, Smita and Relling, Mary V and Kato, Motohiro and Hori, Hiroki and Bhatia, Prateek and Ahmad, Tariq and Yeoh, Allen E J and Stenmark, Pål and Fowler, Douglas M and Yang, Jun J}},
  issn         = {{1091-6490}},
  language     = {{eng}},
  month        = {{03}},
  number       = {{10}},
  pages        = {{5394--5401}},
  publisher    = {{National Academy of Sciences}},
  series       = {{Proceedings of the National Academy of Sciences of the United States of America}},
  title        = {{Massively parallel variant characterization identifies NUDT15 alleles associated with thiopurine toxicity}},
  url          = {{http://dx.doi.org/10.1073/pnas.1915680117}},
  doi          = {{10.1073/pnas.1915680117}},
  volume       = {{117}},
  year         = {{2020}},
}