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Association of Somatic TET2 Mutations With Giant Cell Arteritis

Robinette, Michelle L. ; Weeks, Lachelle D. ; Kramer, Ryan J. ; Agrawal, Mridul ; Gibson, Christopher J. ; Yu, Zhi ; Sekar, Aswin ; Mehta, Arnav ; Niroula, Abhishek LU and Brown, Jared T. , et al. (2023) In Arthritis and Rheumatology
Abstract

Objective: Giant cell arteritis (GCA) is an age-related vasculitis. Prior studies have identified an association between GCA and hematologic malignancies (HMs). How the presence of somatic mutations that drive the development of HMs, or clonal hematopoiesis (CH), may influence clinical outcomes in GCA is not well understood. Methods: To examine an association between CH and GCA, we analyzed sequenced exomes of 470,960 UK Biobank (UKB) participants for the presence of CH and used multivariable Cox regression. To examine the clinical phenotype of GCA in patients with and without somatic mutations across the spectrum of CH to HM, we performed targeted sequencing of blood samples and electronic health record review on 114 patients with GCA... (More)

Objective: Giant cell arteritis (GCA) is an age-related vasculitis. Prior studies have identified an association between GCA and hematologic malignancies (HMs). How the presence of somatic mutations that drive the development of HMs, or clonal hematopoiesis (CH), may influence clinical outcomes in GCA is not well understood. Methods: To examine an association between CH and GCA, we analyzed sequenced exomes of 470,960 UK Biobank (UKB) participants for the presence of CH and used multivariable Cox regression. To examine the clinical phenotype of GCA in patients with and without somatic mutations across the spectrum of CH to HM, we performed targeted sequencing of blood samples and electronic health record review on 114 patients with GCA seen at our institution. We then examined associations between specific clonal mutations and GCA disease manifestations. Results: UKB participants with CH had a 1.48-fold increased risk of incident GCA compared to UKB participants without CH. GCA risk was highest among individuals with cytopenia (hazard ratio [HR] 2.98, P = 0.00178) and with TET2 mutation (HR 2.02, P = 0.00116). Mutations were detected in 27.2% of our institutional GCA cohort, three of whom had HM at GCA diagnosis. TET2 mutations were associated with vision loss in patients with GCA (odds ratio 4.33, P = 0.047). Conclusions: CH increases risk for development of GCA in a genotype-specific manner, with the greatest risk being conferred by the presence of mutations in TET2. Somatic TET2 mutations likewise increase the risk of GCA-associated vision loss. Integration of somatic genetic testing in GCA diagnostics may be warranted in the future.

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type
Contribution to journal
publication status
epub
subject
in
Arthritis and Rheumatology
publisher
John Wiley & Sons Inc.
external identifiers
  • pmid:37909388
  • scopus:85184183840
ISSN
2326-5191
DOI
10.1002/art.42738
language
English
LU publication?
yes
id
42ac2fd0-87e1-436a-9165-4445b7fc4cfc
date added to LUP
2024-02-27 11:47:32
date last changed
2024-04-12 13:09:30
@article{42ac2fd0-87e1-436a-9165-4445b7fc4cfc,
  abstract     = {{<p>Objective: Giant cell arteritis (GCA) is an age-related vasculitis. Prior studies have identified an association between GCA and hematologic malignancies (HMs). How the presence of somatic mutations that drive the development of HMs, or clonal hematopoiesis (CH), may influence clinical outcomes in GCA is not well understood. Methods: To examine an association between CH and GCA, we analyzed sequenced exomes of 470,960 UK Biobank (UKB) participants for the presence of CH and used multivariable Cox regression. To examine the clinical phenotype of GCA in patients with and without somatic mutations across the spectrum of CH to HM, we performed targeted sequencing of blood samples and electronic health record review on 114 patients with GCA seen at our institution. We then examined associations between specific clonal mutations and GCA disease manifestations. Results: UKB participants with CH had a 1.48-fold increased risk of incident GCA compared to UKB participants without CH. GCA risk was highest among individuals with cytopenia (hazard ratio [HR] 2.98, P = 0.00178) and with TET2 mutation (HR 2.02, P = 0.00116). Mutations were detected in 27.2% of our institutional GCA cohort, three of whom had HM at GCA diagnosis. TET2 mutations were associated with vision loss in patients with GCA (odds ratio 4.33, P = 0.047). Conclusions: CH increases risk for development of GCA in a genotype-specific manner, with the greatest risk being conferred by the presence of mutations in TET2. Somatic TET2 mutations likewise increase the risk of GCA-associated vision loss. Integration of somatic genetic testing in GCA diagnostics may be warranted in the future.</p>}},
  author       = {{Robinette, Michelle L. and Weeks, Lachelle D. and Kramer, Ryan J. and Agrawal, Mridul and Gibson, Christopher J. and Yu, Zhi and Sekar, Aswin and Mehta, Arnav and Niroula, Abhishek and Brown, Jared T. and McDermott, Gregory C. and Reshef, Edith R. and Lu, Jonathan E. and Liou, Victor D. and Chiou, Carolina A. and Natarajan, Pradeep and Freitag, Suzanne K. and Rao, Deepak A. and Ebert, Benjamin L.}},
  issn         = {{2326-5191}},
  language     = {{eng}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Arthritis and Rheumatology}},
  title        = {{Association of Somatic TET2 Mutations With Giant Cell Arteritis}},
  url          = {{http://dx.doi.org/10.1002/art.42738}},
  doi          = {{10.1002/art.42738}},
  year         = {{2023}},
}