Somatic TET2 Mutations are Associated with Giant Cell Arteritis
Somatic TET2 Mutations are Associated with Giant Cell Arteritis
Abstract ObjectiveGiant cell arteritis (GCA) is an age-related vasculitis. Prior studies have identified an association between GCA and hematologic malignancies (HM). How the presence of somatic mutations which drive development of HM, or clonal hematopoiesis (CH), may influence clinical outcomes in GCA is not well understood. MethodsTo examine an association between CH and GCA, we analyzed sequenced exomes of 470960 UK Biobank 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. ResultsUKB 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 (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, 3 of whom had HM at GCA diagnosis. TET2 mutations were associated with vision loss in patients with GCA (OR 4.33, p = 0.047). ConclusionsCH increases risk for development of GCA in a genotype-specific fashion, with 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.
Robinette Michelle L.、Liou Victor D.、Yu Zhi、Sekar Aswin、Brown Jared T.、Agrawal Mridul、Natarajan Pradeep、Chiou Carolina A.、Lu Jonathan E、Gibson Christopher J.、McDermott Gregory C.、Niroula Abhishek、Kramer Ryan J.、Mehta Arnav、Ebert Benjamin L.、Rao Deepak A.、Weeks Lachelle D.、Reshef Edith R.、Freitag Suzanne K.
Department of Medical Oncology, Dana-Farber Cancer Institute||Department of Medicine, Division of Rheumatology, Inflammation, and Immunity, Brigham and Women?ˉs HospitalOphthalmic Plastic Surgery Service, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School||The Permanente Medical Group, Kaiser Permanente Northern CaliforniaThe Broad Institute of Massachusetts Institute of Technology and Harvard||Cardiovascular Research Center, Massachusetts General HospitalDepartment of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Data Science, Dana-Farber Cancer InstituteDepartment of Medical Oncology, Dana-Farber Cancer InstituteThe Broad Institute of Massachusetts Institute of Technology and Harvard||Cardiovascular Research Center, Massachusetts General HospitalOphthalmic Plastic Surgery Service, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical SchoolOphthalmic Plastic Surgery Service, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical SchoolDepartment of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Medicine, Division of Rheumatology, Inflammation, and Immunity, Brigham and Women?ˉs HospitalDepartment of Medical Oncology, Dana-Farber Cancer Institute||The Broad Institute of Massachusetts Institute of Technology and Harvard||Department of Laboratory Medicine, Lund UniversityDepartment of Medical Oncology, Dana-Farber Cancer Institute||Duke University School of MedicineMassachusetts General Hospital Cancer Center and Harvard Medical SchoolDepartment of Medical Oncology, Dana-Farber Cancer Institute||The Broad Institute of Massachusetts Institute of Technology and Harvard||Howard Hughes Medical Institute, Dana-Farber Cancer InstituteDepartment of Medicine, Division of Rheumatology, Inflammation, and Immunity, Brigham and Women?ˉs HospitalDepartment of Medical Oncology, Dana-Farber Cancer Institute||Center for Leukemia and Center for Prevention of Progression, Dana-Farber Cancer InstituteOphthalmic Plastic Surgery Service, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School||Ophthalmic Plastic Surgery Service, Department of Ophthalmology, Boston Children?ˉs HospitalOphthalmic Plastic Surgery Service, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School
临床医学内科学遗传学
Robinette Michelle L.,Liou Victor D.,Yu Zhi,Sekar Aswin,Brown Jared T.,Agrawal Mridul,Natarajan Pradeep,Chiou Carolina A.,Lu Jonathan E,Gibson Christopher J.,McDermott Gregory C.,Niroula Abhishek,Kramer Ryan J.,Mehta Arnav,Ebert Benjamin L.,Rao Deepak A.,Weeks Lachelle D.,Reshef Edith R.,Freitag Suzanne K..Somatic TET2 Mutations are Associated with Giant Cell Arteritis[EB/OL].(2025-03-28)[2025-05-10].https://www.medrxiv.org/content/10.1101/2023.07.26.23292945.点此复制
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