Association of Somatic TET2 Mutations With Giant Cell Arteritis

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 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.

Figure 1.. Genetic profile of CH in GCA cohorts.

A) Cumulative incidence of GCA in individuals with CCUS, CHIP and no CHIP/CCUS. P-values are determined by log-rank test. B) Multivariable Cox proportional hazards model showing hazard ratios (HR) for incident GCA among individuals from UKB with CHIP/CCUS relative to no CHIP/CCUS; CHIP or CCUS relative to no CHIP/CCUS; and DNMT3A, TET2, or ASXL1. In all cases, multivariable models were performed with no CHIP/CCUS as the reference group. Forrest plot displays main effects (HR) with 95% confidence intervals. Numerical values for HR (95% CI) with associated p-values are provided to the right of each graph. B,C) Characteristics of CH in individuals with GCA from MGB. B) Stacked bar graph of individuals with mutations VAF ≥0.02 per gene. C) VAF of mutations in sorted cells per cell type. Colors represent gene mutated and shapes represent distinct mutations per gene, with prevalent MN outlined in black. Monocyte versus NK cell VAF: CH + MN p-adj = 0.2783, CH only p-adj = 0.5781. Monocyte versus B cell VAF: CH + MN p-adj = 0.0059; CH only p-adj = 0.0937. Monocyte versus T cell VAF: CH + MN p-adj = 0.0030, CH only p-adj = 0.04680.

Figure 2:. Clinical outcomes in GCA patients with CH.

A) Co-occurrence matrix of severe outcomes in GCA clustered by outcome and genotype, where individuals are represented by one column. B) Forrest plot demonstrating odds ratio for vision loss with TET2 mutation across the MGB cohort. C) Pre-steroid CRP in GCA patients with vision loss with somatic mutation versus no mutation. D) Pre-steroid lymphocyte percentage and absolute lymphocytes counts in GCA patients with vision loss compared to those without vision loss, excluding prevalent MN. E) Maximum VAF of individuals with CHIP/CCUS and vision loss, compared to those without vision loss.