Specific gene domains most commonly affected by CHIP-driver mutations predicting mortality in severe aortic stenosis after transcatheter aortic valve implantation

Abstract

Abstract Background Clonal haematopoiesis of indeterminate potential (CHIP), i.e. expanded somatic blood-cell clones in persons without any other haematological abnormalities, has been shown to predict survival in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve implantation (TAVI). DNMT3A and TET2 are the two most common CHIP-driver mutations. In patients with haematological disorders, specific domains of TET2 and DNMT3A most commonly accounting for detected mutations vary across different haematological malignancies. Purpose The aim of our study was to analyse the distribution of the mutated domains in CHIP-driver genes in patients with severe AS undergoing TAVI, in order to gain a mechanistic insight on its specific role in AS. Methods We used next-generation sequencing to identify mutated domains in DNMT3A and/or TET2 genes in 453 consecutive patients with severe AS undergoing TAVI. The site of detected mutations in DNMT3A was classified as located to the conserved proline-tryptophan-proline-tryptophan (PWWP), zinc-finger (ADD), or methyl-transferase (MTase) domains, or to other non-coding regions. For TET2, mutations were classified as involving dioxygenase (DD) or Cys-rich (CD) domains. Only mutations that are classified as moderate-to-high based on their functional impact on the protein were considered. Results Out of 147 patients with a CHIP-driver mutation, 92 had DNMT3A mutations and 71 had TET2 mutations, with mutations in both genes being present in 16 patients. MTase was the most commonly involved domain in DNMT3A (61% of cases). Other affected regions were PWWP/ADD/MTase (12%), no domain/non-coding region (11%), ADD (7%), ADD/MTase (5%), and PWWP (4%) (Figure 1). Overall, MTase mutations were found in a large majority of patients (78%). Such a “hot-spot” appears to be in line with a potential recently suggested mechanism involving DNA methylation. Most common locations for mutations in TET2 were CD/DD (48%), followed by DD (33%), CD (15%) and no domain/non-coding region (4%) (Figure 2). Overall, mutations in DD were found in a large majority of patients (81%). TET2 appears to be involved in myeloid expansion and impaired immune function with increasing age; this could play a role in its impact on heart disorders. Conclusion In patients with severe AS undergoing TAVI, mutations in certain sites within the most common CHIP-driver genes (MTase domain in DNMT3A gene and CD domain in TET2 gene), appear to be mostly affected. These findings could be a first step to identify “hot spots” for mutated domains associated with severe AS requiring TAVI and suggest some potential mechanistic explanations. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): The study was further supported by the German Center for Cardiovascular Research (DZHK).