No Longer as Vexing: The Role of Somatic Mutations in Rheumatic Diseases

Dr. Robinette explained that next-generation sequencing has revealed that somatic mutations are ubiquitous across the tissues of the body; this is one reason that the National Institutes of Health (NIH) has funded the Somatic Mosaicism across Human Tissues (SMaHT) Network, which aims to create an atlas of somatic mutations in different organs.⁷

Clonal Hematopoiesis

In particular, the study of clonal hematopoiesis (CH), the phenomenon of clonally expanded hematopoietic stem and progenitor cells that have acquired a selective growth advantage, has led to a better understanding of somatic genetic variation and outcomes for patients with malignant and nonmalignant diseases. Dr. Robinette explained that CH is now understood as a precursor to hematologic malignancies (especially myeloid neoplasms) and is associated with increased all-cause mortality and a higher incidence of cardiovascular disease.⁸

Of note for rheumatologists, Dr. Robinette et al. examined the sequenced exomes of more than 470,000 UK Biobank participants and found that individuals with CH had a 1.48-fold increased risk of developing GCA as compared with those without CH. The risk was highest among those individuals with cytopenias and those with mutations in TET2, a gene that is associated with the development of myeloid neoplasms. TET2 mutations were also associated with an increased risk of vision loss in patients with GCA.⁹ These findings suggest that somatic genetic testing may become important in the prognostic evaluation of patients with GCA in the future.

From both lectures it is clear that the concept of what constitutes a genetic disease and the role that genetic sequencing should play in the practice of a rheumatologist is fast-evolving. It is worth paying attention to this growing area, and only time will tell what insights will be gained by researchers willing to explore the wide world of somatic mutations.

Dr. Jason Liebowitz

Jason Liebowitz, MD, FACR, is an assistant professor of medicine in the Division of Rheumatology at Columbia University Vagelos College of Physicians and Surgeons, New York.

References

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