A new study reveals that the pool of genes involved in clonal hematopoiesis is larger than previously thought, and sheds light on the implications for disease and diagnostic testing.
Scientists have discovered 17 more genes that cause abnormal proliferation of mutated blood cells with age. Nature GeneticsIt provides a more comprehensive view of the genetic factors behind clonal hematopoiesis, a process that is associated with aging and leads to an increased risk of blood cancers.
Researchers from the Wellcome Sanger Institute, Calico Life Sciences in California, and the University of Cambridge analyzed sequence data from more than 200,000 people from the UK Biobank cohort. They looked for genes that signal “positive selection,” where mutations lead to a significant expansion of the mutant cell population over time.
The 17 newly discovered genes were found to have similar disease associations to previously known clonal hematopoietic mutations, highlighting their clinical importance in promoting the accumulation of mutated blood cell clones.
Uncovering these previously unrecognized genetic factors opens new avenues for studying the molecular mechanisms underlying clonal hematopoiesis and its role in disease development, potentially leading to new ways to promote healthier aging and potentially leading to better genetic tests to help identify risk for blood cancers and cardiovascular disease.
As we age, cells accumulate random genetic mutations. Some of these mutations confer a competitive growth advantage, allowing mutant cells to proliferate and outnumber healthy cells, forming large “clones” or populations of identical mutant cells. When this positive selection occurs in blood stem cells, it is called clonal hematopoiesis. This process is linked to blood cancers, cardiovascular disease, and other age-related diseases.
Previous studies have identified approximately 70 genes associated with clonal hematopoiesis, but most recently observed cases did not show mutations in any of these known driver genes, suggesting that additional genetic factors are involved.
Leveraging whole-exome sequencing data from over 200,000 individuals from the UK Biobank cohort, the researchers set out to map distinctive patterns of positive selection in the ageing blood system. Beyond the known set of factors, the researchers identified 17 genes that promote the accumulation of mutant cell clones in the blood.
Incorporation of these newly identified genetic variants increased the incidence of clonal hematopoiesis in the UK Biobank cohort by 18 percent, highlighting their impact on ageing.
Dr Michael Spencer Chapman, co-first author of the study from the Wellcome Sanger Institute, said: “Existing genetic tests have been useful for early detection of disease, but our findings suggest that they could be improved upon further. By incorporating an additional 17 genes associated with clonal haematopoiesis, we could enhance genetic testing methods to more accurately identify the associated risk of blood cancers and cardiovascular disease.”
Nick Bernstein, co-first author of the study, formerly of Calico Life Sciences in California and now based at New Limit, said: “The newly identified genes now give us a more complete picture to explore strategies to slow or reverse the overgrowth of abnormal mutant cells in the blood and promote healthier ageing. These genes appear to influence inflammation and immunity, which are key drivers of diseases such as heart disease and stroke. While interventions based on this research are still a long way off, it opens up the possibility of future treatments for a wide range of diseases.”
Dr Jyoti Nangaria, lead author of the study from the Wellcome Sanger Institute and Wellcome-MRC Cambridge Stem Cell Institute at the University of Cambridge, said: “Our study has uncovered a broader set of genes that drive the accumulation of mutated blood cell clones with age, but this is just the beginning. Larger studies in diverse populations are needed to identify the remaining driver genes and gain further insight into the relevance of this process to disease.”
