Researchers Uncover More Genes Linked to Clonal Hematopoiesis

Researchers have identified 17 more genes that cause the aberrant proliferation of blood cells with mutations as humans age. The results were published in the journal Nature Genetics. It offers a more comprehensive understanding of the genetic components underlying clonal hemopoiesis, a process connected to aging and a higher risk of blood cancers.

Scientists from the University of Cambridge, Calico Life Sciences in California, and the Wellcome Sanger Institute examined sequencing data from more than 200,000 members of the UK Biobank cohort. They looked for genes exhibiting “positive selection” signals, which occur when mutations cause mutant cell populations to significantly grow over time.

The clinical importance of the 17 recently identified genes in promoting the generation of mutant blood cell clones was highlighted by the discovery that they shared comparable illness correlations with previously identified clonal haematopoiesis mutations.

The discovery of these hitherto unknown genetic factors creates new opportunities for researching the molecular processes underpinning clonal hemopoiesis and its function in the onset of illness. Better genetic tests that assist in determining the risks of blood malignancies and cardiovascular illnesses may also result from it.

Human cells develop haphazard genetic alterations with aging. Certain mutations can provide mutant cells a competitive growth advantage, enabling them to proliferate and surpass healthy cells in number, resulting in the formation of substantial “clones” or communities of identical mutant cells.

Clonal hemopoiesis is the term for this process of positive selection in blood stem cells. Blood malignancies, cardiovascular disease, and other age-related illnesses are linked to this process.

Although about 70 genes have been connected to clonal hemopoiesis, most instances reported recently do not have mutations in any of these driving genes. This implies the presence of extra genetic variables. 

Using whole exome sequencing data from over 200,000 members of the UK Biobank cohort, researchers from the Wellcome Sanger Institute, Calico Life Sciences, California, and the University of Cambridge set out to uncover distinctive patterns of positive selection in the aging blood system.

In addition to the known drivers, they discovered 17 additional genes responsible for the build-up of mutant cell clones in human blood.

The impact of these newly discovered genes on aging was highlighted by the 18% rise in the prevalence of clonal hemopoiesis in the UK Biobank cohort that resulted from including their mutations. 

While existing genetic tests have been valuable for early disease detection, our findings suggest there are opportunities to improve them further. By incorporating these 17 additional genes linked to clonal haematopoiesis, we can enhance genetic testing methods to better identify risks of associated blood cancers and cardiovascular diseases.” 

Dr Michael Spencer Chapman, Study Co-First Author, Wellcome Sanger Institute

Nick Bernstein, Study Co-First Author, formerly at Calico Life Sciences, California, and now based at NewLimit said, “With our newly identified genes, we now have a more complete picture to explore strategies for delaying or reversing abnormal mutant cell overgrowths in blood to promote healthier aging. These genes seem to affect inflammation and immunity, important factors in conditions like heart disease and strokes. While interventions based on this research are still a long way off, it opens up possibilities for future treatments across a wide range of diseases.”

Our study reveals a much broader set of genes fuelling mutant blood cell clone accumulation with age, but this is only the beginning. Larger studies across diverse populations are needed to identify remaining driver genes and provide further insights into this process and disease links.” 

Dr Jyoti Nangalia, Study Senior Author, Wellcome Sanger Institute 

Nangalia is also from Wellcome-MRC Cambridge Stem Cell Institute at the University of Cambridge.