Clonal Hematopoiesis and Incident Heart Failure

Why it matters

As we age, a blood stem cell that picks up a mutation can come to produce a large share of our blood cells. This is clonal hematopoiesis, a clear example of somatic DNA mutation shaping health in later life. It is already linked to blood cancer and heart attack. Knowing whether it raises heart-failure risk, and which mutated genes matter most, could make it a target for prevention. Clonal hematopoiesis is rare in young adults and becomes common in older ones, so it is one of the most direct ways that mutations acquired during life can raise disease risk. Heart failure affects millions of people, and new modifiable risk factors are valuable.

What they did

Using whole-exome sequencing from the UK Biobank, the researchers studied 417,616 adults (mean age 56) with no heart failure, blood cancer, coronary disease, atrial fibrillation, type 2 diabetes or chronic kidney disease at the start. They looked for CHIP overall and by gene (DNMT3A, TET2, ASXL1, JAK2, DNA-damage-repair genes and spliceosome genes), followed participants for a median of 11 years, and tested how much of any link ran through those other diseases developing.

What they found

7,183 people (1.7%) developed heart failure. Having CHIP was linked to a 27% higher risk (adjusted hazard ratio 1.27), and the effect was driven mainly by CHIP in genes other than DNMT3A (hazard ratio 1.52), including TET2, ASXL1, JAK2 and spliceosome genes. DNMT3A CHIP had a smaller link (hazard ratio 1.15). Developing coronary disease, atrial fibrillation, diabetes or kidney disease explained only about 28% of the link between non-DNMT3A CHIP and heart failure. The authors conclude that CHIP is a heart-failure risk factor and a potential target for treatment.

Limits

This is an observational study, so it shows an association rather than proof that CHIP causes heart failure. UK Biobank participants tend to be healthier than the general population and are mostly of European ancestry. Exome sequencing may miss small clones, and the abstract does not test any treatment.

Key terms

Clonal hematopoiesis (CHIP)

An age-related expansion of blood cells descended from one stem cell carrying an acquired, pre-leukaemic mutation.

Somatic mutation

A DNA change acquired during life in body cells, not inherited.

Whole-exome sequencing

Reading the protein-coding parts of all genes.

Mediation analysis

A method that estimates how much of a link passes through an intermediate factor.

DNMT3A / TET2

The two genes most often mutated in clonal hematopoiesis; both help control DNA methylation.

Hazard ratio

How much more often an event happens in one group than another over time; 1.27 means about 27% more often.