Clonal Hematopoiesis of Indeterminate Potential and Bone Mineral Density in Cohorts from Trans-Omics for Precision Medicine

Why it matters

Clonal hematopoiesis of indeterminate potential, or CHIP, is when a blood stem cell picks up a mutation during life that lets it expand, without causing a blood cancer. It becomes much more common with age and has been linked to atherosclerosis, heart failure, stroke, gout, and liver and kidney disease. The cells that break down bone, osteoclasts, come from the same blood stem cell family, so it is reasonable to ask whether CHIP also changes bone. Since osteoporosis is a major problem of ageing, a link would matter for how we think about somatic mutation and whole-body ageing.

What they did

The researchers used CHIP mutation calls from whole-genome sequencing in the Trans-Omics for Precision Medicine (TOPMed) programme, and bone mineral density measured by DXA scans, a low-dose X-ray test of bone density. They pooled data from the Amish cohort, the Cardiovascular Health Study, the Framingham Heart Study, the San Antonio Family Study and the Women's Health Initiative. Using multiple linear regression, they tested whether CHIP was linked to bone density at the femoral neck (hip) and lumbar spine, adjusting for cohort, age, age squared and sex, and for family relatedness in the family-based cohorts. CHIP was analysed both as present or absent and in grades from no mutation to two or more mutations in different genes.

What they found

A total of 3,368 samples had both CHIP and bone density data, and 10.9% carried at least one CHIP mutation. Having any CHIP mutation was not associated with bone density at either the femoral neck or the lumbar spine. However, people with two or more CHIP mutations in different genes had higher lumbar spine bone density (beta = 0.36, p = 0.015). The authors conclude there was no overall link between CHIP and bone density in this large and diverse sample, and that the higher density with multiple mutations agrees with mouse models in which Dnmt3a and Tet2 mutations increase bone density.

Limits

This synopsis is based on the abstract only; the full paper is paywalled. The study is observational, so it shows associations, not cause and effect. The positive finding comes from a small subgroup with multiple mutations and a modest p-value, so it may not hold up in other samples. The abstract does not say whether the bone scans and blood samples were taken at the same time, or whether fractures, rather than density, were looked at.

Key terms

CHIP

Clonal hematopoiesis of indeterminate potential: an expanded clone of blood cells carrying a somatic mutation, without blood cancer.

Bone mineral density (BMD)

How much mineral is packed into bone; low BMD means weaker bones and higher fracture risk.

DXA

Dual-energy X-ray absorptiometry, the standard low-dose scan used to measure bone density.

Osteoclast

A bone cell, derived from blood stem cells, that breaks down old bone so it can be rebuilt.

TOPMed

Trans-Omics for Precision Medicine, a US research programme that whole-genome sequenced people from many existing cohorts.

Femoral neck and lumbar spine

The upper thigh bone near the hip and the lower back vertebrae, the two standard sites for bone density scans.