Amgen subsidiary deCODE Genetics has identified new risk factors and genes associated with clonal hematopoiesis, a precursor state to blood cancer.
In the results of a study published Nov. 6 in Nature Genetics, the company reported that whole-genome sequence data from thousands of people pointed to 25 gene variants that predispose individuals to developing clonal hematopoiesis. They also showed that a long-reported link between the condition and cardiovascular disease can be largely explained by smoking, which stood out as the biggest risk factor for clonal hematopoiesis apart from age.
Despite being an “inevitable” part of the aging process, “that doesn't alter the fact that [clonal hematopoiesis] is associated with the development of hematological malignancies and age-adjusted high mortality rates,” Simon Stacey, first author and deCODE scientist, said in a company video.
Clonal hematopoiesis is a phenomenon where a mutation in a hematopoietic stem cell, or HSC—a bone marrow-based precursor to other types of cells in the blood—confers a survival benefit that enables it to proliferate much more rapidly than other HSCs. Its daughter blood cells have genetic characteristics that make them more prone to malignancy, putting patients with clonal hematopoiesis at greater risk of cancer.
While scientists have been aware of HSC clones for decades, it wasn’t until the 2010s that researchers recognized their relationship to blood cancer, cardiovascular disease and prevalence in the elderly. These findings sparked an interest in testing for genetic markers of the condition in older people who hadn’t yet developed blood cancer but who showed signs that they might be at higher risk, such as having anemia, certain genetic patterns, or non-blood cancers.
Such screening is now conducted by some cancer centers. The resulting diagnosis—clonal hematopoiesis of indeterminate origin, or CHIP—can be used to see who should be monitored for blood cancer.
The new study from deCODE may help further define CHIP screening candidates, as well as what genetic markers they should be tested for. Using whole genome sequencing data from 176,000 individuals in Iceland or registered in the UK Biobank and a proprietary method to detect the condition from their genetic information, the company’s scientists identified 16,000 people with clonal hematopoiesis.
“We have a very large set of material,” Stacey said in the video, adding later that his team used a “somewhat different method [of detecting the condition] that’s in some sense more sensitive.”
The age-linked pattern held fast: Prevalence was nearly 50% in individuals over 80. And as expected, those with the condition had a greater likelihood of developing future blood cancer.
But when it came to cardiovascular disease, the researchers found that the previously established link might not be what it seemed. Clonal hematopoiesis was associated not just with heart conditions, but many others—all of them related to smoking.
“With these disease associations, it’s very likely that the reason these associations occur is because they’re confounded with smoking behavior,” Stacey said. “If we adjust for smoking behavior, the associations are very much attenuated—it doesn’t completely go away, but the association with these non-hematological diseases is very much reduced, specifically with regards to cardiovascular disease.”
The findings also shed light on previously obscured genetic mutations that appear to drive HSC clone development. The researchers identified 25 gene variants associated with the condition, many of which were completely new. Some had been associated with related phenomena, like Y chromosome loss and diseases where the bone marrow makes too many blood cells.
“They tend to also have effects on blood cell counts, although not big enough effects that they’re overtly pathological,” Stacey said in the video. The genes also influence telomere length, he added.
Amgen acquired deCODE in 2012 for $415 million with the logic that it could use the genetics data analysis company to identify new disease targets, which it continues to do: In its third-quarter earnings report, Amgen execs mentioned that deCODE is spearheading obesity target identification. Meanwhile, it has also been playing a role in drug development: deCODE used data from Amgen’s phase 2 trial on its cardiovascular drug olpasiran to define the patient population for phase 3, and was also involved in making predictions about who would benefit from taking Repatha to prevent cholesterol-associated heart problems.