Amgen’s deCODE Reveals New Clonal Hematopoiesis Risk Factors and Genes

Amgen's deCODE Uncovers New Clonal Hematopoiesis Risk Factors and Genes

Amgen’s subsidiary, deCODE Genetics, has uncovered new risk factors and genes associated with clonal hematopoiesis, a precursor condition to blood cancer.

In a study published on November 6 in Nature Genetics, deCODE Genetics reported that they identified 25 gene variants, using whole-genome sequence data from thousands of individuals, that predispose people to developing clonal hematopoiesis. The study also revealed that the well-known connection between clonal hematopoiesis and cardiovascular disease can largely be attributed to smoking, which emerged as the primary risk factor for clonal hematopoiesis, aside from age.

Although clonal hematopoiesis is considered an inherent aspect of the aging process, it remains associated with an increased risk of hematological malignancies and elevated mortality rates, as explained by Simon Stacey, the first author and a scientist at deCODE, in a company video.

Clonal hematopoiesis occurs when a mutation in a hematopoietic stem cell (HSC), a precursor to various blood cell types in the bone marrow, grants it a survival advantage, allowing it to multiply more rapidly than other HSCs. The resulting blood cells have genetic characteristics that make them more susceptible to malignancy, putting individuals with clonal hematopoiesis at a higher risk of cancer.

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Although scientists have been aware of HSC clones for several decades, it wasn’t until the 2010s that their connection to blood cancer, cardiovascular disease, and prevalence in the elderly was recognized. This revelation sparked interest in screening for genetic markers of clonal hematopoiesis in older individuals who hadn’t yet developed blood cancer but exhibited signs of a higher risk, such as anemia, specific genetic patterns, or non-blood cancers.

Some cancer centers now conduct such screenings, leading to a diagnosis of clonal hematopoiesis of indeterminate origin (CHIP), which helps identify individuals who should be monitored for blood cancer.

The latest study from deCODE may aid in further defining screening criteria for CHIP and the specific genetic markers to test for. By 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.

Prevalence of the condition was nearly 50% in individuals over 80, adhering to the age-related pattern. As expected, those with clonal hematopoiesis had a greater likelihood of developing future blood cancer.

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“We have a very large set of material with a somewhat different method [of detecting the condition] that’s in some sense more sensitive. With these disease associations, it’s very likely that the reason these associations occur is because they’re confounded with smoking behavior. 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. They tend to also have effects on blood cell counts, although not big enough effects that they’re overtly pathological. The genes also influence telomere length.”

– Simon Stacey, deCODE scientist

However, regarding cardiovascular disease, the research indicated that the previously established link might not be as straightforward as it appeared. Clonal hematopoiesis was associated with various heart conditions and other diseases, all of which were linked to smoking.

The study found that these disease associations are likely confounded with smoking behavior, and adjusting for smoking substantially reduced the associations, particularly with regards to cardiovascular disease.

Additionally, the research shed light on previously unclear genetic mutations that drive HSC clone development. The study identified 25 gene variants associated with clonal hematopoiesis, many of which were entirely new and had effects on blood cell counts, telomere length, and related phenomena like Y chromosome loss.

Amgen acquired deCODE in 2012 for $415 million, with the aim of utilizing the genetics data analysis company to identify new disease targets, a mission it continues to pursue. In its third-quarter earnings report, Amgen mentioned that deCODE is leading the identification of obesity targets. DeCODE has also played a role in drug development, utilizing data from Amgen’s phase 2 trial on the cardiovascular drug olpasiran to define the patient population for phase 3 and making predictions about who would benefit from taking Repatha to prevent cholesterol-related heart problems.

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