Scientists at deCODE genetics, a subsidiary of Amgen, have been focusing on actionable genotypes detected in the Icelandic population. Recently, the researchers found that approximately 1 in 25 Icelanders carried an actionable genotype and that carrying such a genotype was associated with a reduced life span.

This research is published in The New England Journal of Medicine, in the paper, “Actionable Genotypes and Their Association with Life Span in Iceland.

Two years ago, a recommendation was made by the American College of Medical Genetics and Genomics (ACMG) to report actionable genotypes in 73 genes. These are genotypes that increase the risk of a disease for which preventive or therapeutic measures have been established. However, there is a lack of understanding of the actionable genotypes in these genes with life span.

Now, scientists used a population-based data set, consisting of 57,933 whole-genome sequenced Icelanders, to assess the fraction of individuals carrying actionable genotypes. More specifically, they assessed the prevalence of coding and splice variants in genes on the ACMG Secondary Findings, version 3.0 (ACMG SF v3.0).

The authors write that they “assigned pathogenicity to all reviewed variants using reported evidence in the ClinVar database, the frequency of variants, and their associations with disease to create a manually curated set of actionable genotypes (variants).” They assessed the relationship between these genotypes and life span and further examined the specific causes of death among carriers.

Utilizing a list of 73 actionable genes from the guidelines from the ACMG, the scientists found that 4% of Icelanders carry an actionable genotype in one or more of these genes. The diseases caused by these genotypes include cardiovascular, cancer, and metabolic diseases.

The largest effect was observed among carriers of cancer-predisposing genotypes, which had three years shorter median survival than noncarriers. A pathogenic variant in BRCA2, predisposing to breast, ovarian, and pancreatic cancer, shortened lifespan by seven years, and a variant in LDLR, which causes high levels of cholesterol and cardiovascular disease, shortened lifespan by six years. “Our results suggest that the actionable genotypes identified in our study, which are all predicted to cause serious disease, may have a drastic effect on lifespan,” said Patrick Sulem, MD, head of clinical sequencing at deCODE genetics.

The results showed that carriers of particular actionable genotypes were more likely to have died from the disease caused by these genotypes. Individuals with a pathogenic variant in BRCA2, have a seven-fold risk of dying from breast, ovarian, or pancreatic cancer. Furthermore, they are 3.5 times more likely to develop prostate cancer and 7 times more likely to die from prostate cancer than those who do not carry the variant.

The researchers determined that 1 in 25 individuals carried an actionable genotype and have, on average, a shortened lifespan. “The identification and disclosure of actionable genotypes to participants can guide clinical decision-making, which may result in improved patient outcomes. This knowledge therefore has significant potential to mitigate disease burden for individuals and society as a whole,” said Kari Stefansson, MD, CEO of deCODE genetics.

The results of this study are among the evidence that has motivated the government of Iceland to announce a nationwide effort in precision medicine. As the delivery of precision medicine to a population requires a considerable amount of data on the genomics, transcriptomic, and proteomics of the population, Icelanders are currently exceptionally well suited for this effort because they behold an unprecedented amount of such data.

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