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Genetic Variation and Life Span in Iceland
Quick Takes
- A significantly higher percentage of persons carrying an actionable genotype in MYBPC3 had cardiomyopathy compared to noncarriers.
- The F5 (factor V) Leiden thrombophilia missense variant and the F2 (factor II) 3′ untranslated region variant were identified, which are common causes of venous thromboembolism among White, Hispanic, and Black persons in the United States.
- Overall, the data suggest that identification and disclosure of actionable genotypes to participants holds considerable potential to mitigate the disease burden on individual persons as well as on society in general.
Study Questions:
What are the relationships between actionable genotypes and both survival and causes of death?
Methods:
The investigators assessed the prevalence of coding and splice variants in genes on the American College of Medical Genetics and Genomics (ACMG) Secondary Findings (SF), version 3.0 (ACMG SF v3.0), list in the genomes of 57,933 Icelanders. 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 further assessed the relationship between these genotypes and life span and further examined the specific causes of death among carriers.
Results:
Through manual curation of 4,405 sequence variants in the ACMG SF v3.0 genes, the authors identified 235 actionable genotypes in 53 genes. Of the 57,933 participants, 2,306 (4.0%) carried at least one actionable genotype. The investigators found shorter median survival among persons carrying actionable genotypes than among noncarriers. Specifically, they found evidence of association between carrying an actionable genotype in certain genes in the cardiovascular disease group and a reduced life span.
Conclusions:
The authors report that approximately 1 in 25 Icelanders carried an actionable genotype and that carrying such a genotype was associated with a reduced life span.
Perspective:
This study reports that 10.4% of persons carrying an actionable genotype in MYBPC3 had cardiomyopathy, whereas only 0.8% of noncarriers had cardiomyopathy. Of note, the effect was diluted for a combination of all MYBPC3-associated conditions, i.e., cardiomyopathy, sudden cardiac death, atrial fibrillation, and heart failure (odds ratio, 1.34; 95% confidence interval, 0.74-2.42). These findings indicate that selecting the relevant diseases or conditions associated with each of the ACMG genes is an important aspect of analyzing causes of death in persons carrying actionable genotypes. The authors also identified the F5 (factor V) Leiden thrombophilia missense variant and the F2 (factor II) 3′ untranslated region variant, which are common causes of venous thromboembolism among White, Hispanic, and Black persons in the United States. Overall, the data suggest that identification and disclosure of actionable genotypes to participants holds considerable potential to mitigate the disease burden on individual persons as well as on society in general.
Clinical Topics: Heart Failure and Cardiomyopathies, Pulmonary Hypertension and Venous Thromboembolism, Vascular Medicine
Keywords: Cardiomyopathies, Genotype, Venous Thromboembolism
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