Highlight
- The somatic JAK2V617F mutation is significantly associated with increased prevalence of ascending aortic aneurysms in a predominantly older male population.
- The risk and size of ascending aortic aneurysms correlate positively with the variant allele frequency (VAF) of JAK2V617F, with higher VAF linked to greater risk.
- No significant associations were identified between the JAK2V617F mutation and descending or abdominal aortic aneurysms after adjustment.
- Screening for JAK2V617F in patients with larger ascending aneurysms and conversely screening JAK2V617F-positive individuals with high VAF for ascending aneurysms may be clinically beneficial.
Study Background and Disease Burden
Aortic aneurysms, characterized by pathological dilation of the aorta, pose serious risks including rupture and sudden death, with ascending aortic aneurysms constituting a distinct clinical entity due to their unique pathobiology and surgical implications. The somatic JAK2V617F mutation, a well-recognized driver mutation in myeloproliferative neoplasms, has emerged as a potential factor influencing vascular pathology beyond hematologic malignancies. Prior observational data hinted at increased vascular events in carriers of this mutation, but its specific relationship with different aortic segments remained unclear. Elucidating such associations is vital given the aging population and the clinical challenge of preemptively identifying high-risk individuals for life-threatening aneurysms.
Study Design
This investigation derives from the Danish Cardiovascular Screening (DANCAVAS) I and II trials, a large multicenter, population-based screening effort involving 15,000 individuals aged primarily 60 to 74 years. Participants underwent comprehensive cardiovascular risk assessments including blood sampling for molecular testing and noncontrast ECG-gated computed tomography (CT) scans. This cross-sectional substudy focused on detecting aortic aneurysms—defined by diameter thresholds of ≥45 mm ascending, ≥35 mm descending, or ≥30 mm abdominal aorta—and testing for the presence and variant allele frequency (VAF) of the somatic JAK2V617F mutation. A total of 8,056 individuals (predominantly men at 90.9%) were analyzed, including aneurysm-detected cases and random aneurysm-free male controls, as well as all women recruited during the pilot phase.
Key Findings
The overall prevalence of the JAK2V617F mutation was 7.1%. The prevalence of ascending, descending, and abdominal aortic aneurysms was 6.6%, 2.9%, and 6.8%, respectively. Stratifying by mutation status and VAF yielded striking associations with ascending aortic aneurysms:
- Ascending aneurysm prevalence among JAK2V617F-negative participants was 6.4%, increased to 9.0% in those with VAF <1%, and rose substantially to 16.5% in those with VAF ≥1% (P<0.001).
- Median VAF was higher in JAK2V617F-positive individuals with ascending aneurysms (9.5%) compared to controls (4.4%; P=0.021), and a modest positive correlation existed between ascending aortic diameter and VAF (Spearman ρ=0.10; P=0.026).
- Adjusted odds ratios for ascending aneurysm risk were 1.4 (95% CI, 1.01-2.0) for VAF <1% and 2.7 (95% CI, 1.5-5.1) for VAF ≥1%, compared to mutation-negative controls, both statistically significant.
- Every doubling of VAF corresponded to an 11% increase in risk for ascending aneurysm (Padjusted=0.013).
- No significant associations were found between JAK2V617F mutation status or VAF and descending or abdominal aneurysm prevalence after adjustment for covariates.
These findings highlight a mutation- and dose-dependent risk specifically for ascending aortic aneurysms, underscoring heterogeneity in aortic pathology linked to somatic clonal hematopoiesis.
Expert Commentary
The study robustly links JAK2V617F clonal hematopoiesis with ascending aortic aneurysm risk in a well-powered population-based cohort, reinforcing the emerging concept that somatic mutations in hematopoietic cells may contribute to vascular remodeling and aneurysm formation, possibly via inflammatory and fibrotic pathways. The mutation’s lack of association with descending or abdominal aneurysms suggests differential regional vascular susceptibility or pathophysiological mechanisms. Clinically, these results advocate for integrating molecular genetic screening into cardiovascular risk stratification, particularly for patients presenting with aneurysmal dilation in the ascending aorta.
Limitations include the predominantly male and older cohort, raising questions about generalizability to women and younger populations. The cross-sectional design precludes causal inference, necessitating longitudinal investigation. Furthermore, identifying the mechanistic links between JAK2V617F-driven clonal hematopoiesis and aneurysm development requires further molecular and cellular studies.
Conclusion
This multicenter population screening study provides compelling evidence that the somatic JAK2V617F mutation—especially with elevated variant allele frequency—is independently associated with increased prevalence and size of ascending aortic aneurysms in men aged 60–74. These findings establish a rationale for targeted screening strategies: patients with larger ascending aneurysms might benefit from JAK2V617F mutation testing, and carriers with higher VAF should be monitored for ascending aortic dilation. Such precision medicine approaches could improve early detection and management, potentially reducing catastrophic aneurysm-related events. Future research should expand demographics, elucidate underlying mechanisms, and explore therapeutic avenues addressing the hematopoietic-vascular interface.
References
Obel LM, Skovbo JS, Diederichsen ACP, Thomassen M, Kjær L, Larsen MK, Knudsen TA, Skov V, Kruse TA, Burton M, Dembic M, Wienecke T, Sabater-Lleal M, Gerke O, Bruun NE, Ellervik C, Brabrand M, Steffensen FH, Frost L, Lambrechtsen J, Busk M, Urbonaviciene G, Egstrup K, Karon M, Feddersen S, Rasmussen LM, Hasselbalch HC, Lindholt JS. Aortic Aneurysm Risk and the Somatic JAK2V617F Mutation: Insights From a Multicenter, Population-Based Cardiovascular Screening Study. Circulation. 2025 Aug 5;152(5):300-312. doi: 10.1161/CIRCULATIONAHA.125.074002. Epub 2025 Jun 4. PMID: 40464064.