Aortic Aneurysm Risk and the Somatic JAK2 V617F Mutation: Insights From a Multicenter, Population-Based Cardiovascular Screening Study

BACKGROUND: The somatic JAK2V617F sequence variation, a key driver of myeloproliferative neoplasms, has been associated with increased risk of aortic aneurysms. This study aimed to explore associations between the JAK2V617F variant allele frequency (VAF) and ascending, descending, and abdominal aortic aneurysms.

METHODS: In the DANCAVAS I and II trials (Danish Cardiovascular Screening), 15 000 individuals underwent cardiovascular risk assessments including blood samples and noncontrast ECG-gated computed tomography scans. In this cross-sectional substudy, individuals with screening-detected aortic aneurysms (≥45 mm ascending, ≥35 mm descending, or ≥30 mm abdominal), random aneurysm-free male controls, and all women (only included during the DANCAVAS I pilot study) were tested for the JAK2V617F sequence variation.

RESULTS: A total of 8056 individuals (90.9% men, mean age 68±4 years) were tested for the JAK2V617F sequence variation, which presented an overall prevalence of 7.1%. Ascending, descending, and abdominal aneurysm prevalences were 6.6%, 2.9%, and 6.8%, respectively. In JAK2V617F-negative participants (n=7486), JAK2V617F-positive participants with VAF <1% (n=491), and JAK2V617F-positive participants with VAF ≥1% (n=79), ascending aortic aneurysms were observed in 6.4%, 9.0%, and 16.5%, respectively (P<0.001). No significant differences were observed across sequence variation groups for descending and abdominal aneurysms. Among JAK2V617F-positive individuals, the median VAF was higher in those with ascending aneurysm (9.5%; interquartile range, 3.0-40.0) than in controls (4.4%; interquartile range, 1.8-20.0; P=0.021). Ascending aortic diameter correlated modestly with VAF (Spearman ρ=0.10; P=0.026). No significant correlations were observed for descending or abdominal diameters. For ascending aneurysms, JAK2V617F VAF <1% and ≥1% presented adjusted odds ratios of 1.4 (95% CI, 1.01-2.0; P=0.045) and 2.7 (95% CI, 1.5-5.1; P=0.002), respectively, compared with JAK2V617F-negative controls. For each doubling in VAF, the risk for ascending aneurysm increased by 11% (Padjusted=0.013). The JAK2V617F sequence variation was not significantly associated with descending or abdominal aneurysms after adjusting for covariates and using these VAF thresholds.

CONCLUSIONS: In a study population of primarily men 60 to 74 years of age, the somatic JAK2V617F sequence variation was strongly and independently associated with ascending aortic aneurysms, presenting a positive correlation between aneurysm size and JAK2V617F VAF. No convincing associations were observed for descending or abdominal aneurysms. Screening patients with larger ascending aortic aneurysms for the JAK2V617F sequence variation, and vice versa, screening JAK2V617F-positve individuals presenting higher VAFs for ascending aneurysms, may be clinically appropriate.