Aortic Aneurysm Risk and the Somatic <i>JAK2</i> ^<i>V617F</i> Mutation: Insights From a Multicenter, Population-Based Cardiovascular Screening Study.

Abstract

The somatic <i>JAK2</i>^<i>V617F</i> 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 <i>JAK2</i>^<i>V617F</i> variant allele frequency (VAF) and ascending, descending, and abdominal aortic aneurysms. 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 <i>JAK2</i>^<i>V617F</i> sequence variation. A total of 8056 individuals (90.9% men, mean age 68±4 years) were tested for the <i>JAK2</i>^<i>V617F</i> 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 <i>JAK2</i>^<i>V617F</i>-negative participants (n=7486), <i>JAK2</i>^<i>V617F</i>-positive participants with VAF <1% (n=491), and <i>JAK2</i>^<i>V617F</i>-positive participants with VAF ≥1% (n=79), ascending aortic aneurysms were observed in 6.4%, 9.0%, and 16.5%, respectively (<i>P</i><0.001). No significant differences were observed across sequence variation groups for descending and abdominal aneurysms. Among <i>JAK2</i>^<i>V617F</i>-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; <i>P</i>=0.021). Ascending aortic diameter correlated modestly with VAF (Spearman ρ=0.10; <i>P</i>=0.026). No significant correlations were observed for descending or abdominal diameters. For ascending aneurysms, <i>JAK2</i>^<i>V617F</i> VAF <1% and ≥1% presented adjusted odds ratios of 1.4 (95% CI, 1.01-2.0; <i>P</i>=0.045) and 2.7 (95% CI, 1.5-5.1; <i>P</i>=0.002), respectively, compared with <i>JAK2</i>^<i>V617F</i>-negative controls. For each doubling in VAF, the risk for ascending aneurysm increased by 11% (<i>P</i>_adjusted=0.013). The <i>JAK2</i>^<i>V617F</i> sequence variation was not significantly associated with descending or abdominal aneurysms after adjusting for covariates and using these VAF thresholds. In a study population of primarily men 60 to 74 years of age, the somatic <i>JAK2</i>^<i>V617F</i> sequence variation was strongly and independently associated with ascending aortic aneurysms, presenting a positive correlation between aneurysm size and <i>JAK2</i>^<i>V617F</i> VAF. No convincing associations were observed for descending or abdominal aneurysms. Screening patients with larger ascending aortic aneurysms for the <i>JAK2</i>^<i>V617F</i> sequence variation, and vice versa, screening <i>JAK2</i>^<i>V617F</i>-positve individuals presenting higher VAFs for ascending aneurysms, may be clinically appropriate.