Aortic Institute at Yale-New Haven Hospital, Yale University School of Medicine, New Haven, CT 06510, USA.
DNA Diagnostics Lab, Yale University School of Medicine, New Haven, CT 06510, USA.
Genes (Basel). 2024 Jul 5;15(7):883. doi: 10.3390/genes15070883.
The V617F somatic variant is a well-known driver of myeloproliferative neoplasms (MPN) associated with an increased risk for athero-thrombotic cardiovascular disease. Recent studies have demonstrated its role in the development of thoracic aortic aneurysm (TAA). However, limited clinical information and level of V617F burden have been provided for a comprehensive evaluation of potential confounders. A retrospective genotype-first study was conducted to identify carriers of the V617F variant from an internal exome sequencing database in Yale DNA Diagnostics Lab. Additionally, the overall incidence of somatic variants in the gene across various tissue types in the healthy population was carried out based on reanalysis of SomaMutDB and data from the UK Biobank (UKBB) cohort to compare our dataset to the population prevalence of the variant. In our database of 12,439 exomes, 594 (4.8%) were found to have a thoracic aortic aneurysm (TAA), and 12 (0.049%) were found to have a V617F variant. Among the 12 V617F variant carriers, five had a TAA (42%), among whom four had an ascending TAA and one had a descending TAA, with a variant allele fraction ranging from 11.2% to 20%. Among these five patients, 60% were female, and average age at diagnosis was 70 (49-79). The mean ascending aneurysm size was 5.05 cm (range 4.6-5.5 cm), and four patients had undergone surgical aortic replacement or repair. UKBB data revealed a positive correlation between the V617F somatic variant and aortic valve disease (effect size 0.0086, = 0.85) and TAA (effect size = 0.004, = 0.92), although not statistically significant. An unexpectedly high prevalence of TAA in our dataset (5/594, 0.84%) is greater than the prevalence reported before for the general population, supporting its association with TAA. V617F may contribute a meaningful proportion of otherwise unexplained aneurysm patients. Additionally, it may imply a potential JAK2-specific disease mechanism in the developmental of TAA, which suggests a possible target of therapy that warrants further investigation.
V617F 体细胞变异是与动脉粥样硬化血栓性心血管疾病风险增加相关的骨髓增殖性肿瘤（MPN）的一个众所周知的驱动因素。最近的研究表明它在胸主动脉瘤（TAA）的发展中起作用。然而，对于潜在混杂因素的全面评估，提供的临床信息和 V617F 负担水平有限。一项回顾性的基于基因型的研究在耶鲁 DNA 诊断实验室的内部外显子组测序数据库中鉴定了 V617F 变体的携带者。此外，根据 SomaMutDB 的重新分析和英国生物银行（UKBB）队列的数据，评估了健康人群中 基因在各种组织类型中的体细胞变异的总体发生率，以将我们的数据集与该变体的人群患病率进行比较。在我们的 12439 个外显子组数据库中，发现 594 例（4.8%）患有胸主动脉瘤（TAA），12 例（0.049%）患有 V617F 变体。在 12 名 V617F 变体携带者中，有 5 名患有 TAA（42%），其中 4 名患有升主动脉 TAA，1 名患有降主动脉 TAA，变异等位基因分数在 11.2%至 20%之间。在这 5 名患者中，60%为女性，诊断时的平均年龄为 70 岁（49-79 岁）。升主动脉瘤的平均大小为 5.05 厘米（范围 4.6-5.5 厘米），4 名患者接受了主动脉置换或修复手术。UKBB 数据显示 V617F 体细胞变体与主动脉瓣疾病（效应大小 0.0086， = 0.85）和 TAA（效应大小 = 0.004， = 0.92）之间存在正相关，尽管没有统计学意义。我们的数据集中 TAA 的高患病率（5/594，0.84%）高于之前报道的一般人群患病率，支持其与 TAA 的关联。V617F 可能导致了相当一部分原因不明的动脉瘤患者。此外，这可能意味着 TAA 发育中存在 JAK2 特异性疾病机制，这表明可能存在需要进一步研究的治疗靶点。
