JAK2 V617F Prevalence Study: Associations in the General Population and Vascular Disease Populations
Authors: Kaizer Hannah , Naik Rakhi P. , Lobner Katie , Moliterno Alison R. 
Published: November 2020

Introduction
Clonal hematopoiesis (CH) is defined as an expansion of blood stem cell clones that bear advantageous somatic mutations. JAK2V617F is not only the most common mutation association with MPN, it is the fifth most common lesion implicated in CH. While the JAK2V617F positive MPN are rare diseases, CH occurs at relatively common rates in the aging population. CH carriers, and in particular JAK2V617F CH carriers, similar to MPN patients, are at increased risk of developing blood cancers, and arterial and venous thromboses. While many large-scale general population studies have examined prevalence of JAK2V617F CH, a comprehensive assessment of associations to disease has not been performed.
Methods
We identified all published studies that evaluated the prevalence of the JAK2V617F and CALR exon 9 mutations in the general population and in vascular disease risk populations. We used PUBMED, EMBASE, and SCOPUS databases. Two reviewers independently performed study selection and extracted study characteristics. Studies were included if they met the following criteria : analysis of JAK2/CALR mutations was performed according commonly accepted criteria and study inclusion of at least 40 patients.
Results
We identified 5793 abstracts/manuscripts that met our search criteria. After title/abstract review, 104 manuscripts were included in the meta-analysis (Figure 1). Thirteen of these studies examined the prevalence of JAK2V617F and CALR exon 9 mutations in a general, unselected population. Among 546,504 participants included in these studies, 1,850 (0.34%) were positive for the JAK2V617F mutation. In contrast, 32 out of 19,958 (0.16%) were positive for CALR exon 9 mutations. In the general population, the JAK2V617F mutation was most commonly associated with male sex, increased age, and smoking. Three studies reported increased blood counts, predominantly platelets and white blood cells. Four studies noted an increased risk of MPN or hematologic cancer in those with the JAK2V617F mutation. The JAK2V617F mutation was associated with an increased risk of venous thrombosis in 3 studies and ischemic heart disease/MI in 2 studies. JAK2V617F variant allele fraction (VAF) when reported ranged 0.004% to 86%.
The prevalence of the JAK2V617F in patients with venous or arterial vasculopathy was examined in 91 studies with a total of 35,982 participants. Of these, 26,279 individuals had a history of thrombotic disease and 8,944 were controls. Of the participants with a history of any type of vascular disease, 1,279 (4.9%) were noted to have the JAK2V617F mutation with VAF, when reported, ranging from 0.2-96.2%. On subgroup analysis, patients with splanchnic vein thrombosis had the highest prevalence of the JAK2V617F mutation (18.7%) followed by patients with ischemic stroke (8.5%) and cerebral vein thrombosis (6.0%) (Table 1). The prevalence of the JAK2V617F mutation in patients with DVT/PE and peripheral arterial disease (PAD) was 1.6% and 3.1% respectively. The prevalence of JAK2V617F among all of the vascular disease subsets was substantially higher than the control populations. Similarly, the prevalence of CALR was noted to be high in studies of splanchnic vein thrombosis and cerebral vein thrombosis. (Table 2).
Conclusions
JAK2V617F and CALR mutations are associated with alterations of blood counts and thrombosis. Even at very low VAF, JAK2V617F is a thrombosis risk factor in the general population and is over-represented in populations with thrombosis. In every thrombosis group, the prevalence in JAK2V617F in thrombosis patients was higher than that in the control population, suggesting the JAK2V617F mutation may contribute to both arterial and venous thrombotic risk, whether in the MPN or CH population context.

Disclosures
Naik: Elsevier: Consultancy; Rigel: Research Funding. Moliterno:Pharmessentia: Consultancy; MPNRF: Research Funding.