Germline variants predispose to both JAK2 V617F clonal hematopoiesis and myeloproliferative neoplasms

David A. Hinds, Kimberly E. Barnholt, Ruben A. Mesa, Amy K. Kiefer, Chuong B. Do, Nicholas Eriksson, Joanna L. Mountain, Uta Francke, Joyce Y. Tung, Huong (Marie) Nguyen, Haiyu Zhang, Linda Gojenola, James L. Zehnder and Jason Gotlib

Key points

  • Germline variants in TERT, SH2B3, TET2, ATM, CHEK2, PINT, and GFI1B are associated with JAK2 V617F clonal hematopoiesis and MPNs.

  • Age-related JAK2 V617F clonal hematopoiesis is found in about 2 out of 1000 individuals in the general population.


We conducted a genome-wide association study to identify novel predisposition alleles associated with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) as well as JAK2 V617F clonal hematopoiesis in the general population. We recruited a web-based cohort of 726 individuals with polycythemia vera, essential thrombocythemia, and myelofibrosis and 252,637 population controls unselected for hematologic phenotypes. Using a SNP array platform with custom probes for the JAK2 V617F mutation (V617F), we identified 497 individuals (0.2%) among the population controls who were V617F carriers. We performed a combined GWAS of the MPN cases plus V617F carriers in the control population (n=1223) versus the remaining controls who were non-carriers for V617F (n=252,140). For these MPN cases plus V617F carriers, we replicated the germline JAK2 46/1 haplotype (rs59384377: odds ratio (OR)=2.4, P=6.6×10−89), previously associated with V617F-positive MPN. We also identified genome-wide significant associations in the TERT gene (rs7705526: OR=1.8, P=1.1×10−32), in SH2B3 (rs7310615: OR=1.4, P=3.1×10−14), and upstream of TET2 (rs1548483: OR=2.0, P=2.0×10−9). These associations were confirmed in a separate replication cohort of 446 V617F carriers versus 169,021 non-carriers. In a joint analysis of the combined GWAS and replication results, we identified additional genome-wide significant predisposition alleles associated with CHEK2, ATM, PINT, and GFI1B. All SNP odds ratios were similar for MPN patients and for controls who were V617F carriers. These data indicate that the same germline variants not only endow individuals with a predisposition to MPN, but also to JAK2 V617F clonal hematopoiesis, a more common phenomenon that may foreshadow the development of an overt neoplasm.

  • Submitted June 22, 2015.
  • Accepted June 5, 2016.