Germ line variants predispose to both JAK2 V617F clonal hematopoiesis and myeloproliferative neoplasms

• Published in: Blood Vol. 128; no. 8; pp. 1121 - 1128
• Main Authors: Hinds, David A., Barnholt, Kimberly E., Mesa, Ruben A., Kiefer, Amy K., Do, Chuong B., Eriksson, Nicholas, Mountain, Joanna L., Francke, Uta, Tung, Joyce Y., Nguyen, Huong (Marie), Zhang, Haiyu, Gojenola, Linda, Zehnder, James L., Gotlib, Jason
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25-08-2016; American Society of Hematology
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Alleles; Case-Control Studies; Child; Child, Preschool; Cohort Studies; Demography; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Germ Cells - metabolism; Hematopoiesis - genetics; Humans; Infant; Janus Kinase 2 - genetics; Male; Middle Aged; Mutation - genetics; Myeloid Neoplasia; Myeloproliferative Disorders - genetics; Polymorphism, Single Nucleotide - genetics; Reproducibility of Results; Young Adult
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2015-06-652941

We conducted a genome-wide association study (GWAS) to identify novel predisposition alleles associated with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) and 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 single-nucleotide polymorphism (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) vs the remaining controls who were noncarriers for V617F (n = 252 140). For these MPN cases plus V617F carriers, we replicated the germ line 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 vs 169 021 noncarriers. 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 ORs were similar for MPN patients and controls who were V617F carriers. These data indicate that the same germ line variants endow individuals with a predisposition not only to MPN, but also to JAK2 V617F clonal hematopoiesis, a more common phenomenon that may foreshadow the development of an overt neoplasm.
•Germ line 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 ∼2 out of 1000 individuals in the general population.