Abstract
Clonal proliferation in myeloproliferative neoplasms (MPN) is driven by somatic mutations in JAK2, CALR or MPL, but the contribution of inherited factors is poorly characterized. Using a three-stage genome-wide association study of 3,437 MPN cases and 10,083 controls, we identify two SNPs with genome-wide significance in JAK2(V617F)-negative MPN: rs12339666 (JAK2; meta-analysis P=1.27 × 10(-10)) and rs2201862 (MECOM; meta-analysis P=1.96 × 10(-9)). Two additional SNPs, rs2736100 (TERT) and rs9376092 (HBS1L/MYB), achieve genome-wide significance when including JAK2(V617F)-positive cases. rs9376092 has a stronger effect in JAK2(V617F)-negative cases with CALR and/or MPL mutations (Breslow-Day P=4.5 × 10(-7)), whereas in JAK2(V617F)-positive cases rs9376092 associates with essential thrombocythemia (ET) rather than polycythemia vera (allelic χ(2) P=7.3 × 10(-7)). Reduced MYB expression, previously linked to development of an ET-like disease in model systems, associates with rs9376092 in normal myeloid cells. These findings demonstrate that multiple germline variants predispose to MPN and link constitutional differences in MYB expression to disease phenotype.
Highlights
Clonal proliferation in myeloproliferative neoplasms (MPN) is driven by somatic mutations in JAK2V617F-negative MPN: rs12339666 (JAK2), CALR or MPL, but the contribution of inherited factors is poorly characterized
Since the bulk of the population-level predisposition to JAK2V617F positive MPN is likely to be accounted for by variation at JAK2 and TERT, the initial aim of this study is to identify additional germline variants that predispose to JAK2V617F-negative essential thrombocythemia (ET) or primary myelofibrosis (PMF) by performing a genome-wide association study (GWAS)
We identify two single-nucleotide polymorphisms (SNPs), rs12339666 within JAK2 and rs2201862, 153 kb downstream of MECOM, which associate with JAK2V617F-negative disease, and two additional SNPs, rs2736100 in TERT and rs9376092 between HBS1L and MYB, when including JAK2V617F-positive cases
Summary
Clonal proliferation in myeloproliferative neoplasms (MPN) is driven by somatic mutations in JAK2, CALR or MPL, but the contribution of inherited factors is poorly characterized. We previously characterized a major predisposition locus at the JAK2 gene, which is associated with the acquisition of V617F mutations[7,8] This specific JAK2 haplotype, called ‘46/1’ or ‘GGCC’ strongly predisposes to JAK2V617F-positive disease (OR 1⁄4 3.7; Fisher’s exact test Po10 À 20). Since the bulk of the population-level predisposition to JAK2V617F positive MPN is likely to be accounted for by variation at JAK2 and TERT, the initial aim of this study is to identify additional germline variants that predispose to JAK2V617F-negative ET or PMF by performing a genome-wide association study (GWAS). The SNP between HBS1L and MYB, rs9376092, has a stronger effect in JAK2V617F-negative cases with somatic CALR and/or MPL mutations and predisposes to essential thrombocythemia in JAK2V617F-positive cases. We demonstrate that the candidate risk allele at rs9376092 is associated with reduced MYB expression in normal myeloid cells
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
