Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms

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Abstract
Clonal proliferation in myeloproliferative neoplasms (MPN) is driven by somatic mutations inJAK2,CALRorMPL, 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 inJAK2V617F-negative MPN: rs12339666 (JAK2;meta-analysisP=1.27 × 10−10) and rs2201862 (MECOM; meta-analysisP=1.96 × 10−9). Two additional SNPs, rs2736100 (TERT) and rs9376092 (HBS1L/MYB), achieve genome-wide significance when includingJAK2V617F-positive cases. rs9376092 has a stronger effect inJAK2V617F-negative cases withCALRand/orMPLmutations (Breslow–DayP=4.5 × 10−7), whereas inJAK2V617F-positive cases rs9376092 associates with essential thrombocythemia (ET) rather than polycythemia vera (allelicχ2P=7.3 × 10−7). ReducedMYBexpression, 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 inMYBexpression to disease phenotype.

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