| Literature DB >> 25849990 |
William Tapper1, Amy V Jones1, Robert Kralovics2, Ashot S Harutyunyan2, Katerina Zoi3, William Leung1, Anna L Godfrey4, Paola Guglielmelli5, Alison Callaway6, Daniel Ward6, Paula Aranaz6, Helen E White1, Katherine Waghorn1, Feng Lin1, Andrew Chase1, E Joanna Baxter4, Cathy Maclean4, Jyoti Nangalia4, Edwin Chen4, Paul Evans7, Michael Short7, Andrew Jack7, Louise Wallis8, David Oscier8, Andrew S Duncombe9, Anna Schuh10, Adam J Mead11, Michael Griffiths12, Joanne Ewing13, Rosemary E Gale14, Susanne Schnittger15, Torsten Haferlach15, Frank Stegelmann16, Konstanze Döhner16, Harald Grallert17, Konstantin Strauch18, Toshiko Tanaka19, Stefania Bandinelli20, Andreas Giannopoulos3, Lisa Pieri5, Carmela Mannarelli5, Heinz Gisslinger21, Giovanni Barosi22, Mario Cazzola23, Andreas Reiter24, Claire Harrison25, Peter Campbell26, Anthony R Green4, Alessandro Vannucchi5, Nicholas C P Cross1.
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.Entities:
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Year: 2015 PMID： 25849990 PMCID： PMC4396373 DOI： 10.1038/ncomms7691
Source DB: PubMed Journal: Nat Commun ISSN： 2041-1723 Impact factor: 14.919