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Tapper, W.* ; Jones, A.V.* ; Kralovics, R.* ; Harutyunyan, A.S.* ; Zoi, K.* ; Leung, W.* ; Godfrey, A.L.* ; Guglielmelli, P.* ; Callaway, A.* ; Ward, D.* ; Aranaz, P.* ; White, H.E.* ; Waghorn, K.* ; Lin, F.* ; Chase, A.J.* ; Baxter, E.* ; Maclean, C.* ; Nangalia, J.* ; Chen, E.* ; Evans, P.* ; Short, M.* ; Jack, A.* ; Wallis, L.* ; Oscier, D.* ; Duncombe, A.S.* ; Schuh, A.* ; Mead, A.J.* ; Griffiths, M.* ; Ewing, J.* ; Gale, R.E.* ; Schnittger, S.* ; Haferlach, T.* ; Stegelmann, F.* ; Döhner, K.* ; Grallert, H. ; Strauch, K. ; Tanaka, T.* ; Bandinelli, S.* ; Giannopoulos, A.* ; Pieri, L.* ; Mannarelli, C.* ; Gisslinger, H.* ; Barosi, G. ; Cazzola, M.* ; Reiter, A.* ; Harrison, C.N.* ; Campbell, P.J.* ; Green, A.R.* ; Vannucchi, A.M.* ; Cross, N.C.P.*

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

Nat. Commun. 6:6691 (2015)
Publ. Version/Full Text DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Polycythemia-vera; Essential Thrombocythemia; Glucocorticoid-receptor; Confers Susceptibility; 6q23.3 Influences; C-myb; Genome; Expression; Haplotype; Cells
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Journal Nature Communications
Quellenangaben Volume: 6, Issue: , Pages: , Article Number: 6691 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Epidemiology II (EPI2)
Institute of Genetic Epidemiology (IGE)