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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
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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
Keywords Polycythemia-vera; Essential Thrombocythemia; Glucocorticoid-receptor; Confers Susceptibility; 6q23.3 Influences; C-myb; Genome; Expression; Haplotype; Cells
Language english
Publication Year 2015
HGF-reported in Year 2015
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
Reviewing status Peer reviewed
Institute(s) Institute of Epidemiology (EPI)
Institute of Genetic Epidemiology (IGE)
POF-Topic(s) 30202 - Environmental Health
30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-504091-002
G-504100-001
PubMed ID 25849990
DOI 10.1038/ncomms7691
WOS ID WOS:000353699000002
Scopus ID 84927153553
Erfassungsdatum 2015-04-09
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