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

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.

journal_name

Nat Commun

journal_title

Nature communications

authors

Tapper W,Jones AV,Kralovics R,Harutyunyan AS,Zoi K,Leung W,Godfrey AL,Guglielmelli P,Callaway A,Ward D,Aranaz P,White HE,Waghorn K,Lin F,Chase A,Baxter EJ,Maclean C,Nangalia J,Chen E,Evans P,Short M,Jack A,Wal

doi

10.1038/ncomms7691

subject

Has Abstract

pub_date

2015-04-07 00:00:00

pages

6691

issn

2041-1723

pii

ncomms7691

journal_volume

6

pub_type

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