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 Communjournal_title
Nature communicationsauthors
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,Waldoi
10.1038/ncomms7691subject
Has Abstractpub_date
2015-04-07 00:00:00pages
6691issn
2041-1723pii
ncomms7691journal_volume
6pub_type
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