期刊
NATURE COMMUNICATIONS
卷 6, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms7691
关键词
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资金
- Leukaemia and Lymphoma Research
- Kay Kendall Leukaemia Fund
- Associazione Italiana per la Ricerca sul Cancro (AIRC, Milano)
- Wellcome Trust [07611]
- Helmholtz Zentrum Munchen-German Research Center for Environmental Health - German Federal Ministry of Education and Research
- State of Bavaria
- Munich Center of Health Sciences (MC Health), Ludwig-Maximilians-Universitat, as part of LMUinnovative
- Italian Ministry of Health [ICS110.1/RF97.71]
- U.S. National Institute on Aging [263 MD 9164, 263 MD 821336]
- Cambridge NIHR Biomedical Research Centre
- Wellcome Trust-MRC Stem Cell Institute
- Cambridge Experimental Cancer Medicine Centre, UK
- Austrian Science Fund (FWF) [P 23257] Funding Source: researchfish
- Cancer Research UK [8961] Funding Source: researchfish
- Medical Research Council [MC_UU_12009/16, MR/L006340/1] Funding Source: researchfish
- MRC [MC_UU_12009/16, MR/L006340/1] Funding Source: UKRI
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 x 10(-10)) and rs2201862 (MECOM; meta-analysis P = 1.96 x 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 x 10(-7)), whereas in JAK2(V617F)-positive cases rs9376092 associates with essential thrombocythemia (ET) rather than polycythemia vera (allelic chi(2) P = 7.3 x 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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