Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms
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 genom...
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| Format: | Online |
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Nature Pub. Group
2015
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4396373/ |
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pubmed-43963732015-04-24 Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms Tapper, William Jones, Amy V. Kralovics, Robert Harutyunyan, Ashot S. Zoi, Katerina Leung, William Godfrey, Anna L. Guglielmelli, Paola Callaway, Alison Ward, Daniel Aranaz, Paula White, Helen E. Waghorn, Katherine Lin, Feng Chase, Andrew Joanna Baxter, E. Maclean, Cathy Nangalia, Jyoti Chen, Edwin Evans, Paul Short, Michael Jack, Andrew Wallis, Louise Oscier, David Duncombe, Andrew S. Schuh, Anna Mead, Adam J. Griffiths, Michael Ewing, Joanne Gale, Rosemary E. Schnittger, Susanne Haferlach, Torsten Stegelmann, Frank Döhner, Konstanze Grallert, Harald Strauch, Konstantin Tanaka, Toshiko Bandinelli, Stefania Giannopoulos, Andreas Pieri, Lisa Mannarelli, Carmela Gisslinger, Heinz Barosi, Giovanni Cazzola, Mario Reiter, Andreas Harrison, Claire Campbell, Peter Green, Anthony R. Vannucchi, Alessandro Cross, Nicholas C.P. Article 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 JAK2V617F-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 JAK2V617F-positive cases. rs9376092 has a stronger effect in JAK2V617F-negative cases with CALR and/or MPL mutations (Breslow–Day P=4.5 × 10−7), whereas in JAK2V617F-positive cases rs9376092 associates with essential thrombocythemia (ET) rather than polycythemia vera (allelic χ2 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. Nature Pub. Group 2015-04-07 /pmc/articles/PMC4396373/ /pubmed/25849990 http://dx.doi.org/10.1038/ncomms7691 Text en Copyright © 2015, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
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Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
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NCBI PubMed |
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Online Access |
| language |
English |
| format |
Online |
| author |
Tapper, William Jones, Amy V. Kralovics, Robert Harutyunyan, Ashot S. Zoi, Katerina Leung, William Godfrey, Anna L. Guglielmelli, Paola Callaway, Alison Ward, Daniel Aranaz, Paula White, Helen E. Waghorn, Katherine Lin, Feng Chase, Andrew Joanna Baxter, E. Maclean, Cathy Nangalia, Jyoti Chen, Edwin Evans, Paul Short, Michael Jack, Andrew Wallis, Louise Oscier, David Duncombe, Andrew S. Schuh, Anna Mead, Adam J. Griffiths, Michael Ewing, Joanne Gale, Rosemary E. Schnittger, Susanne Haferlach, Torsten Stegelmann, Frank Döhner, Konstanze Grallert, Harald Strauch, Konstantin Tanaka, Toshiko Bandinelli, Stefania Giannopoulos, Andreas Pieri, Lisa Mannarelli, Carmela Gisslinger, Heinz Barosi, Giovanni Cazzola, Mario Reiter, Andreas Harrison, Claire Campbell, Peter Green, Anthony R. Vannucchi, Alessandro Cross, Nicholas C.P. |
| spellingShingle |
Tapper, William Jones, Amy V. Kralovics, Robert Harutyunyan, Ashot S. Zoi, Katerina Leung, William Godfrey, Anna L. Guglielmelli, Paola Callaway, Alison Ward, Daniel Aranaz, Paula White, Helen E. Waghorn, Katherine Lin, Feng Chase, Andrew Joanna Baxter, E. Maclean, Cathy Nangalia, Jyoti Chen, Edwin Evans, Paul Short, Michael Jack, Andrew Wallis, Louise Oscier, David Duncombe, Andrew S. Schuh, Anna Mead, Adam J. Griffiths, Michael Ewing, Joanne Gale, Rosemary E. Schnittger, Susanne Haferlach, Torsten Stegelmann, Frank Döhner, Konstanze Grallert, Harald Strauch, Konstantin Tanaka, Toshiko Bandinelli, Stefania Giannopoulos, Andreas Pieri, Lisa Mannarelli, Carmela Gisslinger, Heinz Barosi, Giovanni Cazzola, Mario Reiter, Andreas Harrison, Claire Campbell, Peter Green, Anthony R. Vannucchi, Alessandro Cross, Nicholas C.P. Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms |
| author_facet |
Tapper, William Jones, Amy V. Kralovics, Robert Harutyunyan, Ashot S. Zoi, Katerina Leung, William Godfrey, Anna L. Guglielmelli, Paola Callaway, Alison Ward, Daniel Aranaz, Paula White, Helen E. Waghorn, Katherine Lin, Feng Chase, Andrew Joanna Baxter, E. Maclean, Cathy Nangalia, Jyoti Chen, Edwin Evans, Paul Short, Michael Jack, Andrew Wallis, Louise Oscier, David Duncombe, Andrew S. Schuh, Anna Mead, Adam J. Griffiths, Michael Ewing, Joanne Gale, Rosemary E. Schnittger, Susanne Haferlach, Torsten Stegelmann, Frank Döhner, Konstanze Grallert, Harald Strauch, Konstantin Tanaka, Toshiko Bandinelli, Stefania Giannopoulos, Andreas Pieri, Lisa Mannarelli, Carmela Gisslinger, Heinz Barosi, Giovanni Cazzola, Mario Reiter, Andreas Harrison, Claire Campbell, Peter Green, Anthony R. Vannucchi, Alessandro Cross, Nicholas C.P. |
| author_sort |
Tapper, William |
| title |
Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms |
| title_short |
Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms |
| title_full |
Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms |
| title_fullStr |
Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms |
| title_full_unstemmed |
Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms |
| title_sort |
genetic variation at mecom, tert, jak2 and hbs1l-myb predisposes to myeloproliferative neoplasms |
| description |
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 JAK2V617F-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 JAK2V617F-positive cases. rs9376092 has a stronger effect in JAK2V617F-negative cases with CALR and/or MPL mutations (Breslow–Day P=4.5 × 10−7), whereas in JAK2V617F-positive cases rs9376092 associates with essential thrombocythemia (ET) rather than polycythemia vera (allelic χ2
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. |
| publisher |
Nature Pub. Group |
| publishDate |
2015 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4396373/ |
| _version_ |
1613211485855547392 |