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, Baxter E Joanna, 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
1] Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK [2] Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury SP2 8BJ, UK.
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria.
Nat Commun. 2015 Apr 7;6:6691. doi: 10.1038/ncomms7691.
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.
骨髓增殖性肿瘤(MPN)中的克隆性增殖由JAK2、CALR或MPL的体细胞突变驱动,但遗传因素的作用尚未得到充分表征。通过对3437例MPN病例和10083例对照进行三阶段全基因组关联研究,我们在JAK2(V617F)阴性MPN中鉴定出两个具有全基因组意义的单核苷酸多态性(SNP):rs12339666(JAK2;荟萃分析P = 1.27×10⁻¹⁰)和rs2201862(MECOM;荟萃分析P = 1.96×10⁻⁹)。当纳入JAK2(V617F)阳性病例时,另外两个SNP,rs2736100(TERT)和rs9376092(HBS1L/MYB)达到全基因组意义。rs9376092在具有CALR和/或MPL突变的JAK2(V617F)阴性病例中具有更强的效应(Breslow-Day P = 4.5×10⁻⁷),而在JAK2(V617F)阳性病例中,rs9376092与原发性血小板增多症(ET)相关,而不是真性红细胞增多症(等位基因χ² P = 7.3×10⁻⁷)。先前在模型系统中与ET样疾病发展相关的MYB表达降低,在正常髓系细胞中与rs9376092相关。这些发现表明,多个种系变异易患MPN,并将MYB表达的体质差异与疾病表型联系起来。