Germ line variants predispose to both JAK2 V617F clonal hematopoiesis and myeloproliferative neoplasms
Germ line variants predispose to both JAK2 V617F clonal hematopoiesis and myeloproliferative neoplasms
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DOI：
10.1182/blood-2015-06-652941
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发表时间：
2016-08-25
期刊：
影响因子：
20.3
通讯作者：
Gotlib, Jason
中科院分区：
文献类型：
--
作者：
Hinds, David A.;Barnholt, Kimberly E.;Gotlib, Jason
我们进行了全基因组关联研究，以确定与费城染色体阴性骨髓增生性肿瘤(MPN)和普通人群中JAK2 V617F克隆性造血相关的新的易感等位基因。我们招募了726名真性红细胞增多症、原发性血小板增多症和骨髓纤维化患者和252,637名未选择血液学表型的人群作为网络队列。利用单核苷酸多态(SNP)阵列平台和定制的JAK2 V617F突变(V617F)探针，我们在人群对照中鉴定出497人(0.2%)为V617F携带者。我们对MPN合并V617F携带者的对照组(n=1223)和其余非V617F携带者的对照组(n=252,140)进行了联合GWA。对于这些MPN合并V617F携带者，我们复制了与V617F阳性MPN相关的胚系JAK2 46/1单倍型(rs59384377：优势比[OR]=2.4，P=6.6×10(-89))。我们还发现了TERT基因(rs7705526：OR=1.8，P=1.1×10(-32))、SH2B3(rs7310615：OR=1.4，P=3.1×10(-14))和TET2上游(rs1548483：OR52.0，P=2.0x10(-9))的全基因组显著关联。在446名V617F携带者和169 021名非携带者的单独复制队列中，这些相关性得到了证实。在联合分析GWAS和复制结果的联合分析中，我们确定了与CHEK2、ATM、PINT和GFI1B相关的其他全基因组显著易感基因。在MPN患者和V617F携带者对照组中，所有的SNP OR都是相似的。这些数据表明，相同的胚系变异不仅赋予个体MPN的易感性，也赋予JAK2 V617F克隆性造血的易感性，这是一种更常见的现象，可能预示着一种明显的肿瘤的发展。
We conducted a genome-wide association study (GWAS) to identify novel predisposition alleles associated with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) and JAK2 V617F clonal hematopoiesis in the general population. We recruited a web-based cohort of 726 individuals with polycythemia vera, essential thrombocythemia, and myelofibrosis and 252 637 population controls unselected for hematologic phenotypes. Using a single-nucleotide polymorphism (SNP) array platform with custom probes for the JAK2 V617F mutation (V617F), we identified 497 individuals (0.2%) among the population controls who were V617F carriers. We performed a combined GWAS of the MPN cases plus V617F carriers in the control population (n = 1223) vs the remaining controls who were noncarriers for V617F (n = 252 140). For these MPN cases plus V617F carriers, we replicated the germ line JAK2 46/1 haplotype (rs59384377: odds ratio [OR] = 2.4, P = 6.6 x 10(-89)), previously associated with V617F-positive MPN. We also identified genome-wide significant associations in the TERT gene (rs7705526: OR = 1.8, P = 1.1 x 10(-32)), in SH2B3 (rs7310615: OR = 1.4, P = 3.1 x 10(-14)), and upstream of TET2 (rs1548483: OR52.0, P=2.0x10(-9)). These associations were confirmed in a separate replication cohort of 446 V617F carriers vs 169 021 noncarriers. In a joint analysis of the combined GWAS and replication results, we identified additional genome-wide significant predisposition alleles associated with CHEK2, ATM, PINT, and GFI1B. All SNP ORs were similar for MPN patients and controls who were V617F carriers. These data indicate that the same germ line variants endow individuals with a predisposition not only to MPN, but also to JAK2 V617F clonal hematopoiesis, a more common phenomenon that may foreshadow the development of an overt neoplasm.