Abstract
Germline variations at JAK2, TERT, HBS1L-MYB and MECOM have been found to associate with myeloproliferative neoplasms (MPNs) in European populations. Whether these germline variations are associated with MPNs in Taiwanese population is obscure. Here we aimed to evaluate the association of five germline variations (JAK2 46/1 haplotype tagged by rs12343867, JAK2 intron 8 rs12339666, TERT rs2736100, HBS1L-MYB rs9376092 and MECOM rs2201862) and the risk of MPNs in Taiwanese population. A total of 178 MPN patients (109 essential thrombocythemia, 54 polycythemia vera and 15 primary myelofibrosis) were enrolled into this study. The information of 17033 control subjects was obtained from Taiwan Biobank database. The JAK2 46/1 haplotype, JAK2 rs12339666 and TERT rs2736100 were significantly associated with Taiwanese MPNs (P = 3.6×10-19, 1.9×10-19 and 3.1×10-6, respectively), and JAK2V617F-positive MPNs (n=121) (P = 5.6×10-21, 4.4×10-21 and 8.6×10-7, respectively). In JAK2V617F-negative cases (n=55), only the JAK2 46/1 haplotype and JAK2 rs12339666 remained statistically significant (P= 0.009 and 0.007, respectively). When stratified by disease subtypes, the JAK2 46/1 haplotype and JAK2 rs12339666 were significantly associated with all three MPN subtypes, but TERT rs2736100 was only associated with essential thrombocythemia and polycythemia vera. We did not find any association of these five SNPs with CALR mutations in our cohort. Furthermore, the risk alleles of MECOM rs2201862 and HBS1L-MYB rs9376092 were demonstrated to be negatively associated with the risk of developing polycythemia vera. In conclusion, germline variations at JAK2 (both the 46/1 haplotype and rs12339666) and TERT rs2736100 were associated with MPNs in Taiwanese population.
Highlights
The classic BCR-ABL1-negative myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell diseases, including three major disease entities: polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) [1]
When stratified by disease subtypes, the JAK2 46/1 haplotype and JAK2 rs12339666 were significantly associated with all three MPN subtypes, but TERT rs2736100 was only associated with essential thrombocythemia and polycythemia vera
We found that JAK2 rs12343867, JAK2 rs12339666 and TERT rs2736100 were associated with MPNs in Taiwanese population
Summary
The classic BCR-ABL1-negative myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell diseases, including three major disease entities: polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) [1]. Among the three subtypes of MPNs, PV and ET are characterized by excessive formation of mature red blood cells and platelets, respectively, while PMF appears as fibrosis of the bone marrow, abnormal megakaryocytic proliferation and clustering, extramedullary hematopoiesis and variable peripheral blood counts. Somatic mutations in JAK2V617F, CALR exon 9 and MPL exon 10 have been demonstrated as three major driver mutations in MPNs, are usually mutually exclusive in the majority of cases, and involve in the activation of JAK-STAT signaling [2, 3]. In ET or PMF patients without gene mutations in either JAK2 or MPL, CALR mutations have been observed in approximately 70% of these patients [4,5,6,7,8]
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