Abstract
BackgroundMyeloproliferative neoplasms (MPNs) are a group of haematological malignancies that can be characterised by a somatic mutation (JAK2V617F). This mutation causes the bone marrow to produce excessive blood cells and is found in polycythaemia vera (~95%), essential thrombocythaemia and primary myelofibrosis (both ~50%). It is considered as a major genetic factor contributing to the development of these MPNs. No genetic association study of MPN in the Hong Kong population has so far been reported. Here, we investigated the relationship between germline JAK2 polymorphisms and MPNs in Hong Kong Chinese to find causal variants that contribute to MPN development. We analysed 19 tag single nucleotide polymorphisms (SNPs) within the JAK2 locus in 172 MPN patients and 470 healthy controls. Three of these 19 SNPs defined the reported JAK2 46/1 haplotype: rs10974944, rs12343867 and rs12340895. Allele and haplotype frequencies were compared between patients and controls by logistic regression adjusted for sex and age. Permutation test was used to correct for multiple comparisons. With significant findings from the 19 SNPs, we then examined 76 additional SNPs across the 148.7-kb region of JAK2 via imputation with the SNP data from the 1000 Genomes Project.ResultsIn single-marker analysis, 15 SNPs showed association with JAK2V617F-positive MPNs (n = 128), and 8 of these were novel MPN-associated SNPs not previously reported. Exhaustive variable-sized sliding-window haplotype analysis identified 184 haplotypes showing significant differences (P < 0.05) in frequencies between patients and controls even after multiple-testing correction. However, single-marker alleles exhibited the strongest association with V617F-positive MPNs. In local Hong Kong Chinese, rs12342421 showed the strongest association signal: asymptotic P = 3.76 × 10−15, empirical P = 2.00 × 10−5 for 50,000 permutations, OR = 3.55 for the minor allele C, and 95% CI, 2.59-4.87. Conditional logistic regression also signified an independent effect of rs12342421 in significant haplotype windows, and this independent effect remained unchanged even with the imputation of additional 76 SNPs. No significant association was found between V617F-negative MPNs and JAK2 SNPs.ConclusionWith a large sample size, we reported the association between JAK2V617F-positive MPNs and 15 tag JAK2 SNPs and the association of rs12342421 being independent of the JAK2 46/1 haplotype in Hong Kong Chinese population.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-014-0147-y) contains supplementary material, which is available to authorized users.
Highlights
Myeloproliferative neoplasms (MPNs) are a group of haematological malignancies that can be characterised by a somatic mutation (JAK2V617F)
Detection of JAK2V617F mutation in Hong Kong Chinese All cases and controls were first screened for V617F mutation
Our results show that the significant association between Janus Kinase 2 (JAK2) polymorphisms and MPNs in Hong Kong Chinese is comparable to the results in other populations
Summary
Myeloproliferative neoplasms (MPNs) are a group of haematological malignancies that can be characterised by a somatic mutation (JAK2V617F) This mutation causes the bone marrow to produce excessive blood cells and is found in polycythaemia vera (~95%), essential thrombocythaemia and primary myelofibrosis (both ~50%). The present study focuses on three main MPNs: polycythaemia vera (PV), essential thrombocythaemia (ET), and primary myelofibrosis (PMF) [1] These three non-leukaemic MPNs are characterised by their BCR-ABL-negativity and recurrent genetic aberrations, a somatic mutation, JAK2V617F (hereafter V617F). This point mutation leads to the Val-to-Phe substitution at the amino acid position 617 and constitutively activates the JAK-STAT signalling pathway that is essential for homeostatic processes including proliferation and survival of haematopoietic cells [2,3]. Work remains to be done to identify the causal variants in or flanking the JAK2 locus and to delineate the mechanism by which such casual variants contribute to MPN development
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