The association of the JAK2 46/1 haplotype with non-splanchnic venous thrombosis

Zerjavic, Katja; Zagradišnik, Boris; Lokar, Lidija; Kraševac, Marjana Glaser; Vokač, Nadja Kokalj

doi:10.1016/j.thromres.2013.06.021

Cited by 3 publications

(4 citation statements)

References 34 publications

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“…Accurate information regarding causes of death was not available in the current study but the possibility of differences in leukemic transformation or thrombotic events was adequately addressed and found to be noncontributory. An association between the JAK2 46/1 haplotype and splanchnic as well as nonsplanchnic vein thrombosis in MPN has previously been reported . However, in this study, we found no significant associations with thrombotic events, carefully segregated into arterial vs venous events and timed before and after diagnosis.…”

Section: Discussioncontrasting

confidence: 78%

The germline JAK2 GGCC (46/1) haplotype and survival among 414 molecularly‐annotated patients with primary myelofibrosis

et al. 2018

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JAK2 mutations in myeloproliferative neoplasms (MPNs) are associated with the germline GGCC (46/1) haplotype. In 2010, we reported an association between shortened survival in primary myelofibrosis (PMF) and nullizygosity for the JAK2 46/1 haplotype. In the current study, we have increased the number of informative cases from 130 to 414 (median age 63 years; 63% males), in order to revisit with the phenotypic and prognostic relevance of the JAK2 46/1 haplotype in PMF. JAK2 46/1 haplotype was documented in 69% of the study patients, including 25% in homozygous and 44% in heterozygous state. Driver mutation frequency in patients homozygous/heterozygous/nullizygous for the 46/1 haplotype was 78%/60%/56% JAK2, 10%/20%/18% type 1‐like CALR, 3%/2%/5% type 2‐like CALR, 4%/8%/7% MPL, and 6%/10%/14% triple‐negative (P = .02). In univariate analysis, nullizygosity for the JAK2 46/1 haplotype was associated with inferior overall survival (HR 1.5, 95% CI 1.1‐1.9), most pronounced in JAK2 (P <.001), as opposed to CALR/MPL mutated (P = .48) or triple‐negative cases (P = .27). Multivariable analysis that included karyotype, driver mutational status and high‐molecular risk mutations confirmed the independent prognostic contribution of nullizygosity for the 46/1 haplotype (P = .02; HR 1.4, 95% CI 1.1‐1.8). Nullizygosity for 46/1 also remained significant in the context of the genetically‐inspired GIPSS risk model (P = .04), but not in the context of the integrated genetics‐clinical MIPSS70+ version 2.0 model (P = .4). Leukemia‐free survival was not affected by the 46/1 haplotype (P = .6). The current study confirms the association of nullizygosity for the JAK2 GGCC (46/1) haplotype with inferior survival in JAK2‐mutated PMF.

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Section: Discussioncontrasting

confidence: 78%

The germline JAK2 GGCC (46/1) haplotype and survival among 414 molecularly‐annotated patients with primary myelofibrosis

et al. 2018

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“…Zerjavic et al . [ 27 ] also reported a less significant association for rs12342421 (S8) than for rs10974944 (S9) – a finding different from ours (Table 1 ).…”

Section: Discussioncontrasting

confidence: 99%

“…Although rs12342421 (S8) was analysed in an early study, the results were never reported explicitly [ 10 ]. Two other studies indeed reported the association of rs12342421 (S8) with MPNs in Caucasians [ 16 , 27 ]. However, both studies did not investigate whether rs12342421 (S8) contributed an effect independent of the JAK2 46/1 haplotype [ 16 , 27 ].…”

Section: Discussionmentioning

confidence: 79%

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Genetic association between germline JAK2polymorphisms and myeloproliferative neoplasms in Hong Kong Chinese population: a case–control study

Koh

Yip

Lee³

et al. 2014

BMC Genet

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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.

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JAK2 rs10974944 is associated with both V617F‐positive and negative myeloproliferative neoplasms in a Vietnamese population: A potential genetic marker

Ngoc

Hau

Vuong

et al. 2022

Molec Gen & Gen Med

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The JAK2 gene encodes for a non‐receptor tyrosine kinase that plays a key role in the JAK/STAT signaling transfer pathway. Genetic polymorphisms of this gene have been indicated to be associated with myeloproliferative neoplasm‐associated thrombosis in recent studies. This research aimed to evaluate the association between the variant rs10974944 and different types of Myeloproliferative neoplasms disorders in the Vietnamese population. DNA samples were obtained from 172 essential thrombocythemia patients, 14 primary myelofibrosis patients, 76 polycythemia vera patients, and 192 healthy controls. The JAK2 rs10974944 and V617F genotypes were identified by the polymerase chain reaction‐restriction fragment length polymorphism genotyping and Sanger sequencing methods. Results showed that there was a strong association between rs10974944 and Myeloproliferative neoplasms phenotype (p < .0001) and the most significant association was observed in the recessive model of the mutant allele (G). The G allele carriers had a 1.74, 2.86, and 3.03 higher risk of getting essential thrombocythemia, primary myelofibrosis, and polycythemia vera, respectively. Interestingly, this effect of rs10974944 seemed to be independent of the JAK2 V617F genotype. The distribution of rs10974944 genotypes were significantly different between V617F‐positive and negative groups (p = .008). Moreover, the GG genotype of rs10974944 was observed to be associated with the risk of getting Myeloproliferative neoplasms both in JAK2 V617F‐positive group, and for the first time in JAK2 V617F‐negative patients. A systematic meta‐analysis in different populations strengthened the evidence regarding the correlation between rs10974944 and myeloproliferative neoplasm disorders. To sum up, our results suggested that rs10974944 can be used as a predisposition screening marker for predicting Myeloproliferative neoplasms susceptibility.

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The association of the JAK2 46/1 haplotype with non-splanchnic venous thrombosis

Cited by 3 publications

References 34 publications

The germline JAK2 GGCC (46/1) haplotype and survival among 414 molecularly‐annotated patients with primary myelofibrosis

The germline JAK2 GGCC (46/1) haplotype and survival among 414 molecularly‐annotated patients with primary myelofibrosis

Genetic association between germline JAK2polymorphisms and myeloproliferative neoplasms in Hong Kong Chinese population: a case–control study

JAK2 rs10974944 is associated with both V617F‐positive and negative myeloproliferative neoplasms in a Vietnamese population: A potential genetic marker

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