rs12343867

badMag 5.5

This is a intron variant variant in the JAK2 gene.

Key Literature Trait Associations

Myeloproliferative Neoplasm Susceptibility

The C allele tags the JAK2 46/1 (GGCC) haplotype, which confers a roughly 3-fold increased predisposition to acquiring the somatic JAK2 V617F mutation that drives myeloproliferative neoplasms including polycythemia vera, essential thrombocythemia, and primary myelofibrosis. In a GWAS of 1,172 MPN cases and 7,068 controls of European ancestry, this variant reached genome-wide significance (OR = 3.10, P = 1.4 × 10⁻²⁹). The 46/1 haplotype is hypothesized to create a permissive genetic background that preferentially promotes somatic V617F mutagenesis or clonal expansion.

Li SL et al. “The JAK2 46/1 haplotype (GGCC) in myeloproliferative neoplasms and splanchnic vein thrombosis: a pooled analysis of 26 observational studies.” Annals of Hematology (2014)

Allele C

OR 1.88

p 1.0e-10

N 15,995

Large GWAS

multi-ancestry

Bodemer C et al. “Pediatric mastocytosis is a clonal disease associated with D816V and other activating c-KIT mutations.” The Journal of Investigative Dermatology 130(3):804-815 (2010)

Allele C

OR 3.10

p 1.4e-29

Large GWAS

Pardanani A et al. “The JAK2 46/1 haplotype confers susceptibility to essential thrombocythemia regardless of JAK2V617F mutational status-clinical correlates in a study of 226 consecutive patients.” Leukemia (2010)

Allele C

OR —

p 1.0e-2

N 226

Candidate gene study

European

Tefferi A et al. “JAK2 germline genetic variation affects disease susceptibility in primary myelofibrosis regardless of V617F mutational status: nullizygosity for the JAK2 46/1 haplotype is associated with inferior survival.” Leukemia (2010)

Allele C

OR —

p 1.0e-2

N 130

Candidate gene study

European

Paes J et al. “The Contribution of JAK2 46/1 Haplotype in the Predisposition to Myeloproliferative Neoplasms.” International Journal of Molecular Sciences (2022)

Allele C

OR —

p —

Candidate gene study

multi-ancestry

“A common JAK2 haplotype confers susceptibility to myeloproliferative neoplasms”

Allele C

OR —

p —

Candidate gene study

European

Splanchnic vein thrombosis

The rs12343867 C allele and the JAK2 46/1 haplotype are overrepresented in patients with splanchnic vein thrombosis (SVT), including Budd-Chiari syndrome and portal vein thrombosis, particularly in those who are JAK2 V617F-positive. The CC genotype is frequently observed in SVT patients lacking overt JAK2 V617F mutation, suggesting an independent predisposing role. Evidence from the large pooled meta-analysis (PMID 25015051) found that overall SVT association was driven primarily by V617F-positive cases, with the CT vs TT model non-significant, indicating the effect may be partially mediated through MPN predisposition.

Smalberg JH et al. “The JAK2 46/1 haplotype in Budd-Chiari syndrome and portal vein thrombosis.” Blood (2011)

Allele C

OR —

p 1.0e-2

N 199

Candidate gene study

European

Li SL et al. “The JAK2 46/1 haplotype (GGCC) in myeloproliferative neoplasms and splanchnic vein thrombosis: a pooled analysis of 26 observational studies.” Annals of Hematology (2014)

Allele C

OR 1.88

p 1.0e-4

N 15,995

Preliminary work

multi-ancestry

Colaizzo D et al. “The JAK2 rs12343867 CC genotype frequently occurs in patients with splanchnic venous thrombosis without the JAK2V617F mutation: a retrospective study.” Journal of Thrombosis and Haemostasis : Jth (2010)

Allele C

OR —

p —

Candidate gene study

European

Venous thrombosis

Beyond splanchnic vessels, rs12343867 C allele carriage has been associated with non-splanchnic venous thrombosis (deep vein thrombosis, pulmonary embolism) in a study of 438 patients (OR=1.83, p=7.02×10⁻⁵). The TC+CC genotypes were significantly overrepresented versus controls, suggesting the JAK2 46/1 haplotype may predispose to venous thromboembolism more broadly, possibly via sub-threshold clonal myeloid expansion or JAK2-mediated platelet activation. Replication in large prospective cohorts is needed to fully establish this association independent of MPN.

Zerjavic K et al. “The association of the JAK2 46/1 haplotype with non-splanchnic venous thrombosis.” Thrombosis Research (2013)

Allele C

OR 1.83

p 7.0e-5

N 1,123

Preliminary work

European

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Research that mentions this SNP (1)

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The G allele of the JAK2 rs10974944 SNP, part of JAK2 46/1 haplotype, is strongly associated with JAK2 V617F-positive myeloproliferative neoplasms

AssociationN=299Adrian P. Trifa et al.(2010)· Annals of Hematology

This case-control study of 149 myeloproliferative neoplasm (MPN) patients and 150 controls demonstrates that the G allele of JAK2 rs10974944 (part of the JAK2 46/1 haplotype) is strongly associated with JAK2 V617F-positive MPN (p<0.0001, OR=5.2 for GG/CG vs CC). The association is specific to V617F-positive cases and correlates with higher mutant allele burden (>50% vs <50%, p=0.0006, OR=6.1).

Traits studied:Essential thrombocythemiaMyeloproliferative neoplasmsPolycythemia veraPrimary myelofibrosis

rs12343867

Key Literature Trait Associations

Myeloproliferative Neoplasm Susceptibility

Splanchnic vein thrombosis

Venous thrombosis

Research that mentions this SNP (1)

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