No association between myeloproliferative neoplasms and the Crohn’s disease-associated STAT3 predisposition SNP rs744166

We read with interest the paper by Kristinsson and colleagues who described an increased incidence of myeloproliferative neoplasms (MPNs) in individuals with a prior autoimmune disorder.1 In a large and carefully controlled population-based study from Sweden, 11,039 myeloproliferative neoplasm cases and 43,550 matched controls were analyzed to assess the associations between a previous history of a range of autoimmune disorders and the risk of developing myeloproliferative neoplasm. Of all myeloproliferative neoplasm cases, 288 (2.6%) were reported to have had a prior autoimmune disease, with the highest associations recorded for giant cell arteritis, aplastic anemia, and Reiter’s syndrome. Furthermore, there was a 2- to 3- fold elevated risk for myeloproliferative neoplasm among patients with a history of immune thrombocytopenic purpura, Crohn’s disease and polymyalgia rheumatica. Collectively, this suggests that individuals with a preceding history of immune-related diseases are 20% more likely to developing a myeloproliferative neoplasm compared to controls.

One possible explanation for these associations is a common genetic susceptibility factor(s) to both autoimmune diseases and myeloproliferative neoplasms. Crohn’s disease was recently the focus of a genome-wide association study (GWAS),2,3 an unbiased genetic approach to identify relatively common, low penetrance predisposition variants. The results confirmed a previously described association with IL23R and also identified predisposition variants mapping close to IL12B, STAT3, and JAK2, amongst others. JAK2 and STAT3 are downstream components of IL-12 and IL-23 signaling and thus these findings strongly implicate both pathways in the pathogenesis of Crohn’s disease. This is consistent with previous data indicating that Crohn’s disease may result from aberrant inflammatory responses mediated by Th1 and Th17 T-cell subsets.4

Strikingly, the JAK2 single nucleotide polymorphism associated with Crohn’s disease tags the same 46/1 haplotype identified by us and others as strongly predisposing to JAK2 mutated myeloproliferative neoplasms.5–8 Although it is not yet clear to what extent 46/1 accounts for the observed association of myeloproliferative neoplasm and Crohn’s disease, these findings strengthen the notion that common functional genetic variants impacting on JAK2 signaling predispose to these two clinically very diverse conditions. Moreover, 46/1 JAK2 should be considered as a prime candidate as a predisposing factor for the other diseases that Kristinsson and colleagues found to be associated with myeloproliferative neoplasm.

Table 1.Summary of the genotype results for the STAT3 SNP rs744166 in JAK2 V617F positive and V617F negative MPN compared to WTCCC controls.

We considered the possibility that the STAT3 SNP, rs744166, identified in the Crohn’s GWAS studies (rs744166 risk variant A achieved a combined significance level of 6.82×10)2, also predisposes to myeloproliferative neoplasm. Peripheral blood leukocyte-derived DNA from previously described Caucasian patients with JAK2 V617F positive polycythemia vera (PV)5 and V617F negative essential thrombocythemia (ET)9 were genotyped for rs744166 using pyrosequencing.10 STAT3 is located at 17q21, a region that is rarely targeted by copy number changes or acquired uniparental disomy in myeloproliferative neoplasms and thus the results were assumed to faithfully reflect constitutional genotypes. Allele frequencies were compared to the control data provided by the Welcome Trust Case Control Consortium (WTCCC) from the UK blood donor cohort (n=1,500).11 As shown in Table 1, no significant difference was seen between the cases and controls and we therefore conclude that this particular variant of STAT3 does not predispose to myeloproliferative neoplasms. More systematic searches will therefore be required to determine if there are other shared genetic susceptibility factors between myeloproliferative neoplasms and immune-related disorders.