Cytokine pathway variants modulate platelet production: IFNA16 is a thrombocytosis susceptibility locus in humans

Inflammatory stimuli have divergent effects on peripheral platelet counts, although the mechanisms of thrombocytopenic and thrombocytotic responses remain poorly understood. A candidate gene approach targeting 326 polymorphic genes enriched in thrombopoietic and cytokine signaling pathways was applied to identify single nucleotide variants (SNVs) implicated in enhanced platelet responses in cohorts with reactive thrombocytosis (RT) or essential (myeloproliferative neoplasm [MPN]) thrombocytosis (ET). Cytokine profiles incorporating a 15-member subset, pathway topology, and functional interactive networks were distinct between ET and RT, consistent with distinct regulatory pathways of exaggerated thrombopoiesis. Genetic studies using aggregate (ET 1 RT) or ET-restricted cohorts identified associations with 2 IFNA16 (interferon-a16) SNVs, and the ET associations were validated in a second independent cohort (P 5 .0002). Odds ratio of the combined ET cohort (n 5 105) was 4.92, restricted to the JAK2^V617F-negative subset (odds ratio, 5.01). ET substratification analysis by variant IFNA16 exhibited a statistically significant increase in IFN-a16 levels (P 5 .002) among 16 quantifiable cytokines. Recombinantly expressed variant IFN-a16 encompassing 3 linked non-synonymous SNVs (E⁶⁵H⁹⁵P¹³³) retained comparable antiviral and pSTAT signaling profiles as native IFN-a16 (V⁶⁵D⁹⁵A¹³³) or IFN-a2, although both native and variant IFN-a16 showed stage-restricted differences (compared with IFN-a2) of IFN-regulated genes in CD34¹-stimulated megakaryocytes. These data implicate IFNA16 (IFN-a16 gene product) as a putative susceptibility locus (driver) within the broader disrupted cytokine network evident in MPNs, and they provide a framework for dissecting functional interactive networks regulating stress or MPN thrombopoiesis.