Blood Adv. 2022 Apr 5:bloodadvances.2021005648. doi: 10.1182/bloodadvances.2021005648. Online ahead of print.
ABSTRACT
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 (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 + RT) or ET-restricted cohorts identified associations with 2 IFNA16 (interferon-α16) SNVs, and the ET associations were validated in a second independent cohort (p-value 0.0002). Odds Ratio (OR) of the combined ET cohort (N = 105) was 4.92, restricted to the JAK2V617F-negative subset (OR 5.01). ET sub-stratification analysis by variant IFNA16 demonstrated statistically significant increase in interferon-α16 levels (p = 0.002) among 16 quantifiable cytokines. Recombinantly-expressed variant IFN-α16 encompassing 3 linked non-synonymous SNVs (E65 H95 P133) retained comparable antiviral (AV) and pSTAT signaling profiles as native IFN-α16 (V65 D95 A133) or IFN-α2, although both native and variant IFN-α16 demonstrated stage-restricted differences (compared to IFN-α2) of interferon-regulated genes in CD34+-stimulated megakaryocytes. These data implicate IFNA16 (IFN-α16 gene product) as a putative susceptibility locus (driver) within the broader disrupted cytokine network evident in MPNs, and provide a framework for dissecting functional interactive networks regulating stress or MPN thrombopoiesis.
PMID:35381074 | DOI:10.1182/bloodadvances.2021005648
