Germline genetic factors influence the outcome of interferon-α therapy in polycythemia vera.

Abstract

Interferon-α (IFN-α)-based treatments can induce hematologic and molecular responses (HRs and MRs, respectively) in polycythemia vera (PV); however, patients do not respond equally. Germline genetic factors have been implicated in differential drug responses. We addressed the effect of common germline polymorphisms on HR and MR after treatment of PV in the PROUD-PV and CONTINUATION-PV studies in a total of 122 patients who received ropeginterferon alfa-2b. Genome-wide association studies using longitudinal data on HR and MR over a 36-month follow-up did not reveal any associations at the level of genome-wide statistical significance. Furthermore, we performed targeted association analyses at the interferon lambda 4 (IFNL4) locus, well known for its role in hepatitis C viral clearance and recently reported to influence HR during treatment of myeloproliferative neoplasms. We did not observe any association of IFNL4 polymorphisms with HR in our study cohort; however, we demonstrated a statistically significant effect of the functionally causative IFNL4 diplotype (haplotype pair, including the protein-coding variants rs368234815/rs117648444) on MR (P = 3.91 × 10-4; odds ratio, 10.80; 95% confidence interval, 2.39-69.97) as reflected in differential JAK2V617F mutational burden changes according to IFNL4 diplotype status. Stratification of patients with PV based on IFNL4 functionality may allow for optimizing patient management during IFN-α-based therapy.

• Authors: Roland Jäger, Heinz Gisslinger, Elisabeth Fuchs, Edith Bogner, Jelena D Milosevic Feenstra, Jakob Weinzierl, Fiorella Schischlik, Bettina Gisslinger, Martin Schalling, Michael Zörer, Kurt Krejcy, Christoph Klade, Robert Kralovics
• Journal: Blood (Blood) Vol. 137 Issue 3 Pg. 387-391 (01 21 2021) ISSN: 1528-0020 [Electronic] United States
• PMID: 32814349 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 by The American Society of Hematology.

Chemical References

• IFNL4 protein, human
• Interferon-alpha
• Interleukins

Topics

• Follow-Up Studies
• Genetic Predisposition to Disease
• Germ Cells (metabolism)
• Humans
• Interferon-alpha (therapeutic use)
• Interleukins (genetics)
• Open Reading Frames (genetics)
• Polycythemia Vera (drug therapy, genetics)
• Polymorphism, Single Nucleotide (genetics)
• Treatment Outcome