Loss-of-function polymorphism in IL6R reduces risk of JAK2V617F somatic mutation and myeloproliferative neoplasm: A Mendelian randomization study. (April 2020)

• Record Type: Journal Article
• Authors: Pedersen, Kasper Mønsted; Çolak, Yunus; Ellervik, Christina; Hasselbalch, Hans Carl; Bojesen, Stig Egil; Nordestgaard, Børge Grønne
• Is Part Of: EClinicalMedicine. Volume 21(2020)
• Publication Date: 2020-04
• Subjects: Mendelian randomization -- Myeloproliferative neoplasm -- Essential thrombocythemia -- Polycythemia vera -- Myelofibrosis -- Drug target; Medicine -- Research -- Periodicals; Medical policy -- Periodicals; Clinical Medicine; Health Policy; Public Health; Medical policy; Medicine -- Research; Periodical; Electronic journals; Periodicals; 613
• DOI: 10.1016/j.eclinm.2020.100280
• Languages: English
• ISSNs: 2589-5370

Abstract

Abstract: Background: Whether inflammation is independently associated with development of JAK2 V617F mutation and myeloproliferative neoplasm is not clear. We tested the hypothesis that a loss-of-function polymorphism in IL6R (marked by rs4537545) reduces risk of JAK2 V617F mutation and myeloproliferative neoplasm in a Mendelian randomization study. Methods: We genotyped 107, 969 Danes from the Copenhagen General Population Study for the IL6R rs4537545 genotype, where the T-allele is associated with impaired interleukin-6 receptor signaling and reduced inflammation. JAK2 V617F was examined in a subset of 49, 143 individuals. We investigated the association between IL6R rs4537545 and risk of JAK2 V617F using logistic regression and myeloproliferative neoplasm using Cox regression. Findings: 36, 871 were non-carriers, 52, 500 heterozygotes, and 18, 598 homozygotes for the T-allele of the IL6R rs4537545 genotype. Among 107, 969 individuals, 352 were diagnosed with myeloproliferative neoplasm, and among 49, 143 individuals, 62 were JAK2 V617F-positive (of these 62 individuals, 46 had myeloproliferative neoplasm diagnosed). Compared to non-carriers, age- and sex-adjusted odds ratios for risk of JAK2 V617F were 0·55(95%CI:0·32–0·94) in heterozygotes, 0·51(0·24–1·12) in homozygotes, 0·54(0·33–0·89) in carriers, and 0·66(0·45–0·96) per T-allele. Compared to non-carriers, age- and sex-adjusted hazard ratios for risk of myeloproliferative neoplasm were 0·82(95% CI: 0·65–1·02) in heterozygotes, 0·65(0·47–0·91) in homozygotes, 0·77(0·63–0·96) in carriers, and 0·81(0·70–0·94) per T-allele. Associations were primarily observed for polycythaemia vera and myelofibrosis, and for JAK2 V617F-positive myeloproliferative neoplasm. Interpretation: A loss-of-function polymorphism in IL6R reduces risk of JAK2 V617F mutation and myeloproliferative neoplasm. This finding supports inflammation as an independent risk factor for JAK2 V617F mutation and myeloproliferative neoplasm and indicates that therapeutics designed to block interleukin-6 receptor signaling might prevent or retard progression of myeloproliferative neoplasm. Funding: Karen Elise Jensen Foundation.