Loss-of-function polymorphism in <i>IL6R</i> reduces risk of <i>JAK2</i>V617F somatic mutation and myeloproliferative neoplasm: A Mendelian randomization study.

Abstract

Whether inflammation is independently associated with development of <i>JAK2</i>V617F mutation and myeloproliferative neoplasm is not clear. We tested the hypothesis that a loss-of-function polymorphism in <i>IL6R</i> (marked by rs4537545) reduces risk of <i>JAK2</i>V617F mutation and myeloproliferative neoplasm in a Mendelian randomization study. We genotyped 107,969 Danes from the Copenhagen General Population Study for the <i>IL6R</i> rs4537545 genotype, where the T-allele is associated with impaired interleukin-6 receptor signaling and reduced inflammation. <i>JAK2</i>V617F was examined in a subset of 49,143 individuals. We investigated the association between <i>IL6R</i> rs4537545 and risk of <i>JAK2</i>V617F using logistic regression and myeloproliferative neoplasm using Cox regression. 36,871 were non-carriers, 52,500 heterozygotes, and 18,598 homozygotes for the T-allele of the <i>IL6R</i> rs4537545 genotype. Among 107,969 individuals, 352 were diagnosed with myeloproliferative neoplasm, and among 49,143 individuals, 62 were <i>JAK2</i>V617F-positive (of these 62 individuals, 46 had myeloproliferative neoplasm diagnosed). Compared to non-carriers, age- and sex-adjusted odds ratios for risk of <i>JAK2</i>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 <i>JAK2</i>V617F-positive myeloproliferative neoplasm. A loss-of-function polymorphism in <i>IL6R</i> reduces risk of <i>JAK2</i>V617F mutation and myeloproliferative neoplasm. This finding supports inflammation as an independent risk factor for <i>JAK2</i>V617F mutation and myeloproliferative neoplasm and indicates that therapeutics designed to block interleukin-6 receptor signaling might prevent or retard progression of myeloproliferative neoplasm. Karen Elise Jensen Foundation.