TY - JOUR

T1 - Loss-of-function polymorphism in IL6R reduces risk of JAK2V617F somatic mutation and myeloproliferative neoplasm

T2 - A Mendelian randomization study

AU - Pedersen, Kasper Mønsted

AU - Çolak, Yunus

AU - Ellervik, Christina

AU - Hasselbalch, Hans Carl

AU - Bojesen, Stig Egil

AU - Nordestgaard, Børge Grønne

PY - 2020

Y1 - 2020

N2 - Background: Whether inflammation is independently associated with development of JAK2V617F 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 JAK2V617F 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. JAK2V617F was examined in a subset of 49,143 individuals. We investigated the association between IL6R rs4537545 and risk of JAK2V617F 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 JAK2V617F-positive (of these 62 individuals, 46 had myeloproliferative neoplasm diagnosed). Compared to non-carriers, age- and sex-adjusted odds ratios for risk of JAK2V617F 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 JAK2V617F-positive myeloproliferative neoplasm. Interpretation: A loss-of-function polymorphism in IL6R reduces risk of JAK2V617F mutation and myeloproliferative neoplasm. This finding supports inflammation as an independent risk factor for JAK2V617F 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.

AB - Background: Whether inflammation is independently associated with development of JAK2V617F 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 JAK2V617F 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. JAK2V617F was examined in a subset of 49,143 individuals. We investigated the association between IL6R rs4537545 and risk of JAK2V617F 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 JAK2V617F-positive (of these 62 individuals, 46 had myeloproliferative neoplasm diagnosed). Compared to non-carriers, age- and sex-adjusted odds ratios for risk of JAK2V617F 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 JAK2V617F-positive myeloproliferative neoplasm. Interpretation: A loss-of-function polymorphism in IL6R reduces risk of JAK2V617F mutation and myeloproliferative neoplasm. This finding supports inflammation as an independent risk factor for JAK2V617F 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.

KW - Drug target

KW - Essential thrombocythemia

KW - Mendelian randomization

KW - Myelofibrosis

KW - Myeloproliferative neoplasm

KW - Polycythemia vera

U2 - 10.1016/j.eclinm.2020.100280

DO - 10.1016/j.eclinm.2020.100280

M3 - Journal article

C2 - 32382712

AN - SCOPUS:85079891411

VL - 21

JO - EClinicalMedicine

JF - EClinicalMedicine

SN - 2589-5370

M1 - 100280

ER -