Research
Print page Print page
Switch language
The Capital Region of Denmark - a part of Copenhagen University Hospital
Published

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

Research output: Contribution to journalJournal articleResearchpeer-review

  1. Tocilizumab and soluble interleukin-6 receptor in JAK2V617F somatic mutation and myeloproliferative neoplasm

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Two-fold risk of pneumonia and respiratory mortality in individuals with myeloproliferative neoplasm: A population-based cohort study

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. Antibiotic exposure in infancy and development of BMI and body composition in childhood

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. Algorithmic prediction of HIV status using nation-wide electronic registry data

    Research output: Contribution to journalJournal articleResearchpeer-review

  5. Pregnancy Loss and Cancer Risk: A Nationwide Observational Study

    Research output: Contribution to journalJournal articleResearchpeer-review

  1. Cardiac chamber volumes and left ventricular mass in people living with HIV and matched uninfected controls

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Impact of cardiovascular risk factors and genetics on 10-year absolute risk of dementia: risk charts for targeted prevention

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. Low high-density lipoprotein and increased risk of several cancers: 2 population-based cohort studies including 116,728 individuals

    Research output: Contribution to journalJournal articleResearchpeer-review

View graph of relations

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.

Original languageEnglish
JournalEClinicalMedicine
Volume21
Pages (from-to)100280
ISSN2589-5370
DOIs
Publication statusPublished - Apr 2020

ID: 59818145