Dear Editor
We read with interest the study published by Pedersen and colleagues which reported that a genetic variant in the IL6R gene reduces the risk of the JAK2V617F somatic mutation and thus the risk to develop a myeloproliferative neoplasm [1]. They report that the variant rs4537545 is in high linkage disequilibrium with the IL6R variant rs2228145, which causes the non-synonymous exchange of Asp-358 to Ala-358 of the IL-6R protein [2], resulting in increased soluble IL-6R (sIL-6R) levels and reduced membrane-bound IL-6R due to increased proteolytic IL-6R cleavage [3].
While the finding is of high relevance and links an extracellular IL-6R variant with a mutation in an intracellular kinase by a so-far unknown mechanism, we would like to raise two important points to consider. First, the authors characterize the IL6R variant as anti-inflammatory due to reduced amounts of membrane-bound IL-6R on hepatocytes and thus diminished CRP production in homozygous carriers. While this is certainly true, we emphasize that increased sIL-6R in individuals in combination with soluble gp130 (sgp130) in the circulation acts as a natural buffer that can neutralize IL-6 [4,5] and thereby reduce low-level inflammation, which is in line with the arguments put forward by Pedersen and colleagues [1].
Second, the authors compare these increased sIL-6R levels with patients under Tocilizumab treatment, which display even higher sIL-6R levels. In our opinion, these two scenarios cannot be compared, because Tocilizumab blocks all (s)IL-6R molecules in treated patients and renders them biologically inactive, while all (s)IL-6R molecules in individuals homozygous for rs2228145 are fully biologically active.
Declaration of Competing Interest
C. G. has received a research grant from Corvidia Therapeutics (Waltham, MA, USA). S.R.-J. has acted as a consultant and speaker for AbbVie, Chugai, Roche, Genentech Roche, Pfizer and Sanofi. He also declares that he is an inventor on patents owned by CONARIS Research Institute, which develops the sgp130Fc protein Olamkicept and he has stock ownership in CONARIS.
Funding
Work in the groups of the authors is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – Projektnummer 125440785 – SFB 877 (projects A1, A10 and A14).
References
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