Download Potential Significance of IL-6 Receptor Genotype on ALS Disease

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Title: Potential Significance of IL-6 Receptor Genotype on ALS Disease Progression
Additional authors (in order):Marlena Wosiski-Kuhn*, Mac Robinson**, James Caress#,
Gregory Hawkins##, Carol Milligan**
Institution name, city, state, country of additional authors: *Neuroscience Program;
**Department of Neurobiology and Anatomy; #Department of Neurology; ## Center for
Genomics and Personalized Medicine
Abstracts must contain the background, hypothesis, methods, results to date (if ongoing) and
discussion/conclusions. Not to Exceed 350 Words. Typed font must be Times New Roman
and no smaller than 11 Pt. Do not use continuation pages, tables, or illustrations.
Tocilizumab, an antibody to block the interleukin 6 receptor (IL-6R), is currently being evaluated in a clinical trial for
Amyotrophic Lateral Sclerosis (ALS). Interleukin-6 (IL-6) is a key regulator of inflammation, and its expression is
associated with muscle atrophy and compromised respiratory function, both hallmarks of ALS pathophysiology. We
have previously presented increased levels of IL-6 in ALS serum and CSF as compared to control samples. The
functional effect of IL-6 is contextual in terms of cell type and if the ligand interaction is mediated through the
membrane bound or soluble receptor. Through its soluble receptor (sIL-6R), IL-6 can signal across all cells, as
opposed to the small immune subset only expressing the membrane bound receptor. This can promote a
proinflammatory environment and suppress anti-inflammatory responses. A functional single nucleotide
polymorphism (SNP) in the IL-6 receptor sequence, rs2228145, present in 35% of the Caucasian population
(Thousand Genomes CEU: 2011), results in a dose-dependent increase of sIL-6R in serum with the presence of the
minor, variant allele. Presence of the polymorphism correlates with disease severity in asthma and other disorders.
The goal of this study was to evaluate levels of IL-6 and sIL-6R in paired serum and CSF samples from ALS and
control subjects obtained from the NEALS biorepository. The presence of rs2228145 was also determined. Because
DNA was no longer available from NEALS, we isolated DNA from rare peripheral mononuclear blood cells
(PMBCs) and/or fragments from lysed cells in serum in order to conduct genotyping. We show here that there is a
positive correlation between paired CSF and serum levels of sIL-6R protein and stepwise increase in sIL-6R with
presence of the variant allele. Identification of genotype is critical to evaluating IL-6 signaling; however, lacking
critical clinical parameters on each sample, limits the ability of our results to aid in the prediction of a subset of
patients who may vary in severity or who may be ideal responders to therapeutics such as tocilizumab. In the era of
precision medicine, our results reinforce the importance of clinical data to the interpretation of molecular findings.
This work was supported by Hope for Tomorrow- a gift in the memory of Dr. Murray Abrams.
Please return the abstract form/abstract to:
Tara Lincoln
NEALS Program Director
[email protected]