A Common Variant of IL-6R is Associated with Elevated IL-6 Pathway Activity in Alzheimer's Disease Brains

Patrick C G Haddick, Jessica L. Larson, Nisha Rathore, Tushar R. Bhangale, Qui T. Phung, Karpagam Srinivasan, David V. Hansen, Jennie R. Lill, Margaret A Pericak-Vance, Jonathan Haines, Lindsay A. Farrer, John S. Kauwe, Gerard D. Schellenberg, Carlos Cruchaga, Alison M. Goate, Timothy W. Behrens, Ryan J. Watts, Robert R. Graham, Joshua S. Kaminker, Marcel Van Der Brug

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

The common p.D358A variant (rs2228145) in IL-6R is associated with risk for multiple diseases and with increased levels of soluble IL-6R in the periphery and central nervous system (CNS). Here, we show that the p.D358A allele leads to increased proteolysis of membrane bound IL-6R and demonstrate that IL-6R peptides with A358 are more susceptible to cleavage by ADAM10 and ADAM17. IL-6 responsive genes were identified in primary astrocytes and microglia and an IL-6 gene signature was increased in the CNS of late onset Alzheimer's disease subjects in an IL6R allele dependent manner. We conducted a screen to identify variants associated with the age of onset of Alzheimer's disease in APOE ϵ4 carriers. Across five datasets, p.D358A had a meta P 3 ×10-4 and an odds ratio 1.3, 95 confidence interval 1.12-1.48. Our study suggests that a common coding region variant of the IL-6 receptor results in neuroinflammatory changes that may influence the age of onset of Alzheimer's disease in APOE ϵ4 carriers.

Original languageEnglish (US)
Pages (from-to)1037-1054
Number of pages18
JournalJournal of Alzheimer's Disease
Volume56
Issue number3
DOIs
StatePublished - 2017

Keywords

  • Alzheimer's disease
  • astrocytes
  • IL-6
  • metalloproteases
  • microglia

ASJC Scopus subject areas

  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

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  • Cite this

    Haddick, P. C. G., Larson, J. L., Rathore, N., Bhangale, T. R., Phung, Q. T., Srinivasan, K., Hansen, D. V., Lill, J. R., Pericak-Vance, M. A., Haines, J., Farrer, L. A., Kauwe, J. S., Schellenberg, G. D., Cruchaga, C., Goate, A. M., Behrens, T. W., Watts, R. J., Graham, R. R., Kaminker, J. S., & Van Der Brug, M. (2017). A Common Variant of IL-6R is Associated with Elevated IL-6 Pathway Activity in Alzheimer's Disease Brains. Journal of Alzheimer's Disease, 56(3), 1037-1054. https://doi.org/10.3233/JAD-160524