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

Article type: Research Article

Authors: Haddick, Patrick C.G.^{a; 1; 3} | Larson, Jessica L.^{b; 1; 2} | Rathore, Nisha^{c; 1} | Bhangale, Tushar R.^{c; 1} | Phung, Qui T.^d | Srinivasan, Karpagam^e | Hansen, David V.^e | Lill, Jennie R.^d | Alzheimer’s Disease Genetic Consortium (ADGC), Alzheimer’s Disease Neuroimaging Initiative (ADNI)⁴ | Pericak-Vance, Margaret A.^{f; g} | Haines, Jonathan^h | Farrer, Lindsay A.^{i; j; k; l; m} | Kauwe, John S.ⁿ | Schellenberg, Gerard D.^o | Cruchaga, Carlos^{p; q} | Goate, Alison M.^{r; s} | Behrens, Timothy W.^c | Watts, Ryan J.^{e; 3} | Graham, Robert R.^{c; *} | Kaminker, Joshua S.^{b; *} | van der Brug, Marcel^{a; *}

Affiliations: [a] Department of Diagnostic Discovery, Genentech Inc., South San Francisco, CA, USA | [b] Department of Bioinformatics and Computational Biology, Genentech Inc., South San Francisco, CA, USA | [c] Department of Human Genetics, Genentech Inc., South San Francisco, CA, USA | [d] Department of Protein Chemistry, Genentech Inc., South San Francisco, CA, USA | [e] Department of Neuroscience, Genentech Inc., South San Francisco, CA, USA | [f] The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA | [g] Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, FL, USA | [h] Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA | [i] Department of Medicine (Biomedical Genetics), Boston University Schools of Medicine and Public Health, Boston, MA, USA | [j] Department of Neurology, Boston University Schools of Medicine and Public Health, Boston, MA, USA | [k] Department of Ophthalmology, Boston University Schools of Medicine and Public Health, Boston, MA, USA | [l] Department of Epidemiology, Boston University Schools of Medicine and Public Health, Boston, MA, USA | [m] Department of Biostatistics, Boston University Schools of Medicine and Public Health, Boston, MA, USA | [n] Department of Biology, Brigham Young University, Provo, UT, USA | [o] Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA | [p] Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA | [q] Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA | [r] Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York City, NY, USA | [s] Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York City, NY, USA

Correspondence: [*] Correspondence to: Marcel van der Brug, Biomarker Discovery OMNI, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Tel.: +1 650 225 4535; E-mails: vanderbrug.marcel@gene.com (M.v.d.B.); graham.robert@gene.com (R.R.G.); kaminker.josh@gene.com (J.S.K.).

Note: [1] These authors contributed equally to this work.

Note: [2] Current address: GenePeeks, New York City, NY, USA.

Note: [3] Current address: Denali Therapeutics, South San Francisco, CA, USA.

Note: [4] Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (http://adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf.

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 ɛ4 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 ɛ4 carriers.

Keywords: Alzheimer’s disease, astrocytes, IL-6, metalloproteases, microglia

DOI: 10.3233/JAD-160524

Journal: Journal of Alzheimer's Disease, vol. 56, no. 3, pp. 1037-1054, 2017