title: A Common Variant of IL-6R is Associated with Elevated IL-6 Pathway Activity in Alzheimer's Disease Brains.
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.
authors.affiliation: Department of Diagnostic Discovery, Genentech Inc., South San Francisco, CA, USA.
authors.forename: Patrick C G
authors.initials: PC
authors.lastname: Haddick
authors.affiliation: Department of Bioinformatics and Computational Biology, Genentech Inc., South San Francisco, CA, USA.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Larson
authors.affiliation: Department of Human Genetics, Genentech Inc., South San Francisco, CA, USA.
authors.forename: Nisha
authors.initials: N
authors.lastname: Rathore
authors.affiliation: Department of Human Genetics, Genentech Inc., South San Francisco, CA, USA.
authors.forename: Tushar R
authors.initials: TR
authors.lastname: Bhangale
authors.affiliation: Department of Protein Chemistry, Genentech Inc., South San Francisco, CA, USA.
authors.forename: Qui T
authors.initials: QT
authors.lastname: Phung
authors.affiliation: Department of Neuroscience, Genentech Inc., South San Francisco, CA, USA.
authors.forename: Karpagam
authors.initials: K
authors.lastname: Srinivasan
authors.affiliation: Department of Neuroscience, Genentech Inc., South San Francisco, CA, USA.
authors.forename: David V
authors.initials: DV
authors.lastname: Hansen
authors.affiliation: Department of Protein Chemistry, Genentech Inc., South San Francisco, CA, USA.
authors.forename: Jennie R
authors.initials: JR
authors.lastname: Lill
authors.affiliation: The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA.|Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, FL, USA.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Pericak-Vance
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Haines
authors.affiliation: Department of Medicine (Biomedical Genetics), Boston University Schools of Medicine and Public Health, Boston, MA, USA.|Department of Neurology, Boston University Schools of Medicine and Public Health, Boston, MA, USA.|Department of Ophthalmology, Boston University Schools of Medicine and Public Health, Boston, MA, USA.|Department of Epidemiology, Boston University Schools of Medicine and Public Health, Boston, MA, USA.|Department of Biostatistics, Boston University Schools of Medicine and Public Health, Boston, MA, USA.
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Farrer
authors.affiliation: Department of Biology, Brigham Young University, Provo, UT, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Kauwe
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: Gerard D
authors.initials: GD
authors.lastname: Schellenberg
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.|Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cruchaga
authors.affiliation: Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York City, NY, USA.|Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York City, NY, USA.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Goate
authors.affiliation: Department of Human Genetics, Genentech Inc., South San Francisco, CA, USA.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Behrens
authors.affiliation: Department of Neuroscience, Genentech Inc., South San Francisco, CA, USA.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Watts
authors.affiliation: Department of Human Genetics, Genentech Inc., South San Francisco, CA, USA.
authors.forename: Robert R
authors.initials: RR
authors.lastname: Graham
authors.affiliation: Department of Bioinformatics and Computational Biology, Genentech Inc., South San Francisco, CA, USA.
authors.forename: Joshua S
authors.initials: JS
authors.lastname: Kaminker
authors.affiliation: Department of Diagnostic Discovery, Genentech Inc., South San Francisco, CA, USA.
authors.forename: Marcel
authors.initials: M
authors.lastname: van der Brug
mesh_terms: D000072197:ADAM10 Protein / Q000378:metabolism; D000072198:ADAM17 Protein / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D053327:Apolipoprotein E4 / Q000235:genetics; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018920:Coculture Techniques; D015331:Cohort Studies; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D017628:Microglia / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D019947:Receptors, Interleukin-6 / Q000235:genetics* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D053327:Apolipoprotein E4; C508603:IL6R protein, human; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins; C577686:interleukin-6, mouse; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein
keywords: Alzheimer’s disease; IL-6; astrocytes; metalloproteases; microglia