A Common Variant of IL-6R is Associated with Elevated IL-6 Pathway Activity in Alzheimer’s Disease Brains
Open accessAbstract
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.
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The IL6R variant leads to increased cleavage by ADAM10 and ADAM17 of membrane bound IL6R.
“as this variant leads to increased cleavage by ADAM10 and ADAM17 of membrane bound IL6R18.”
From Genomic atlas of the proteome from brain, CSF and plasma prioritizes proteins implicated in neurological disorders (2021) · cites this paper as [18]
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References 64 · Cited by 55
- Authors
- Haddick, P. C. G., Alzheimer’s Disease Genetic Consortium (ADGC), A. D. N. I. (., 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.
- Affiliations
- Genentech (US)
- The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA
- Case Western Reserve University (US)
- Boston University (US)
- Brigham Young University (US)
- University of Pennsylvania (US)
- Washington University in St. Louis (US)
- Icahn School of Medicine at Mount Sinai (US)
- Department of Diagnostic Discovery, Genentech Inc., South San Francisco, CA, USA
- Corresponding author
- Graham, Robert R.
- Kaminker, Joshua S.
- ORCID
- Venue
- Journal of Alzheimer's Disease
- Publisher
- SAGE Publications
- Published
- 2017-02-03
- Volume
- 56
- Issue
- 3
- Pages
- 1037-1054
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- PMC
- PMC5667357
- OpenAlex
- W2574956428
- Cited by
- 55
- References
- 64
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 7 · 2023: 7 · 2022: 6 · 2021: 8 · 2020: 13 · 2019: 6 · 2018: 2
- FWCI
- 0.70
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Alzheimer s Disease (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (R01AG035083, U01AG032984, R01AG044546, P50AG005681, P01AG003991, P30AG013846, U01AG049508, P01AG026276, U24AG021886)
- National Institute of Neurological Disorders and Stroke (R01NS085419)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- IL-6 receptor, rs2228145
- MeSH terms
- ADAM10 Protein, ADAM17 Protein, Aged, Aged, 80 and over, Alleles, Alzheimer Disease, Animals, Astrocytes, Brain, Female, Humans, Male, Recombinant Proteins, Cohort Studies, CD4-Positive T-Lymphocytes, Interleukin-6, Microglia, Coculture Techniques, Receptors, Interleukin-6, Polymorphism, Single Nucleotide, Mice, Apolipoprotein E4, HEK293 Cells
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