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Title | A Common Variant of IL-6R is Associated with Elevated IL-6 Pathway Activity in Alzheimer's Disease Brains. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Haddick PCG, Larson JL, Rathore N, Bhangale TR, Phung QT, Srinivasan K, Hansen DV, Lill JR, Pericak-Vance MA, Haines J, Farrer LA, Kauwe JS, Schellenberg GD, Cruchaga C, Goate AM, Behrens TW, Watts RJ, Graham RR, Kaminker JS, van der Brug M |
Corporate Authors | Alzheimer’s Disease Genetic Consortium(ADGC), Alzheimer’s Disease Neuroimaging Initiative(ADNI) |
Journal | J Alzheimers Dis |
Volume | 56 |
Issue | 3 |
Pagination | 1037-1054 |
Date Published | 2017 |
ISSN | 1875-8908 |
Keywords | ADAM10 Protein, ADAM17 Protein, Aged, Aged, 80 and over, Alleles, Alzheimer Disease, Animals, Apolipoprotein E4, Astrocytes, Brain, CD4-Positive T-Lymphocytes, Coculture Techniques, Cohort Studies, Female, HEK293 Cells, Humans, Interleukin-6, Male, Mice, Microglia, Polymorphism, Single Nucleotide, Receptors, Interleukin-6, Recombinant Proteins |
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. |
DOI | 10.3233/JAD-160524 |
Alternate Journal | J. Alzheimers Dis. |
PubMed ID | 28106546 |
PubMed Central ID | PMC5667357 |
Grant List | R01 AG044546 / AG / NIA NIH HHS / United States U24 AG021886 / AG / NIA NIH HHS / United States U01 AG032984 / AG / NIA NIH HHS / United States R01 NS085419 / NS / NINDS NIH HHS / United States P01 AG003991 / AG / NIA NIH HHS / United States P50 AG005681 / AG / NIA NIH HHS / United States P30 AG013846 / AG / NIA NIH HHS / United States P01 AG026276 / AG / NIA NIH HHS / United States U01 AG049508 / AG / NIA NIH HHS / United States R01 AG035083 / AG / NIA NIH HHS / United States |