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

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

来源：Journal of Alzheimer's Disease, 2017, 56(3): 1037-1054.

DOI：10.3233/JAD-160524

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

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 epsilon 4 carriers. Across five datasets, p.D358A had a meta P = 3 x 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 epsilon 4 carriers.

• 出版日期2017