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

被引：47

作者：

Haddick, Patrick C. G. ^{[1
]}

Larson, Jessica L. ^{[2
,20
]}

Rathore, Nisha ^{[3
]}

Bhangale, Tushar R. ^{[3
]}

Phung, Qui T. ^{[4
]}

Srinivasan, Karpagam ^{[5
]}

Hansen, David V. ^{[5
]}

Lill, Jennie R. ^{[4
]}

Pericak-Vance, Margaret A. ^{[6
,7
]}

Haines, Jonathan ^{[8
]}

Farrer, Lindsay A. ^{[9
,10
,11
,12
,13
]}

Kauwe, John S. ^{[14
]}

Schellenberg, Gerard D. ^{[15
]}

Cruchaga, Carlos ^{[16
,17
]}

Goate, Alison M. ^{[18
,19
]}

Behrens, Timothy W. ^{[3
]}

Watts, Ryan J. ^{[5
,21
]}

Graham, Robert R. ^{[3
]}

Kaminker, Joshua S. ^{[2
]}

van der Brug, Marcel ^{[1
]}

机构：

[1] Genentech Inc, Dept Diag Discovery, San Francisco, CA 94080 USA

[2] Genentech Inc, Dept Bioinformat & Computat Biol, San Francisco, CA 94080 USA

[3] Genentech Inc, Dept Human Genet, San Francisco, CA 94080 USA

[4] Genentech Inc, Dept Prot Chem, San Francisco, CA 94080 USA

[5] Genentech Inc, Dept Neurosci, San Francisco, CA 94080 USA

[6] Univ Miami, John P Hussman Inst Human Genom, Miami, FL USA

[7] Univ Miami, Dr John T Macdonald Fdn, Dept Human Genet, Miami, FL USA

[8] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA

[9] Boston Univ, Sch Med & Publ Hlth, Dept Med, Biomed Genet, Boston, MA 02215 USA

[10] Boston Univ, Sch Med & Publ Hlth, Dept Neurol, Boston, MA 02215 USA

[11] Boston Univ, Sch Med & Publ Hlth, Dept Ophthalmol, Boston, MA 02215 USA

[12] Boston Univ, Sch Med & Publ Hlth, Dept Epidemiol, Boston, MA 02215 USA

[13] Boston Univ, Sch Med & Publ Hlth, Dept Biostat, Boston, MA 02215 USA

[14] Brigham Young Univ, Dept Biol, Provo, UT 84602 USA

[15] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

[16] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA

[17] Washington Univ, Sch Med, Hope Ctr Neurol Disorders, St Louis, MO USA

[18] Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA

[19] Icahn Sch Med Mt Sinai, Ronald M Loeb Ctr Alzheimers Dis, New York, NY 10029 USA

[20] GenePeeks, New York, NY USA

[21] Denali Therapeut, San Francisco, CA USA

来源：

JOURNAL OF ALZHEIMERS DISEASE | 2017年 / 56卷 / 03期

基金：

美国国家卫生研究院;

关键词：

Alzheimer's disease; astrocytes; IL-6; metalloproteases; microglia; GENOME-WIDE ASSOCIATION; FIBRILLARY ACIDIC PROTEIN; INTERLEUKIN-6; RECEPTOR; IDENTIFIES VARIANTS; GENE-EXPRESSION; SOLUBLE IL-6R; LOCI; RISK; METAANALYSIS; POLYMORPHISM;

D O I：

10.3233/JAD-160524

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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.

引用

页码：1037 / 1054

页数：18

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