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Identification of ceruloplasmin as a gene that affects susceptibility to glomerulonephritis through macrophage function

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Title: Identification of ceruloplasmin as a gene that affects susceptibility to glomerulonephritis through macrophage function
Authors: Chen, T
Rotival, M
Behmoaras, JV
Chiu, LY
Bagnati, M
Jo, JH
Srivastava, PK
Petretto, E
Pusey, CD
Lai, PC
Aitman, TJ
Cook, HT
Behmoaras, J
Item Type: Journal Article
Abstract: Crescentic glomerulonephritis (Crgn) is a complex disorder where macrophage activity and infiltration are significant effector causes. In previous linkage studies using the uniquely susceptible Wistar Kyoto (WKY) rat strain, we have identified multiple crescentic glomerulonephritis QTL (Crgn) and positionally cloned genes underlying Crgn1 and Crgn2, which accounted for 40% of total variance in glomerular inflammation. Here, we have generated a backcross (BC) population (n = 166) where Crgn1 and Crgn2 were genetically fixed and found significant linkage to glomerular crescents on chromosome 2 (Crgn8, LOD = 3.8). Fine mapping analysis by integration with genome-wide expression QTLs (eQTLs) from the same BC population identified ceruloplasmin (Cp) as a positional eQTL in macrophages but not in serum. Liquid chromatography-tandem mass spectrometry confirmed Cp as a protein QTL in rat macrophages. WKY macrophages overexpress Cp and its downregulation by RNA interference decreases markers of glomerular proinflammatory macrophage activation. Similarly, short incubation with Cp results in a strain-dependent macrophage polarization in the rat. These results suggest that genetically determined Cp levels can alter susceptibility to Crgn through macrophage function and propose a new role for Cp in early macrophage activation.
Issue Date: 7-Jun-2017
Date of Acceptance: 5-Apr-2017
URI: http://hdl.handle.net/10044/1/47836
DOI: https://dx.doi.org/10.1534/genetics.116.197376
ISSN: 1943-2631
Publisher: Genetics Society of America
Start Page: 1139
End Page: 1151
Journal / Book Title: Genetics
Volume: 206
Issue: 2
Copyright Statement: © 2017 Chen et al. Available freely online through the author-supported open access option.This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduct
Sponsor/Funder: Wellcome Trust
Kidney Research UK
Medical Research Council (MRC)
Medical Research Council (MRC)
Imperial College London
Funder's Grant Number: 081462/Z/06/Z
RP9/2013
MR/M004716/1
MR/N01121X/1
Keywords: Genetics of Immunity
QTL
eQTL
fine mapping
glomerulonephritis
macrophages
positional cloning
Developmental Biology
0604 Genetics
Publication Status: Published
Appears in Collections:Clinical Sciences
Molecular Sciences
Department of Medicine
Faculty of Medicine



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