Genetic variants associated with autoimmunity drive NFκB signaling and responses to inflammatory stimuli.

Sci Transl Med
Authors
Keywords
Abstract

The transcription factor nuclear factor κB (NFκB) is a central regulator of inflammation, and genome-wide association studies in subjects with autoimmune disease have identified a number of variants within the NFκB signaling cascade. In addition, causal variant fine-mapping has demonstrated that autoimmune disease susceptibility variants for multiple sclerosis (MS) and ulcerative colitis are strongly enriched within binding sites for NFκB. We report that MS-associated variants proximal to NFκB1 and in an intron of TNFRSF1A (TNFR1) are associated with increased NFκB signaling after tumor necrosis factor-α (TNFα) stimulation. Both variants result in increased degradation of inhibitor of NFκB α (IκBα), a negative regulator of NFκB, and nuclear translocation of p65 NFκB. The variant proximal to NFκB1 controls signaling responses by altering the expression of NFκB itself, with the GG risk genotype expressing 20-fold more p50 NFκB and diminished expression of the negative regulators of the NFκB pathway: TNFα-induced protein 3 (TNFAIP3), B cell leukemia 3 (BCL3), and cellular inhibitor of apoptosis 1 (CIAP1). Finally, naïve CD4 T cells from patients with MS express enhanced activation of p65 NFκB. These results demonstrate that genetic variants associated with risk of developing MS alter NFκB signaling pathways, resulting in enhanced NFκB activation and greater responsiveness to inflammatory stimuli. As such, this suggests that rapid genetic screening for variants associated with NFκB signaling may identify individuals amenable to NFκB or cytokine blockade.

Year of Publication
2015
Journal
Sci Transl Med
Volume
7
Issue
291
Pages
291ra93
Date Published
2015 Jun 10
ISSN
1946-6242
URL
DOI
10.1126/scitranslmed.aaa9223
PubMed ID
26062845
PubMed Central ID
PMC4574294
Links
Grant list
AI039671 / AI / NIAID NIH HHS / United States
5T32AI007019-36 / AI / NIAID NIH HHS / United States
T32 AI007019 / AI / NIAID NIH HHS / United States
AI045757 / AI / NIAID NIH HHS / United States
U19 AI070352 / AI / NIAID NIH HHS / United States
AI070352 / AI / NIAID NIH HHS / United States
NS24247 / NS / NINDS NIH HHS / United States
R37 NS024247 / NS / NINDS NIH HHS / United States
R01 NS067305 / NS / NINDS NIH HHS / United States
P30 AR053495 / AR / NIAMS NIH HHS / United States
R01 NS024247 / NS / NINDS NIH HHS / United States
NS067305 / NS / NINDS NIH HHS / United States
P01 AI039671 / AI / NIAID NIH HHS / United States
RC2 GM093080 / GM / NIGMS NIH HHS / United States
P01 AI045757 / AI / NIAID NIH HHS / United States
AI046130 / AI / NIAID NIH HHS / United States
U19 AI046130 / AI / NIAID NIH HHS / United States
P01 AI073748 / AI / NIAID NIH HHS / United States
GM093080 / GM / NIGMS NIH HHS / United States