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

The transcription factor nuclear factor kappa B (NF kappa B) is a central regulator of inflammation, and genome-wide association studies in subjects with autoimmune disease have identified a number of variants within the NF kappa B 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 NF kappa B. We report that MS-associated variants proximal to NF kappa B1 and in an intron of TNFRSF1A (TNFR1) are associated with increased NF kappa B signaling after tumor necrosis factor-alpha (TNF alpha) stimulation. Both variants result in increased degradation of inhibitor of NF kappa B alpha (I kappa B alpha), a negative regulator of NF kappa B, and nuclear translocation of p65 NF kappa B. The variant proximal to NF kappa B1 controls signaling responses by altering the expression of NF kappa B itself, with the GG risk genotype expressing 20-fold more p50 NF kappa B and diminished expression of the negative regulators of the NF kappa B pathway: TNF alpha-induced protein 3 (TNFAIP3), B cell leukemia 3 (BCL3), and cellular inhibitor of apoptosis 1 (CIAP1). Finally, naive CD4 T cells from patients with MS express enhanced activation of p65 NF kappa B. These results demonstrate that genetic variants associated with risk of developing MS alter NF kappa B signaling pathways, resulting in enhanced NF kappa B activation and greater responsiveness to inflammatory stimuli. As such, this suggests that rapid genetic screening for variants associated with NF kappa B signaling may identify individuals amenable to NF kappa B or cytokine blockade.