GWAS analysis implicates NF-κB-mediated induction of inflammatory T cells in multiple sclerosis

Abstract

Objective To identify genes and biologically relevant pathways associated with risk to develop multiple sclerosis (MS). Methods The Genome-Wide Association Studies noise-reduction method (GWAS-NR) was applied to MS genotyping data. Regions of association were defined based on significance of linkage disequilibrium (LD) blocks. Candidate genes were cross-referenced based on a review of current literature, with attention to molecular function and directly interacting proteins. Supplementary annotations and pathway enrichment scores were generated using The Database for Annotation, Visualization and Integrated Discovery (DAVID). Results The candidate set of 220 MS susceptibility genes prioritized by GWAS-NR was highly enriched with genes involved in biological pathways related to positive regulation of cell, lymphocyte, and leukocyte activation (p=6.1E-15, 1.2E-14, and 5.0E-14, respectively). Novel gene candidates include key regulators of NF-κB signaling and CD4+ T helper type 1 (Th1) and T helper type 17 (Th17) lineages. Conclusions A large subset of MS candidate genes prioritized by GWAS-NR were found to interact in a tractable pathway regulating the NF-κB-mediated induction and infiltration of pro-inflammatory Th1/Th17 T-cell lineages, and maintenance of immune tolerance by T-regulatory cells. This mechanism provides a biological context that potentially links clinical observations in MS to the underlying genetic landscape that may confer susceptibility.

Choriodecidual leukocytes display a unique gene expression signature in spontaneous labor at term

“…In addition, the responsiveness of peripheral leukocytes to be attracted to chemotactic stimuli derived from the chorioamniotic membranes seems to be a key feature in this process [26]. Consistent with such a hypothesis, previous studies have demonstrated that peripheral leukocytes displayed increased chemotactic activity and cytokine production during the process of labor [27,28], resembling an inflammatory phenotype similar to that observed in pathological conditions [29,30]. Collectively, these data suggest that the chorioamniotic membranes, and most likely the decidual stromal cells, recruit maternal circulating leukocytes into the choriodecidua prior to and during the process of labor.…”

Constrained release of lamina-associated enhancers and genes from the nuclear envelope during T-cell activation facilitates their association in chromosome compartments

“…See also Supplemental Figure S7. 2009; Wallner et al 2012). Consistent with these important regulatory activities, the dysregulation or loss of function of a number of these peripherally regulated gene products is associated with autoimmunity (Watanabe et al 2003;Rosenblum et al 2004;Sharma et al 2011;Wallner et al 2012;Johansen et al 2015;Hussman et al 2016). Thus, in all cases, the tighter regulation of these genes in resting lymphocytes from adding spatial control would benefit the organism.…”

The Genetics of Multiple Sclerosis

“…Furthermore, GO analysis on the 79 MS risk genes arranged in networks in at least one of the two studies highlighted the categories "leukocyte activation," "apoptosis," and "positive regulation of macromolecule metabolic process" as well as the KEGG pathways "JAK-STAT signaling pathway," "acute myeloid leukemia," and "T cell receptor signaling" (30). Extending pathway analysis to all the 110 non-MHC variants identified after the ImmunoChip study also detected the NF-kB cascade to be significantly associated with MS risk genes (22,31).…”