Background/Purpose: Endoplasmic recticulum (ER) stress is caused by excessive demands on the protein-processing capacity of the ER; inefficiencies in response to ER stress lead to human diseases such as ankylosing spondylitis (AS). ER stress has been linked to inflammatory pathways. To study the role of ER stress in disease susceptibility, we identified the genes and pathways involved in ER stress response in human cells, assessed individual variation in these pathways, and mapped DNA sequence variants that influence ER stress response.

Methods: To study ER stress response in B-cells, we exposed the cells from 131 normal unrelated individuals to tunicamycin, a chemical inducer of ER stress, and measured changes in gene expression before and following ER stress. Then, to determine the genetic basis of variation in gene expression response to ER stress, we carried out genetic mapping using B-cells from members of 15 extended families.

Results: We identified 1,523 ER stress-responsive genes which showed at least 1.5 fold changes in gene expression following ER stress.  The results showed extensive individual variation in gene expression response to ER stress.  For instance, TNFSF13B (BAFF/Blys), a potent activator of B cells, has a mean induction of 1.6-fold but there is a 2.4-fold difference in its level between the individuals with the lowest and highest induction of this gene.  XBP1 and DDIT3 (CHOP), which encode key ER stress transcription factors, vary by 5-fold and 9-fold. From our linkage and association studies, we focused our analysis on 778 ER stress-responsive genes and identified DNA sequence variants that regulate the response of 497 of the genes, including TNFSF13B.  Regulators of gene expression response to ER stress include susceptibility genes for autoimmune diseases: BLK (systemic lupus erythematosus, rheumatoid arthritis, Kawasaki disease); SVIL (multiple sclerosis); ANTXR2, RUNX3 and ERAP1 (AS). Genes associated with neurodegenerative diseases in which ER stress is known to play a role in disease pathology—amyotrophic lateral sclerosis, Alzheimer disease, Parkinson disease—are also represented among the regulators.

Conclusion: These results allowed us to identify genes and their regulators involved in ER stress response in human B-cells. The presence of susceptibility genes for autoimmune diseases among the regulators identified in our study implicates ER stress in disease pathology. Identification of TNFSF13B as an ER stress-responsive gene in human B-cells provides further evidence of a link between ER stress and inflammation.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/autoimmune-susceptibility-genes-are-regulators-of-gene-expression-response-to-er-stress/