Category: General autoimmunity
In diploid organisms, transcription of most genes is bi-allelic with expected equal transcripts originating from each the maternal and paternal alleles. However, this could be altered in a heterozygous individual when the genomic region harbors a variant that regulates transcription, resulting in allelic imbalance. The increased power that is inherent in using the other allele from the same subject has made Allele Specific Expression (ASE) a useful tool to study regulatory non-coding variants. In this study, we used Allele Specific Expression to guide our investigation of four autoimmunity-associated Single Nucleotide Polymorphisms (SNPs) that are intronic in - or proximal to - TNFSF14/LIGHT, its receptor TNFRSF14/HVEM, TNFRSF5/CD40 as well as TRAF3 (TNF receptor associated factor 3) which had previously been shown to interact with both TNFSF14 and CD40. One of the main challenges in translating findings from Genome Wide Association Studies (GWAS) to functional understanding is the lack of the cellular context in which these variants may promote disease. To address this, we derived/differentiated more than 30 cell populations under different activation states from peripheral blood mononuclear cells (PBMC) of five healthy volunteers who are heterozygous for all four SNPs recruited through Cambridge Bioresource. We then used a targeted Next Generation Sequencing (NGS) approach to survey ASE in these cell subsets/activation conditions. We show that while some variants affected expression across multiple subsets, some are associated with a statistically significant ASE only in a specific cell type and in some cases only following activation or in-vitro differentiation.